Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012

GLUTAMATE RECEPTORS; FROM BASIC PHARMACOLOGY TO CLINICAL APPLICATIONS

NAYIRA A. ABDEL BAKY

Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, KSA

ABSTRACT

The existence of glutamate receptors as important neurotransmitter receptors was not fully accepted until the 1980s. It is now generally agreed that glutamate is the major fast excitatory neurotransmitter in brain, and plays a major role in brain development, affecting neuronal migration, neuronal differentiation, axon genesis, and neuronal survival through its action on the glutamate receptors. There are two classes of glutamate receptors; the ionotropic glutamate receptors (iGluRs), and the metabotropic glutamate receptors (mGluRs). Glutamate receptors are important mediators of a wide range of neuronal functions from primary sensory perception to cognition and also play a role in a number of neurodegenerative diseases. Understanding the role of glutamate in these neurological diseases may highlight treatment potentials of different agonists and antagonists to glutamatergic transmission. In this review, the basic biology of glutamate receptors will be explored. The second part of this article presents a review of the literature for the role of glutamate agonists and antagonists in neurological disease.

Keywords : Glutamate receptors, neurotransmitter, neurodegenerative diseases

1. INTRODUCTION Glutamate plays a major role in brain development, affecting neuronal migration, neuronal Since the late 1950s, glutamate, which was differentiation, axon genesis, and neuronal survival previously considered to be solely a metabolic (Coyle et al., 2002; Hassel and Dingledine, 2006) precursor, has been known to excite neurons (Curtis Glutamate receptors are also important mediators of et al., 1959). However, as most central neurons are a wide range of neuronal functions from primary excited by glutamate, this was originally interpreted sensory perception to cognition (Collingridge and as a nonspecific effect. The existence of glutamate Bliss, 1995 ;Collingridge and Singer, 1990; receptors as important neurotransmitter receptors Danysz et al., 1995; Dingledine et al., 1999).It is was not fully accepted until the 1980s. The also known that glutamate receptors play a role in a realization that glutamate activates a number of number of neurodegenerative diseases and epilepsy pharmacologically distinct subtypes (Ascher and (Gillessen et al., 2002). In addition, glutamate Nowak, 1988; Collingridge and Lester, 1989) and receptors seem to have functional roles outside of the plays an important role in long-term potentiation nervous system (as in insulin secretion, bone (Bliss and Collingridge, 1993) led to the resorption, cardiac pacemaking, and tactile recognition that most excitatory neurotransmission in sensation) (Ault and Hildebrand, 1993; Carlton et the central nervous system is mediated by glutamate al., 1995; Chenu et al., 1998; Gill et al., 1998; receptors. It is now generally agreed that glutamate Inagaki et al., 1995; Jorgensen et al., 1995; Patton is the major fast excitatory neurotransmitter in brain. et al., 1998; Weaver et al., 1996).

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1.1. Glutamate Synthesis and Release There are three major types of ionotropic glutamate L-glutamate can be synthesized in nerve terminals receptors (iGluRs), which are named after the from a-ketoglutarate (formed from gluconeogenesis agonists that were originally identified to activate and the tricarboxylic acid cycle) by the enzyme them selectively, and are, thus, called N-methyl-D- glutamate dehydrogenase, and from glutamine by the aspartate (NMDA), α-amino-3-hydroxy-5- glutaminase enzyme (Hashimoto et al., 2005; methyl-4-isoazolepropionic acid (AMPA) and Hashimoto and Hattori, 2007). Upon 2-carboxy-3-carboxymethyl-4- depolarization glutamate is released into the cleft, isopropenylpyrrolidine (kainate) receptors where the glutamate either (i) is bound to pre- and (Collingridge and Lester, 1989). Native receptors post-synaptic receptors, (ii) is actively taken back up of all of these families are likely teteromeric via a glutamate transporter and repackaged, (iii) assemblies comprising more than one type of subunit diffuses away from the cleft, or (iv) is internalised by (Laube et al., 1998), and the subunits that comprise glial glutamate transporters (Anderson and these are specific for each of the three families Swanson, 2000; Attwell, 2000). In the glial cells, (Dingledine and Conn, 2000). The subunit glutamate is converted to glutamine by the glial composition determines the biophysical properties of enzyme glutamine synthetase. Glutamine is the receptor and to a variable extent its transported from glia into nerve terminals by specific pharmacology. transporters, followed by re-conversion to glutamate via glutaminase and repackaged in synaptic vesicles, Ionotropic glutamate receptor subunits possess an completing the so called ‘glutamine cycle’ that is extracellular amino terminal domain, followed by a proposed to ensure the efficient replenishment of first transmembranen domain and then a pore neurotransmitter glutamate (Chaudhryet al., 2002). forming membrane-residing domain that does not Glutamate which accumulated in the synaptic cross the membrane but forms a reentrant loop vesicles is released again into the synaptic cleft upon entering from and exiting to the cytoplasm. The depolarization, achieving high concentrations at the second and third transmembrane domains are linked postsynaptic membrane (Anderson and Swanson, by a large extracellular loop and the third 2000; Meldrum, 2000). transmembrane domain is followed by an There are two classes of glutamate receptors; First intracellular carboxy terminus (Dingledine et al., the ionotropic glutamate receptors (iGluRs): which 1999; Mayer and Armstrong, 2004). The crystal are ligand gated ion channels receptors consist of structure of the iGluR ligand binding domains, four subunits. The assembled subunits may or may which comprise polypeptides in both the amino not be homologous, these different combinations of terminus (S1 domain) and the extracellular loop subunits result in channels with different between transmembrane domains 3 and 4 (S2 characteristics (Dingledine et al., 1999). These domain), has confirmed this topology model for the receptors mediate fast synaptic transmission between ionotropic glutamate receptor family (Armstrong et neurons in mammalian brain. al., 1998; Mayer and Armstrong, 2004). The second class is the metabotropic glutamate receptors (mGluRs): which are G-protein coupled The ionotropic receptors themselves are ligand receptors that have transmembrane segments similar gated ion channels. Once the ligand is bounded to to other G-protein coupled receptors, that have the receptor, charged ions such as Na+ and Ca2+ pass extracellular Amino terminal domain (ATD) process through a channel in the centre of the receptor some structural homology to that in iGluRs (O’Hara complex. This flow of ions results in a depolarization et al., 1993). of the plasma membrane and the generation of an electrical current that is propagated down the 2. Glutamate Receptors processes (dendrites and axons) of the neuron to the next in line (Mayer and Westbrook, 1987). These 2.1. Ionotropic Glutamate Receptors (iGluRs) ionotropic glutamate receptors are an extremely diverse group of receptors. This diversity is P-33 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 generated both before and after gene transcription. glutamate is on different binding sites localized on Individual receptors are multimeric assemblies of the GluN1 (Kuryatov et al., 1994 ; Wafford et al., subunits, transcribed from separate genes. However, 1995; Kew et al. 2000) and GluN2 (Laube et al., following gene transcription, the resultant pre- 1997; Anson et al., 1998) subunits, respectively. mRNA may be modified. For instance, different Electrophysiological studies have demonstrated that regions of this mRNA molecule can be spliced NMDA receptor activation requires occupation of together, giving rise to multiple mRNAs that are two independent glycine sites and two independent translated into different proteins. This is known as glutamate sites (Benveniste and Mayer, 1991; 'splice variation' and is very common among Clements and Westbrook, 1991). Thus, the neuroreceptors (Sommer et al., 1990). minimal requirement for a functional NMDA receptor is likely to be a tetramer composed of two A further modification leading to diversification is GluN1and two GluN2 subunits. In agreement, recent RNA editing, in which selected nucleotides in the studies have provided convincing evidence that, like mRNA sequence transcribed from the gene sequence the other iGluRs, NMDA receptors are of tetrameric are enzymatically modified, changing the amino-acid structure and are likely composed of pairs, or dimers, coded for (Melcher et al., 1996). of dimers (e.g. an GluN1 dimer in combination with an GluN2X dimer) (Schorge and Colquhoun, 2003; 2.1.1. NMDA Receptors Mayer and Armstrong, 2004). In receptors NMDA receptors are essential for normal containing GluN1, GluN2 and GluN3 subunits, it physiological processes in the central nervous seems likely that an GluN3 subunit substitutes for system. As these receptors are implicated in neuronal one of the GluN2 subunits. Thus, GluN1 subunits survival and maturation (Simon et al. 1984;Balazs are combined with different GluN2 subunits and et al., 1989), neuronal migration (Komuro and GluN3 to generate a large number of different Rakic, 1993), induction of long-term potentiation NMDA receptors with differing pharmacological and (LTP) (Bliss and Collingridge, 1993), formation of biological properties. sensory maps (Cline et al. 1987;Simon et al. 1992), NMDA receptors have also separate binding sites and neurodegeneration (Meldrum and Garthwaite, for magnesium ions (Mg+2), zinc ions (Zn+2), as well 1990; Lipton and Rosenberg, 1994; Cull-Candy et as a polyamine recognition site (Lodge, 1997). Mg+2 al., 2001). Excessive activation of NMDARs can ions provide a voltage-dependent block of NMDA- lead to neuronal damage in many acute (hypoxic gated channels. Where, at resting membrane ischemic injury) and chronic neurodegenerative potentials, NMDA receptors are inactive. This is due diseases (Alzheimer, Parkinson, Huntington). to a voltage-dependent block of the channel pore by The NMDA receptor family is composed of seven magnesium ions, preventing ion flows through it subunits, GluN1, GluN2A–D and GluN3A and B, (Nowak et al., 1984). Sustained activation of AMPA which are all products of separate genes. Functional receptors by, for instance, a train of impulses NMDA receptors appear to be comprised of GluN1 arriving from a pre-synaptic terminal, depolarizes the in combination with one or more GluN2 subunits or post-synaptic cell, releasing the channel inhibition GluN1 in combination both GluN2 and GluN3 and thus allowing NMDA receptor activation. subunits (Watanabe et al., 1992, 1993;Monyer et On the other hand, the zinc and polyamine sites al., 1992; Zhong et al. ,1995; Wenzel et al., 1997). are not needed for activation of NMDA receptors, NMDA receptor is unique amongst ligand-gated but affect the efficacy of the channel. Zinc blocks the ion channels in its requirement for two obligatory channel in a voltage-independent manner co-agonists (Kleckner and Dingledine, 1988). As (Westbrook and Mayer, 1987). The polyamine site, not only the binding of glutamate is required to is a regulatory site for molecules that modulate the activate the channel, but a micromolar functioning of the NMDA receptor , binds concentrations of glycine must also be present compounds such as spermine or spermidine, either (Johnson and Ascher, 1987, Kleckner and potentiating (Ranson and Stec, 1988; Williams et Dingledine, 1988). The binding of glycine and al., 1994) or inhibiting (Williams et al., 1994) the P-34 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 activity of the receptor, depending on the is much lower than the affinity at NMDA receptors combination of subunits forming each NMDA (Dingledine et al., 1999). The associated channels receptor (Williams et al., 1994). are rapidly activated and inactivated, and appear to The unique property of being both voltage- be present on all neurons within the CNS dependent and ligand gated gives the NMDAR the (Tzschentke, 2002). ability to act as a coincidence detector for presynaptic activity (glutamate release) and post- There are four known subunits GluA1 to GluA4 synaptic activity (adequate depolarization of the which are widely, and differentially distributed post-synaptic membrane). Glutamate binding onto an throughout the CNS (Hollmann and Heinemann, NMDA receptor opens non-selective cation 1994). The types of subunits forming these receptors channels, resulting in a conductance increase. The determine their biophysical properties and high conductance channel associated with these pharmacological sensitivity. Two alternative splice receptors is more permeable to Ca+2 than Na+ ions variants for all GluA1 to GluA4 subunits designated (Mayer and Westbrook, 1987).Thus NMDA as ‘flip’ and ‘flop’ have been shown to differ in their receptor activation leads to a calcium influx into the expression throughout the brain and during post-synaptic cells, a signal that is instrumental in development, and to impart different the activation of a number of signaling cascades that pharmacological properties (Monyer et al., 1990; can subsequently affect synaptic plasticity and gene Sommer et al., 1990). transcription (Bading et al., 1993). Induction of Native AMPA receptor channels are impermeable NMDAR-dependent forms of synaptic plasticity, to calcium, a function controlled by the GluA2 such as LTP, is thought to underlie many types of subunit. The calcium permeability of the GluA2 learning and memory formation (Nicoll, 2003). subunit is determined by the post-transcriptional However, overactivation of the receptor relieves editing of the GluA2 mRNA. Where,in the primary the Mg2+ block and causes an excessive amount of transcript of GluA2, a codon for glutamine (Q) in the Ca2+ influx into the nerve cell, which then triggers transmembrane II (TMII) region is edited to one for a variety of processes that can lead to necrosis, arginine (R) by adenosine deaminase that converts apoptosis, or dendritic/synaptic damage. These an adenosine to an inosine (Seeburg and Hartner, detrimental processes include Ca2+ /overload of 2003). This is the so called Q/R editing site, where mitochondria, resulting in oxygen free radical GluA2(Q) is calcium permeable whilst GluA2(R) is formation, activation of caspases, and release of not. Almost all the GluA2 protein expressed in the apoptosis inducing factor; Ca2+-dependent CNS is in the GluA2(R) form, giving rise to calcium activation of neuronal NOS, leading to increase NO impermeable AMPA receptors. This, along with the production and the formation of toxic peroxynitrite interactions with other intracellular proteins, makes (ONOO–) and stimulation of mitogen-activated GluA2 perhaps the most important AMPA receptor protein kinase p38 (MAPK p38), which activates subunit (Dingledine et al., 1999; Seeburg and transcription factors that can go into the nucleus to Hartnerm, 2003). influence neuronal injury and apoptosis (Dawson et al., 1991; Bonfoco et al., 1995; Okamoto et al., 2.1.3. Kainate Receptors 2002;Hara et al., 2005). Kainate receptors constitute a separate group from the NMDA and AMPA receptors, although they 2.1.2. AMPA Receptors share many of the same structural characteristics. AMPA receptors are the receptors responsible for Kainate receptors are composed of two related most rapid excitatory transmission within the subunit families, GluR5–7 and KA-1 and KA-2. vertebrate CNS and their modulation is the ultimate Once again, native receptors are likely tetrameric mechanism that underlies much of the plasticity of combinations, possibly of both homomeric and excitatory transmission that is expressed in the brain. heteromeric combinations (Bettler et al., 1990; However, the affinity of AMPA receptors for L- Egebjerg et al., 1991). KA-1 and KA-2subunits do glutamate, the endogenous ligand for these receptors, not form functional homomeric receptors but do P-35 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 form high-affinity kainate binding sites and can, is crucial for receptor activation, since binding of L- thus, bind agonist ligands. KA-1 and KA-2combine glutamate to one or two of the ATDs of the dimer in heteromeric assemblies with members of the increase the probability of the ATDs to close and GluR5–7 subfamily to form functional receptors cause a conformational change of the ATDs relative resembling native kainate receptors (Bleakman et to each other (Pin et al., 2003). Most likely, this al., 2002).Unlike the Kan subunits, the GluR5, 6 and conformational change brings the lower parts of the 7 subunits can form functional homomeric receptors two ATDs of the dimer closer together resulting in a as well as combine with KA-1 and KA-2 to form similar heteromeric receptors with distinct pharmacological relative movement of the two seven trans- properties (Alt et al., 2004). membrane domains (7TMD) to an active receptor KA receptors are permeable to Na+ and K+ ions conformation capable of activating G-proteins and, like NMDA and AMPA receptors, contribute to (Kunishima et al., 2000). Recently, it was shown excitatory postsynaptic currents. The role of KA that binding of agonist to one ATD partially receptors in synaptic plasticity is less well-defined, activated the receptor, while binding of agonist to however, KA receptors have been found to be both ATDs was required for full receptor activation localized presynaptically where they can modulate (Kniazeff et al., 2004; MRC, 2009; Brock et al., neurotransmitter release (Huettner, 2003). 2007). This binding of an agonist as glutamate to ATD of a mGluR causes G proteins bound to the 2.2. Metabotropic Glutamate Receptors intracellular region to be phosphorylated, affecting (mGluRs) multiple biochemical pathways and ion channels in It was first suggested that metabotropic glutamate the cell (Platt,2007). Because of this, mGluRs can receptors (mGluRs) might exist in 1985, after it was both increase or decrease the excitability of the post noted that glutamate could stimulate phospholipase synaptic cell, thereby causing a wide range of C through the activation of a receptor that did not physiological response. In addition to producing belong to any of the ionotropic glutamate receptor excitatory and inhibitory postsynaptic potentials, families (Temple et al., 2001). The suspicion that mGluRs serve to modulate the function of other mGluRs existed was confirmed in 1987, and in 1991 receptors (such as NMDA receptors),and changing the first mGluR was cloned (Temple et al., 2001). the synapse's excitability (Chu and Hablitz, 2000; They are found in pre- and postsynaptic neurons in Endoh, 2004; Bonsi et al., 2005, Platt, 2005). synapses of the hippocampus, cerebellum (Hinoi et There are eight metabotropic glutamate receptors al., 2001), and the cerebral cortex, as well as other (mGlu1 to mGlu8) that are placed into three groups; parts of the brain and peripheral tissues (Chu and I, II, and III on the basis of sequence homology, Hablitz, 2000). These mGluRs perform a variety of agonist pharmacology, and coupling to intracellular functions in the central and peripheral nervous transduction mechanisms (Chu and Hablitz, 2000; systems: for example, they are involved in learning, Hinoi et al., 2001; Endoh, 2004; Bonsi et al., memory, anxiety, and the perception of pain (Ohashi 2005). et al., 2002). Unlike ionotropic receptors, mGluR are not directly linked to ion channels, but may affect 2.2.1. Group I them by activating biochemical cascades. As these The mGluRs in group I, including mGlu1(splice mGluRs are a members of guanine nucleotide- variants: mGlu1a, -b, -c, -d, -e) and mGlu5 (splice binding protein -coupled receptors (GPCRs) (Bonsi variants: mGlu5a and -b) receptors, are stimulated et al., 2005). most strongly by the excitatory amino acid analog L- Many GPCRs can be activated as individual, quisqualic acid (Chu and Hablitz, 2000; Bates et monomeric receptors, however, most also exist as al., 2002). These receptors are coupled to homodimers. This is particularly true of Class C postsynaptic inositol phosphate metabolism, as GPCRs like the mGluR ,GABAB, Ca+2sensing stimulation of these receptors causes an associated pheromone and taste receptors (Kuang et al., 2005; phospholipase C molecule to hydrolyze Pin et al., 2003). Receptor dimerization at the ATD phosphoinositide phospholipids in the cell's plasma P-36 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 membrane (Chu and Hablitz, 2000; Endoh, 2004; where activation inhibits cAMP formation) Bonsi et al., 2005). This leads to formation of (Okamoto et al., 1994; Flor et al., 1995b; 1997; inositol 1,4,5-trisphosphate (IP3) and diacylglycerol Duvoisin et al., 1995; Corti et al.,1997). mGlu4, (DAG) as second messengers. Due to its hydrophilic mGlu7 and mGlu8 receptors are predominantly character IP3 can travel to the endoplasmic reticulum localized to axon terminals wherethey are in a where it induces the opening of calcium channels. position to control the synaptic availability of The lipophilic DAG remains in the membrane acting glutamate, as well as of GABA, dopamine, and as a cofactor for the activation of protein kinase C serotonin (Cartmell and Schoepp, 2000; Ferraguti (PKC), increasing by these ways the cytosolic and Shigemoto, 2006). As opposed to other group calcium concentrations. These receptors are usually III mGlu receptors, mGlu7a and b receptors are found on postsynaptic membranes (Endoh, 2004) restricted to the center of the presynaptic active zone and are rarely found presynaptically. They are also of axon terminals (i.e., the site of synaptic vesicle associated with Na+ channels and K+ channels (Chu fusion) (Ferraguti and Shigemoto, 2006).As such, and Hablitz, 2000). Their action can be excitatory, mGlu7 receptors are well positioned to play the role increasing conductance, causing more glutamate to of the main glutamatergic autoreceptor responsible be released from the presynaptic cell (Chu and for the regulation of glutamate release under normal Hablitz, 2000). They can also inhibit glutamate physiological conditions (Schoepp, 2001). release and can modulate voltage-dependent calcium channels (Endoh, 2004). mGluR5, are positively 3. Glutamate Receptors Pharmacology coupled to NMDA receptor function via PKC (Brakeman et al., 1997 ;Tu et al., 1999; Xiao et 3.1. Inotropic Glutamate Receptors al., 2000; Szumlinski et al., 2006). Pharmacology 3.1.1. NMDA Receptor Agonists 2.2.2. Group II i. Agonist at the glutamate site The receptors in group II, including mGluRs 2 and Early structure–activity studies established that an 3 (Flor et al., 1995a; Emile et al., 1996), are ideal structure for activating NMDARs is negatively coupled to adenylyl cyclase thereby represented by (S)-glutamate. NMDA is several-fold reducing intracellular cyclic adenosine weaker as an agonist than (S)-glutamate. However, monophosphate (cAMP) formation in many NMDA has a low affinity for the plasma membrane expression systems, but it also may be coupled to transporters and thus can appear more potent than other transduction mechanisms under physiological glutamate in some physiological assays. NMDA conditions (Chu and Hablitz, 2000; Hinoi et al., shows little selectivity between the NMDA receptor 2001; Bonsi et al., 2005; MRC, 2009). They are subtypes, however, it displays no activity at other found on both pre- and postsynaptic membranes, and glutamate receptors (Watkins, 1981). are involved in presynaptic inhibition (Endoh, 2004). However, they do not appear to affect postsynaptic membrane potential by themselves. By incorporating ring systems into the glutamate Receptors in groups II and III reduce the activity of structure, rigid glutamate analogues that are potent postsynaptic potentials, both excitatory and NMDAR agonists have been developed. They mimic inhibitory, in the cortex (Chu and Hablitz, 2000). the active, partially folded, conformation of (S)- glutamate and include homoquinolinate (Brown et 2.2.3. Group-III al, 1998), (2S,1′R,2′S) 2-(carboxycyclopropyl) This group of mGlu receptors include the subtypes glycine (L-CCG-IV) (Kawai et al., 1992), (1R,3R) mGlu4 (splice variants: mGlu4a and -b), mGlu6, 1-aminocyclopentane-1,3-dicarboylic acid (ACPD) mGlu7 (splice variants mGlu7a and -b), and mGlu8 (Sunter et al., 1991), and 1-aminocyclobutane-1,3- (splices variants: mGlu8a and-b). Group III mGluR dicarboxylic acid (ACBD) (Jane et al., 1994). Other are all coupled to Gi proteins in transfected cells (i.e. selective, reasonably full agonists at NMDA they are negatively coupled to adenylylcyclase receptors include L-aspartate, quinolinate and P-37 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 homocysteate, whilst cis-2,3-piperidinedicarboxylic 3.1.2.1. Competitive Antagonists acid is a fairly low efficacy partial agonist (Priestley i. Antagonists of the glutamate recognition site and Kemp, 1994). A large number of competitive antagonists of the glutamate recognition site of the NMDA receptor ii. Agonist and partial agonist at the glycine co- have been synthesized. The vast majority are agonist site conformationally constrained, α-amino carboxylic Initially it was thought that endogenous levels of acids with an appropriately placed ω-phosphonic extracellular glycine were enough to saturate the acid group (Jane et al., 1994). Examples of high- glycine binding site; however, later studies suggest affinity glutamate site antagonists include (R)-2- that this is not the case and it may be possible to amino-5 phosphonopentanoate (DAP5), (±)-cis-4- develop positive modulators of NMDAR function phosphonomethyl-2-piperidine carboxylic acid (CGS via interaction with the glycine binding site (Danysz 19755), D,L-(E)-2-amino-4-propyl-5-phosphono- 3- and Parsons, 1998). Amino acids such as (R)- pentenoic acid (CGP 39653), (2-amino-4,5-(1,2- alanine and (R)-serine display high affinities for the cyclohexyl))-7-phosphonoheptanoic acid (NPC glycine site and behave as full agonists (Leeson and 12626), (±)-6-phosphonomethyl- Iversen, 1994). A number of compounds were decahydroisoquinoline-3-carboxylic acid (LY identified as having agonist, or partial agonist, 274614), (S)-alpha-amino-5-phosphonomethyl[1,1′- activity at the glycine co-agonist site on the NR1 biphenyl]-3-propanoic acid (SDZ EAB-515) and (S)- subunit. Conformationally constrained analogues of alpha-amino-5-phosphonomethyl[1,1′:4′,1″- glycine such as ACPC, a cyclopropylanalogue terphenyl]- 3-propanoic acid (SDZ 215-439). (Watson and Lanthorn, 1990), and ACBC, a Although these compounds have in vivo activity, cyclobutane analogue (Hood et al., 1989), are partial they penetrate the blood–brain barrier (BBB) agonists with different degrees of efficacy. At lower relatively poorly due to their highly charged nature doses, they show antischizophrenic properties in and equilibrate slowly in the brain. animal models but this effect is reversed at higher doses when they act like antagonists (Javitt, 2002). In general, these compounds show only modest Additionally, some vinyl substituted glycine NMDA, receptor subtype selectivity, although there derivatives, such as S-hydroxyethylvinyl glycine, act are some notable exceptions. For example, some 5- as reasonably potent glycine site agonists. Glycine- phosphonomethylquinoxalinediones have been site partial agonists, in order of decreasing levels of shown to have marked preference for the human intrinsic activity, include L-alanine, D-cycloserine, NR1/NR2A, rather than NR1/NR2B, subunit R(+)-3-amino-1-hydroxypyrrolid-2-one [(+)-HA- containing NMDA receptors. The best of these are 966] and R(+)-cis-β-methyl-3-amino-1- (1RS,1′S)-PEAQX (Auberson et al., 2002) and its hydroxypyrrolid-2-one (L-687,414) (Kemp and active diastereomer, NVP-AAM077 (Chaperon et Leeson, 1993). al., 2003). Conantokin G (Con G) is a 17-amino- acid peptide antagonist of NMDA receptors isolated 3.1.2. NMDA Receptor Antagonists from the venom of the marine cone snail, NMDAR antagonists can be categorized Conusgeographus, which also acts at the glutamate pharmacologically into three major groups according recognition site but shows considerable selectivity to site of action on the receptor-channel complex for NR2B subtype containing receptors (Donevan (Wong and Kemp, 1991). Competitive NMDAR and McCabe, 2000). As expected of a large peptide, antagonists acting on either (i) the glutamate conantokin G is not active following systemic (agonist) recognition site, or (ii) the glycine (co- administration. agonist) site; uncompetitive NMDAR antagonists (NMDAR open channel blockers; that block the ii. Antagonists of glycine recognition site channel pore following activation by the agonists); The first full antagonist found to bind to the glycine and allosteric inhibitors act at modulatory sites, such site was kynurenic acid, after that a large number of as the high-affinity Zn2+ site, and the polyamine site. glycine recognition site antagonists have been P-38 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 identified. Many of these were derived from sites such that they can access to, then dissociation medicinal chemistry efforts based around kynurenic from the binding site) and voltage-dependent acid (Bristow et al., 1996). However, compounds of mechanism have been identified (Huettner and this class tend to bind very tightly to plasma proteins Bean, 1988). These compounds include the and this compromises their BBB penetration and in dissociative anaesthetics, phencyclidine and vivo activity (Rowley et al., 1997). Nevertheless, ketamine (Aniset al., 1983). Phencyclidine,1-(1- numerous high-affinity derivatives (e.g. quinolines, phenylcyclohexyl) piperidine commonly initialized quinolones and indoles) possessing systemic activity as (PCP), and also known as angel dust ,was (Leeson and Iversen, 1994), exemplified by the formerly used as an anesthetic agent.Ketamine is following: 7-chloro- 4-hydroxy-3-(3-phenoxy)- NMDAR antagonists that have been used in clinical phenyl-2(H) quinolone (L-701-324) (Bristow et al., practice for many years but for non-neurological 1996); (E)-3[(phenylcarbamoil)ethenyl]- 4,6- indications (MacDonald et al., 1991). Ketamine is dichloroindole-2-carboxylic acid (Gavestinel/GV150 commonly used as a dissociative anesthetic. Other 526A) (Di Fabio et al., 1997); 5-nitro-6,7- dichloro- NMDAR antagonist is dextromethorphan which is a 1,4- dihydro-2,3-quinoxalinedione (licostinel/Acea commonly used cough suppressant and its 1021) and derivatives (Zhou et al., 2003); 7-chloro- metabolite, dextrorphan, antagonizes the NMDAR 4-hydroxy-2-(4-methoxy-2-methylphenyl)-1,2,5,10- by binding to a site within the channel pore tetrahydropyridazino[4,5-b]quinoline-1,10-dione (Franklin and Murray, 1992; LePage and (ZD9379) (Takano et al., 1997); (E)-3-(2-phenyl-2- Ishmael, 2005). carboxyethenyl)-4,6-dichloro-1H-indole- 2- carboxylic acid (MDL 105,519) (Baron et al., Initial identification of ketamine and 1997);(3S)-7-chloro-3-[2-((1R)-1-carboxyethoxy)-4 phencyclidine as selective NMDA receptor aminomethylphenyl] aminocarbonylmethyl- antagonists led to the development of selective high 1,3,4,tetrahydrobenz[c,d]indole- 2-carboxylic acid affinity NMDAR channel blockers such as hydrochloride (SM-31900) (Ohtani et al., 2002). dizocilpine (MK-801) (Gill et al., 1987).The kinetic These compounds act as full antagonists at the action of channel blocking and unblocking exhibited glycine site, i.e. they completely inhibit NMDA by MK-801 depends on the NR2 subunit responses at sufficiently high concentrations. composition of the NMDAR complex. Slower channel blocking kinetics were observed for NR2C- 3.1.2.2. Uncompetitive Antagonists containing receptors compared to those containing To be clinically acceptable antagonist of NMDAR, NR2A or NR2B (Monaghan and Larson, 1997). the drug must block excessive activation of the This is consistent with the shorter open times of NMDAR while leaving normal function relatively NR2C-containing receptors. intact in order to avoid side-effects. Drugs that simply compete with glutamate or glycine at the Subsequently, numerous compounds have been agonist binding sites block normal function and identified as selective blockers of the NMDA therefore do not meet this requirement, and have thus receptor ion channel e.g. N-1- naphthyl-N′-(3- failed in clinical trials to date because of side-effects ethylphenyl)-N′-methylguanidine (drowsiness, hallucinations, and even coma; (aptiganel/CNS1102) (Reddy et al., 1994) These Hickenbottom and Grotta, 1998; Lutsep and compounds act as open channel blockers and can Clark, 1999; Palmer, 2001). This directed the become trapped inside the closed channel, which, clinical research more to uncompetitive antagonists. coupled with their high affinity and slow Blockers of the ion channel pore of the NMDA reversibility, results in them having very steep dose– receptor have been a fruitful source of potent, response curves and little or no separation between selective and drug like antagonists. A number of their therapeutic effect and unacceptable side effects compounds that block NMDAR channels by a use- (Kemp and Kew, 1998). dependent (channels must be opened via binding of glycine and glutamate to their respective binding P-39 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012

Amantadine is NMDAR antagonist that was the Riluzole is another NMDAR antagonist that was first member of a class of organic molecules called originally synthesized by researchers in France, and aminoadamantanes to be introduced into clinical use. early laboratory studies in the 1980s suggested it had It was first marketed in the 1960s for prophylaxis of anticonvulsant properties (Mizoule et al., 1985). respiratory infections due to influenza A virus but However, the discovery that riluzole can disrupt was serendipitously discovered to have beneficial glutamate neurotransmission to prevent NMDAR- effects on extrapyramidal symptoms in a patient with mediated neuronal death in experimental models Parkinson’s disease taking amantadine for influenza (Malgouris et al., 1994) promoted its further prophylaxis (Schwab et al., 1969). Initially, development. The entire mechanism of its amantadine was assumed to have its neuroprotective action has not yet been fully antiparkinsonian effects through direct delineated but is due, at least in part, to multiple dopaminomimetic activity based on indirect in-vivo effects on the NMDAR-glutamate system. First, evidence (Danysz et al., 1997). Later studies have riluzole inhibits Na+ channels on glutamate- shown that the dominant mechanism of action for containing neurons and thereby selectively reduces amantadine is its NMDAR antagonistic properties, presynaptic release of glutamate (Prakriya and acting as an open-channel blocker (Kornhuber et Mennerick, 2000). Second, riluzole might block al., 1994). NMDAR activation, preventing Ca2+ entry via the channel. Riluzole either acts directly on the Memantine,1,3-dimethyl-5-aminoadamantane, is NMDAR, although a binding site for riluzole on the NMDAR antagonists that has been approved for receptor has not been identified (Debono et al., human use (Farlow, 2004). It exhibits fast on-and- 1993), or indirectly, possibly via a G-protein off kinetics, allowing it to rapidly bind to and, dependent signalling pathway (Hubert et al., 1994). quickly dissociate from the receptor and reduced Third, riluzole facilitates glutamate reuptake by tendencies to produce adverse reactions such as increasing the activity of glutamate transporters psychotomimetic effects (Parsons et al., 1999). In expressed on neurons and glia (Fumagalli et al., addition, memantine has pronounced voltage- 2008). dependency and, therefore, will dissociate from the NMDAR channel upon strong postsynaptic Finally, two new NMDAR-targeting drugs, depolarization, as occurs during normal neramexane and dimebon, are in clinical trials. physiological activation, but will remain blocking Neramexane belongs to a recently described group of the channel during moderate long-lasting NMDAR open-channel blockers known as the depolarization, as during chronic excitotoxic amino-alkyl-cyclohexanes (Danysz et al., 2002). conditions (Parsons et al., 1999). Therefore, The drug has similar kinetics and voltage- memantine’s favorable clinical profile might also dependency to memantine, and comparable clinical result from preservation of normal synaptic activity tolerability. Although there are no clinical trials of while inhibiting excitotoxicity. Memantine also neramexane registered, this drug is being developed affects the cholinergic neurotransmitter system; in for treatment of Alzheimer’s disease (Rammes and particular, it inhibits α7 nicotinic acetylcholine Schierloh, 2006). Dimebon, a drug predominantly receptors (nAChRs) (Aracava et al., 2005). This developed in Russia, is being assessed in clinical effect might also contribute to its favorable clinical trials in patients with Alzheimer’s (Doody et al., profile as there is some evidence that α7 nAChR 2008) and Huntington’s diseases. A small inhibition results in attenuation of pathological preliminary clinical trial done in Moscow suggested processes associated with Alzheimer’s disease some improvement in cognitive function and (Wang et al., 2003). Memantine is now in clinical reduction in neuropsychiatric symptoms with use for treatment of cognitive deficits in moderate to dimebon in patients with mild to moderate severe Alzheimer’s disease. Alzheimer’s disease (Bachurin et al., 2001). Dimebon was initially classified as an antihistamine but its mechanism of action seems to be more P-40 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 complex (Lermontova et al., 2001; Bachurin et exhibit greater selectivity for NR2B over other al., 2003). Studies suggest dimebon blocks receptor subtypes and ion channels, suggesting a NMDARs but likely at a site distinct from reduced probability of cardiovascular side effects memantine (Grigorev et al., 2003). (McCauley et al., 2004). They have been useful for 3.1.2.3. NMDA Receptor Negative Allosteric defining the actions of NR2B-containing receptors in Modulators the brain. Troxoprodil possesses high selectivity and One of the potentially most important recent has been through phase III clinical trials for the developments in NMDA receptor pharmacology has treatment of traumatic brain injury. However, the been the identification of highly subtype selective clinical utility of these compounds for chronic antagonists which act allosterically through an indications has been compromised by their poor oral interaction with the extracellular ATD of the NR2 bioavailability and pharmacokinetic profiles, mainly subunits (Perin- Dureau et al., 2002; Malherbe et due to high first pass liver metabolism and high al., 2003). Most of these compounds are selective for clearance rates (Gogas , 2006). NR2B subunit containing receptors and, so far, only zinc has been identified as being NR2A subunit 3.1.3. NMDA Receptor Positive Allosteric selective through an interaction with this domain. Modulators Zinc displays a voltage-dependent inhibition of The polyamines, spermine and spermidine, were the NMDAR responses in heteromeric NR1/NR2A and first potentiators of NMDA receptor function to be NR1/NR2B receptors. At lower concentrations, it described (Ransom and Stec, 1988). They appear to shows a voltage-independent inhibition of enhance NMDA receptor function through two NR1/NR2A receptors (Chen et al., 1997). Since zinc mechanisms, one glycine-dependent, mediated by is co-released with glutamate from pre-synaptic enhancing receptor affinity for glycine, and one terminals, zinc modulation of NMDARs may be glycine-independent characterized by increases in physiologically relevant (Aniksztejn et al., 1987). A the maximal amplitudes of NMDAR responses, large number of pharmacological agents bind and which persists in the presence of saturating inhibit NMDAR activity specifically at NR2B- concentrations of glycine, and is only present at containing receptors. The prototype is ifenprodil, a NR2B subunit containing receptors (Williams1997). phenylethanolamine that binds at a site distinct from In the absence of glutamate and glycine, polyamines the glutamate- and glycine-binding sites (Legendre have no effect on NMDAR activity. However, they and Westbrook, 1991). Ifenprodil exhibits greater increase glycine affinity (Sacaan and Johnson, than a 100-fold selectivity for NR2B over NR2A 1989; McGurk et al., 1990), and thus increase containing receptors (Williams, 1993), and very low NMDAR responses at subsaturating glycine affinity at NR2C- and NR2D-containing receptors concentrations by increasing glycine association. (Williams, 1995). Under saturating glycine conditions, polyamines still potentiate NMDAR responses (glycine-independent In addition to their activity at NMDA receptors, potentiation). ifenprodil and its analogue eliprodil are also antagonists of α1-adrenergic receptors, serotonin Moreover, at negative potentials, polyamines receptors and calcium channels, suggesting that the reduce channel conductance by partial channel therapeutic effectiveness of these compounds might block. Consistent with early studies (Ransom and be compromised by accompanying cardiovascular Stec, 1988), these polyamine effects are interactions (Gogas, 2006). There have been several noncompetitive with glutamate, glycine, and channel ‘second generation’ ifenprodil analogues developed, blockers, suggesting distinct binding sites for which readily penetrate the brain and are active polyamines (McBain and Mayer, 1994). Spermine, systemically including traxoprodil (Chenard et al., spermidine and other compounds active at the 1995), and (R-(R*, S*)-α-(4-hydroxyphenyl)-β- polyamine site are all highly positively charged and, methyl-4-(phenylmethyl)-1- piperidine propanol (Ro thus, it appears difficult to target this site with 25-6981) (Fischer et al., 1997). Both compounds systemically active drugs. Magnesium mimics all of P-41 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 the potentiating effects of the polyamines (Kew and (Kohara et al., 1998); and [1,2,3,4-tetrahydro-7- Kemp, 1998) and may be an endogenous ligand for morpholinyl-2,3-dioxo-6-(trifluoromethyl) this site (Paoletti et al., 1995). quinoxalin-1-yl]methylphosphonate (ZK200775) (Turskiet al., 1998). 3.1.4. AMPA Receptor Agonists The agonists glutamate, AMPA, and kainate, are Most of these quinoxaline derivatives have limited widely employed for activating AMPARs, and they water solubility and, as a consequence, display modest selectivity among homomeric representatives have failed clinical trials due to receptors (Keinanen et al., 1990; Kew and Kemp, nephrotoxicity (Turskiet al., 1998). However, 2005). Moreover, a large number of AMPA receptor ZK200775 and YM872 are water soluble, AMPA agonists have been described and many of them, like receptor selective and active in in-vivo models of AMPA itself, have been derived from classic stroke (Turski et al., 1998; Takahashi et al. 2002). structure activity studies using ibotenic acid, Both these compounds entered clinical trials for the quisqualic acid and willardiine as leads (Stensbol et treatment of acute ischemic stroke: the trial with al., 2002). One of the interesting aspects of AMPA ZK200775 was stopped prematurely due to safety receptor agonists is that they can vary dramatically concerns (Elting et al., 2002) and the trial with in the amount of receptor desensitization that they YM872 was completed but no further information is induce. Thus, whilst glutamate and AMPA act as full available. agonists and induce rapidly desensitizing responses, kainate acts as a partial agonist and induces AMPA 3.1.6. Non-Competitive AMPA Receptor receptor responses that show little desensitization. A Antagonists number of 5-substituted willardiines act as partial Several chemical series of non-competitive AMPA agonists with varying levels of intrinsic activity at receptor antagonists that are also known as negative AMPA receptors whilst the potent AMPA analogue, allosteric modulators have been reported. These ligands (R,S)-2-amino-3-(3-carboxy-5-methyl-4 isoxazolyl) are comprised of several distinct chemical classes, propionic acid (ACPA) induces much less steady- including the 2,3-benzodiazepines, quinazolinones, state desensitization than AMPA itself (Stensbol et arylphthalazines, and tetrahydrosioquinolines. The latter al., 2002; Mayer and Armstrong, 2004). two series are structural derivatives of 2,3- benzodiazepines(Pelletier et al., 1996; Gitto et al., 3.1.5. AMPA Receptor Competitive Antagonist 2003). Following the identification of 1-(4- The first somewhat selective and useful AMPA aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3- receptor antagonists were 6-cyano-7- benzodiazepine (GYKI 52466) as a selective, non- nitroquinoxaline-2,3-dione (CNQX) and 6,7-dinitro- competitive AMPA receptor antagonist (Solyom and quinoxaline-2,3-dione (DNQX) (Drejer and Tarnawa, 2002), a family of 2,3-benzodiazepine Honore, 1988). However, these compounds also had compounds was elaborated. The 2,3-benzodiazepines activity at the glycine binding site on NMDA include(R)-1-(4-aminophenyl)-4-methyl-7,8- receptors and, thus, lacked sufficient selectivity to be methylenedioxy-4,5-dihydro-3methylcarbomyl-2,3 really useful agents (Birch et al., 1988). benzodiazepine (GYKI 53784/LY303070) and (R)-7- Nevertheless, they served as the starting point for acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3- various more selective competitive AMPA receptor dioxolo(4,5-h)(2,3)benzodiazepine antagonists, such as 2,3-dihydroxy-6-nitro-7- (GYKI53773/LY300164) (Tarnawa et al., 1993; Ruel sulfamoyl-benzo(F) quinoxaline (NBQX) et al., 2002). These compounds exhibit relatively little (Sheardown et al., 1990); 1,4,7,8,9,10-hexahydro-9- selectivity between AMPA receptor subtypes but are methyl-6-nitropyrido[3,4-f]-quinoxaline-2,3-dione selective for AMPA over kainate and NMDA receptors (PNQX) ;6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)- (Ruel et al., 2002). The 2,3-benzodiazepines are quinoxalinedione (YM-90K) (Ohmori et al., 1994); systemically bioavailable (Szabados et al., 2001) and [2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4- indeed GYKI 53773/LY300164 has entered clinical tetrahydro-1-quinoxalinyl]-aceticacid (YM872) P-42 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 trials for indications including epilepsy (Langan et al., as cognition enhancing or ‘nootropic’ drugs. Indeed 2003). representatives have entered clinical trials which have yielded encouraging results (Danysz, 2002; A series of quinazolinone derivatives has also been O’Neill et al., 2004a). identified as selective non-competitive AMPA receptor antagonists, typified by 3-(2-Chloro-phenyl) Several distinct chemical classes of these -2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6- compounds have been reported, including the fluoro-3H quinazolin-4-one (CP-465,022) ,and 2-{2- benzamides (e.g., aniracetam, and CX-614), the [3-(2-Chloro-phenyl)-6-fluoro-4-oxo-3,4-dihydro- benzothiadiazines (e.g., cyclothiazide), and a broad quinazolin-2-yl]-vinyl}-nicotinomnitrile(CP-526,427) collection of arylsulfonamides (e.g., LY-404187 and (Welch et al. 2001;Lazzaro et al. 2002). The binding PEPA)(Kew and Kemp, 2005; Morrow et al., site of CP-526,427 is distinct from the glutamate 2006). The observation that cognitive enhancing binding site but appears to overlap with that of the 2,3- ‘nootropic agents’ such as 1-(4-methoxybenzoyl)-2- benzodiazepines (Menniti et al. 2000). Like the 2,3- pyrrolidinone (aniracetam) facilitated AMPA benzodiazepines,CP-465,022 is systemically receptor-mediated activity (Ito et al., 1990) led to bioavailable (Menniti et al. 2003) and is selective for the elucidation of a structurally related series of AMPA over kainite and NMDA receptors whilst benzamide compounds, also known as exhibiting little selectivity between AMPA receptor ‘AMPAkines=ampakines’, including 1-(quinoxalin- subtypes (Lazzaro et al. 2002). 6-ylcarbonyl)-piperidine(CX516), 1-(1,4 benzothiadiazine1,1-dioxide (CX546) and Initial studies evaluating the effects of naturally 2H,3H,6aH-pyrrolidino[2″,1″-3′2′]1,3- occurring polyamine toxins across multiple AMPAR oxazino[6′5′5,4]benzo[e]1,4-dioxan-1one(CX614) subtypes demonstrated that these compounds (Danysz, 2002; Lynch, 2004; O’Neill et al., generally are selective for a subset of AMPARs— 2004a). namely, channels lacking the GluA2 subunit (i.e., GluA1, GluA3, GluA4). For example, the natural A second series of modulators were identified product Joro spider toxin (JSTX-3) blocks nearly all following the observation that the benzothiadiazides, of the current from GluA1, GluA3 and GluA4 7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1- homomers, while having no effect on the dioxide (diazoxide) and6-Chloro-3,4-dihydro-3-(5- heteromeric receptors tested (i.e., GluA1/A2 and norbornen-2-yl)-2H-1,2,4-benzothiazidiazine GluA2/A3) (Blaschke et al., 1993). Similarly, sulfonamide-1,1-dioxide (cyclothiazide) also argiotoxin-636 (ArgTx-636) inhibits GluA1, GluA3, enhanced AMPA receptor-mediated currents and GluA4 homomers with nearly equal potency, (Yamada and Tang, 1993). Subsequent studies and is more than 10-fold less potent at GluA1/A2 have resulted in the identification of the related 7- heteromers (Herlitze et al., 1993). chloro-3-methyl-3,4-dihydro-2H-1,2,4- benzothiadiazine 1,1-dioxide (IDRA-21), and ((4-[2- 3.1.7. AMPA Receptor Positive Allosteric (phenylsulphonylamino)ethylthio]-2,6- Modulators difluorophenoxyacetamide (PEPA) (Sekiguchi et A number of AMPA receptor positive allosteric al., 1997; O’Neill et al., 2004a). modulators have been identified. These compounds potentiate AMPAR-mediated currents by attenuating More recently, a series of receptor desensitization and/or deactivation, but do biarylpropysulphonamides has been reported not activate the receptor when applied alone. Such including (R,S)-N-2(4(3thienyl)phenyl)propyl-2- compounds have been shown to facilitate AMPA propane sulfonamide (LY392098), N-2-[4-(4- receptor-mediated synaptic activity both in-vitro and cyanophenyl)phenyl]propyl2-propanesulphonamide in-vivo and have exhibited activity in a variety of (LY404187) ,N-2-(4-(N-benzamido) phenyl) propyl- behavioral assays, most notably in models of 2-propanesulfonamide (LY395153) and (R)-4′-[1- cognition and have been pursued for their potential fluoro-1-methyl-2-(propane-2-sulphonylamino)- P-43 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 ethyl]-biphenyl-4-carboxylic acid methylamide fast agonist-induced desensitization (Zhou et al., (LY503430) (Miuetal., 2001; Murray et al., 2003; 1997) and thus essentially performs as an antagonist O’Neill et al.,2004a). of these receptors. The naturally occurring marine toxins, dysiherbaine and its natural analogue The positive modulators exhibit distinct neodysiherbaine, also act as potent kainate-receptor mechanistic profiles and selectivity for individual agonists (Swanson et al., 2002; Sanders et al., AMPA receptor subunits and their splice variants. 2005). For example, PEPA attenuates receptor desensitization without effect on deactivation, 3.1.9. Kainate-Receptor Antagonists cyclothiazide inhibits receptor desensitization but A small number of compounds have been described has little effect on receptor deactivation, whereas as selective antagonists of kainate receptors, they CX614 both blocks desensitization and slows mainly target GluR5. Compounds of the deactivation (Sekiguchi et al., 2002). LY404187 quinoxalinedione family, including CNQX and also suppresses receptor desensitization with a NBQX, act as competitive antagonists at native and distinct time-dependence in the presence of agonist recombinant kainite receptors; whereas CNQX that may reflect receptor ‘desensitization’ (Quirk exhibits little selectivity for kainate over AMPA and Nisenbaum, 2002). receptors, NBQX is far more potent at AMPA receptors (Mayer et al., 2006). Some 3.1.8. Kainate Receptor Agonists pyrrolilquinoxalinedione derivatives have been Historically, the study of kainate receptor physiology found to have a higher affinity for kainate than for has been hampered by the lack of selective ligands. AMPA receptors. This is particularly true for In addition to glutamate, both recombinant and LU97175, which displays an extremely high native kainate receptors are activated by agonists selectivity for GluR5 and GluR6 and, especially, for including kainate and domoate. However, both GluR7 (Loscher et al., 1999). compounds also elicit non-desensitizing responses at Compounds of a new series of 6-substituted AMPA receptors and exhibit only moderate decahydroisoquinolines display more selectivity selectivity for kainate receptors (Lerma et al., towards kainate receptors and act as potent 2001). Several kainate receptor selective agonists antagonists at certain subunits. This is the case for have now been identified (Lerma et al., 2001; LY382884, a compound derived from the non- Bleakman et al., 2002). This include 5-tert-butyl-4 competitive AMPA receptor antagonist LY293558, isoxazole propionic acid (ATPA), (S)-5- which displays selectivity towards the GluR5 subunit iodowillardiine, (2S,4R) 4-methyl glutamic acid (Alt et al., 2004), and for LY377770 (O’Neill et al., (SYM2081) and (2S,4R,6E)-2-amino-4-carboxy-7- 1998). The willardiine derivative UBP296 has been (2-naphthyl)hept-6-enoic acid (LY339434). ATPA, a reported as the most potent and selective antagonist substituted analogue of AMPA and (S)-5- at GluR5- containing kainate receptors, with activity iodowillardiine are potent, selective GluR5 agonists residing in the S enantiomer, UBP302 (More et al., that display low affinity at AMPAR and GluR6 or 2004). GluR7-containing receptors (Swanson et al., 1998; More recently, another series of willardiine Alt et al., 2004). AMPA, ATPA and (S)-5- derivatives has been synthesized and tested for iodowillardiine can also activate GluR6/KA2 antagonist activity. The N3-2-carboxybenzyl heteromeric receptors, despite functioning only as substituted analogue (UBP310) has been found to be partial agonists (Swanson et al., 1998; Alt et al., a potent and selective antagonist of GluR5- 2004). containing kainite receptors when tested on native rat The gamma substituted glutamate analogues and human recombinant AMPA and kainate-receptor SYM2081 and LY339434 are also more selective for subtypes (Dolman et al., 2005). Interestingly, kainate than for AMPA receptors (Small et al., MSVIII-19, a synthetic analogue of the natural 1998; Alt et al., 2004). However, SYM2081 inhibits agonist dysiherbaine, also acts as a potent antagonist currents through kainate receptors by a process of of homomeric GluR5 (Sanders et al., 2005). In P-44 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 addition, kainate-receptor function can also be 3.2.2.Group I mGluR Antagonist antagonized by lanthanides, particularly lanthanum A number of phenylglycine derivatives have been and gadolinium (Huettner et al., 1998), with a identified as group I mGluR antagonists, some of significantly higher potency than for AMPA which exhibit selectivity for mGluR1 vs mGluR5 receptors. (Schoepp et al., 1999). Many of the early compounds also exhibited activity at mGluR2, with 3.1.10. Allosteric Modulators the best example, (S)-4-carboxyphenylglycine [(S)- Plant lectins, such as concanavalin A, 4CPG] exhibiting approximately tenfold selectivity succinylconcanavalin A, soybean agglutinin and for mGluR1 vs mGluR2 (Thomsen et al., 1994). wheat germ agglutinin, have been proposed to block Subsequent optimization of this template resulted in the process of desensitization of kainate receptors, the identification of more selective ligands with low being more effective on homomeric assemblies micromolar activity including (R,S)-1- aminoindan- (Wong and Mayer, 1993; Yue et al., 1995). On 1-5-dicarboxylic acid (AIDA) (Pellicciari et al., GluR6 homomeric receptors, concanavalin A exerts 1995;Moroni et al., 1997) and (S)-2-methyl-4- its action via non-specific binding to any of the N- carboxyphenylglycine (LY367385) (Clark et al., glycosylation sites, even those artificially introduced 1997), both of which are selective for mGluR1 vs (Everts et al., 1999), and have been suggested to mGluR5(Kingston et al., 2002). Generally, the “lock” the receptor in the activatable state, inhibiting pharmacokinetic profile of both competitive agonist the conformational changes required to shift the and antagonists has restricted their utility as in vivo receptor to the desensitized state (Wong and Mayer, tools with CNS delivery only possible via 1993; Yue et al., 1995). An alternative mechanism intracerebroventricular administration. has been proposed. Neurons also express endogenous lectins but whether they are involved in 3.2.3. Group I mGluR Negative Allosteric regulating kainite receptor function is not yet known. Modulators High-affinity, non-competitive modulators have been 3.2. Metabotropic Glutamate Receptors identified which are selective between mGluR1 and Pharmacology mGluR5. The first non-competitive mGluR ligand to be identified was 7- 3.2.1. Group I mGluR Agonist hydroxyiminocyclopropan[b]chromen-1a-carboxylic The most potent group I mGluR agonist identified to acid ethyl ester (CPCCOEt) (Annoura et al., 1996). date is quisqualic acid, which exhibits potent activity CPCCOEt inhibited mGluR1 activity, and without at rat recombinant mGluR1 and 5 and is selective effect on glutamate binding and is selective for over the group II and III receptors (Bräuner- mGluR1 vs mGluR5 and the group II and III mGluRs Osborne and Krogsgaard-Larsen, 1998). (Hermans et al,. 1998; Litchig et al., 1999). However, its utility is severely limited by its agonist Subsequently, a number of higher affinity, selective activity at AMPA receptors (Watkins et al., 1990). mGluR1 negative modulators have been identified The first selective group I mGluR agonist to be including [(3aS,6aS)-6a-Naphtalen-2-ylmethyl-5- identified was (S)- 3,5-dihydroxyphenylglycine [(S)- methyliden-hexahydro-cyclopental [c] furan-1-on] DHPG] (Schoepp et al., 1994) which exhibits low (BAY36-7620) (Carroll et al., 2001); 1-(3,4-dihydro- micromolar potency at mGluR1 and 5 and is 2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone selective vs the group II and III mGluRs (Schoepp et (R214127) (Lavreysen et al., 2003); and 1-ethyl-2- al., 1999). No agonists selective for mGluR1 over methyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo [d] azepin- mGluR5 have been reported to date. However, 3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile (R,S)-2- chloro-5-hydroxyphenylglycine (CHPG) (EMTBPC) (Malherbe et al., 2003). was identified as a low-potency agonist at rat recombinant mGluR5 and is selective vs mGluR1, The first non-competitive mGluR5 antagonists to whilst its activity at the group II and III mGluRs has be described were 6-methyl-2-(phenylazo)-3- not been reported (Doherty et al., 1997). pyridinol (SIB-1757) and (E)-2-methyl-6-(2- P-45 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 phenylethenyl)pyridine (SIB- 1893) ( Varney et al., as rat native mGluR5, increasing agonist potency 1999). Both compounds are selective for mGluR5 vs with no apparent increase in maximum response and mGluR1 and the family II and III mGluRs Structural without affecting the binding affinity of optimization around SIB-1757 and SIB-1893 led to [3H]quisqualate (O’Brien et al., 2003, 2004). the identification of 2-methyl-6-(phenylethynyl)- Interestingly, both DFB and CPPHA appear to pyridine (MPEP), a significantly more potent ligand increase the intrinsic efficacy of partial agonists at (Gasparini et al., 1999) which exhibits inverse the orthosteric binding site (O’Brien et al., 2003, agonism (Pagano et al., 2000). Further elaboration 2004). Both compounds were devoid of activity at has led to the discovery of 3-[2-methyl-1,3-thiazol-4- mGluR1 and the group II and III mGluRs but yl) ethynyl] pyridine (MTEP), which exhibits exhibited weak antagonist activity at mGluR4 and improved selectivity and CNS mGluR8. bioavailability(Cosford et al., 2003). 3.2.5 Group II mGluR Agonist 3.2.4. Group I mGluR Positive Allosteric A number of potent group II mGluR agonists have Modulators been identified with selectivity vs the group I; Two chemical series have been reported as positive however, they do not discriminate between mGluR2 allosteric modulators for mGluR1: 2-phenyl-1- and 3. These include 2′3′- benzenesulfonyl-pyrrolidine derivatives, exemplified dicarboxycyclopropylglycine (DCG-IV) (Brabet et by (S)-2-(4-fluoro-phenyl)-1-(toluene-4- sulfonyl)- al., 1998) and a series of highly potent compounds pyrrolidine (Ro 67-7476); diphenylacetyl- and(9H- including (1S,2S,5R,6S)-2-amino- xanthene-9-carbonyl)-carbamic acid esters, bicyclo[3.1.0]hexane-2, 6-di-carboxylic acid exemplified by diphenylacetyl-carbamic acid ethyl (LY354740) (Monn et al., 1997), (−)- 2-oxa-4- ester (Ro 01- 6128) and (9H-xanthene-9-carbonyl)- aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid carbamic acid butyl ester (Ro 67-4853) (Knoflach et (LY379268) (Monn et al., 1999) and (1R,2S,5S,6S)- al., 2001). In both rat recombinant and native 2-amino- 6-fluoro-4 oxobicyclo [3.1.0]hexane 2,6- receptor assay systems, these compounds did not dicarboxylic acid (MGS0028) (Nakazato et al., exhibit intrinsic agonist activity but markedly 2000). Notably, LY354740, LY379268 and facilitated agonist-induced responses, increasing MGS0028 exhibit nanomolar potency at mGluR2 potency and maximum efficacy. Notably, both Ro and -3 and are systemically active (Cartmell et al., 67-7476 and Ro 01-6128 also increased the binding 1999; Nakazato et al., 2000).The only agonist affinity of the agonist ligand [3H] quisqualate, reported to date which discriminates between without a significant effect on the number of binding mGluR2 and mGluR3 is the endogenous sites. All these compounds were mGluR1 selective neuropeptide N-acetyl aspartylglutamate (NAAG), vs group II and III mGluRs with Ro 67-7476 and which is a relatively low potency mGluR3 agonist Ro 01-6128 also selective vs mGluR5, whilst with moderate selectivity over mGluR2 and the other positive modulator activity at mGluR5 was noted mGluR family members (Schweitzer et al., 2000). with Ro 67-4853 at high concentrations (Wichmann et al., 2002). 3.2.6 Group II mGluR Antagonist 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)- 3- The first mGluR5 positive allosteric modulators to (xanth-9-yl) propanoic acid (LY341495) is the most be described derive from two structural classes, the potent group II mGluR antagonist identified, which first represented by 3,3′-difluorobenzaldazine (DFB) exhibits nanomolar affinity at both mGluR2 and -3 (O’Brien et al., 2003) and the second by N-{4- (Kingston et al., 1998). LY341495 is systemically chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) bioavailable and has been used to block the activity methyl] phenyl}-2-hydroxybenzamide (CPPHA) of group II agonists in vivo (Cartmell et al., 1999). (O’Brien et al., 2004). Both DFB and CCPHA have Several other selective competitive ligands have no intrinsic agonist activity but potentiate agonist been identified (Schoepp et al., 1999) including responses at both human and rat recombinant as well (2S,4S)-2-amino-4-(2,2- diphenylethyl) pentanedioic P-46 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 acid which exhibits low micromolar activity at the mixed mGluR2/3 agonists, suggesting that mGluR2 and -3 and greater than tenfold selectivity agonist efficacy is predominantly mediated via vs the group I and III mGluRs and ionotropic mGluR2. Recently, a novel class of mGluR2- glutamate receptors (Escribanoet al., 1998). selective positive modulators typified by 1-(2- 3.2.7 Group II mGluR Negative Allosteric hydroxy-3-propyl-4-{4-[4-(2H-tetrazol-5-yl) Modulators phenoxy] butoxy} phenyl)-ethanone was reported Three 8-arylethynyl-1,3-dihydro- (Pinkerton et al., 2004). This compound attenuated benzo[b][1,4]diazepin-2- one derivatives, 3-(4-oxo- ketamine-induced noradrenaline release in rat ventral 7-phenylethynyl-4,5-dihydro- 3H- hippocampus and also inhibited ketamine-induced benzo[b][1,4]diazepin-2-yl)-benzonitrile (Ro 67- hyperactivity. However, due to limited brain 6221), 8-(4-fluoro-phenylethynyl)-7-hydroxy-4-(3- penetration, its utility was restricted to delivery via imidazol-1-yl-phenyl)-1,3-dihydro-benzo [b] intracerebroventricular administration. [1,4]diazepin-2-one (Ro 71- 8216) and 8-(4-fluoro phenylethynyl)-7-hydroxy-4-(3-[1,2, 3]triazol-1-yl- 3.2.9. Group III mGluR Agonist phenyl)-1,3-dihydro benzo[b][1,4]diazepin-2- one The discovery of selective ligands for group III (Ro 71-8218) were described that exhibited high mGluRs has trailed behind that of the group I and II affinity, non-competitive antagonism at rat mGluR2 receptors. (S)-4-Phosphono-2-aminobutyric acid (S- with selectivity vs group I and III mGluRs. AP4) exhibits low micromolar agonist activity at Preliminary observations also revealed the antagonist mGluR4, -6 and 8 and is selective vs the group I and activity of Ro 67-6221 and Ro 71-8218 at II mGluRs and vs mGluR7 at which it exhibits high mGluR3. Interestingly, whilst these ligands exhibited micromolar potency (Schoepp et al., 1999). In fact, a noncompetitive pharmacological profile, they it is notable that mGluR7 is differentiated from other partially displaced binding of the orthosteric agonist group III mGluRs by its relatively low sensitivity to [3H]-LY354740 at mGluR2, suggesting an allosteric both glutamate and synthetic agonists (Ahmadian et interaction between the two binding sites (Kew and al., 1997). A number of group III mGluR subtype Kemp, 2005). selective ligands have been identified. (S)-2-Amino- 4-(3-hydroxy-5- methylisoxazol-4-yl) butyric acid 3.2.8 Group II mGluR Positive Allosteric (S-homo-AMPA) is a selective agonist at mGluR6 Modulators (Ahmadian et al., 1997). (R,S)-4- A series of pyridylmethyl sulfonamide mGluR2 Phosphonophenylglycine (PPG) is a potent group III positive allosteric modulators typified by N-(4-(2- mGluR agonist which exhibits greater than tenfold methoxyphenoxy) phenyl)-N-(2,2,2- selectivity for mGluR8 vs mGluR4, 6 and 7 trifluoroethylsulfonyl)prid-3-ylmethylamine (Gasparini et al., 1999). (S)-3,4- (LY487379) has been identified via functional Dicarboxyphenylglycine (DCPG) is a potent and screening (Johnson et al., 2003). LY487379 was selective mGluR8 agonist (Thomas et al., 2001). without intrinsic activity but potentiated sub- maximal glutamate responses, increasing agonist 3.2.10. Group III mGluR Antagonist potency and maximum efficacy, and mGluR2 was A number of competitive group III mGluR selective over mGluR3, the group I, and III mGluRs antagonists have been identified as (R,S)-α- (Johnson et al., 2003; Schaffhauser et al., 2003). cyclopropyl-4- phosphonophenylglycine (CPPG) and LY487389 also increased the binding affinity of the (R,S)-α-methylserine- O-phosphate (MSOP) orthosteric agonist ligand, [3H]DCG-IV, but not the (Schoepp et al., 1999). However, pharmacological antagonist, [3H]LY341495, at mGluR2, this was characterization of these compounds against the suggested to be due to an increase in receptor/G- mGluR family members is incomplete. In addition, protein coupling in the presence of the positive the group II selective antagonist, LY341495, also modulator (Schaffhauser et al., 2003). To date, exhibits activity at the group III mGluRs (Kingston mGluR2-selective positive allosteric modulators et al., 1998). LY341495 also exhibits low appear to exhibit an in vivo profile similar to that of P-47 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 micromolar antagonist activity at the group I that leads to the malfunctioning of neural networks mGluRs. in the neocortex (Bennett, 2008). The possible mechanism of such regression involves the loss of 3.2.11. Group III mGluR Allosteric Modulators synaptic spines associated with excessive activation No non-competitive group III mGluR antagonists of glutamate receptors by increased glutamate levels, (negative allosteric modulators) have been reported under conditions of oxidative and metabolic stress to date. The mGluR5 positive allosteric modulators, (Mattson, 2008;Bennett, 2008). DFB and CPPHA, both exhibit weak antagonist The non-competitive NMDA receptor antagonist activity at both mGluR4 and mGluR8 (O’Brien et ketamine has been demonstrated to have al., 2003, 2004). (−)-N-Phenyl-7-(hydroximino) antidepressant effects in animal models of cyclopropa [b] chromen- 1a-carboxamide ((−)- depression. Where, Chaturvedi et al. (1999) has PHCCC) is a close structural analogue of the reported the antidepressant effects of dizocilpine and mGluR1 antagonist, CPCCOEt, and is itself a weak ketamine on shock-induced behavioral changes in antagonist at mGluR1 (Annoura et al., 1996), but mice. Furthermore, ketamine showed antidepressant acts with equivalent potency as a positive allosteric effectsin a forced-swim test (Yilmaz et al., 2002). modulator of mGluR4 (Marino et al., 2003). (−)- Very recently, Zarate et al. (2006a) demonstrated PHCCC was devoid of intrinsic agonist activity but the robust and rapid antidepressant effects of a single increased agonist potency and efficacy at mGluR4. dose of ketamine (0.5 mg/kg, i.v. infusion for 40 The mGluR5 antagonists, SIB-1893 and MPEP, also min) in treatment-resistant major depression. It is exhibit mGluR4 positive allosteric modulator assumed that directly targeting the NMDA receptor activity (Mathiesen et al., 2003). Similar to (−)- complex may bring about rapid and relatively PHCCC, both compounds were devoid of intrinsic sustained antidepressant effects (Zarate et al., agonist activity but increased agonist potency and 2006a). However, the clinical applicability of the efficacy. non-competitiveopen-channel NMDA receptor antagonists such as PCP and ketamine is limited by 4. Clinical Application of Glutamate Receptors’ their propensity to cause psychotomimetic effects Agonists and Antagonists (Javitt and Zukin, 1991; Krystal et al., 2005). Memantine is a derivative of amantadine, a low 4.1. Major Depressive Disorder affinity, non-competitive, open-channel NMDA There is growing evidence that the glutamatergic receptor blocker. However, unlike ketamine, system plays an important role in the neurobiology memantine failed to improve depression (Zarate et and treatment of major depressive disorder MDD al.,2006b). The precise reasons for this discrepancy (Sen and Sanacora, 2008). As there are a number of are unclear. One possibility is that high-affinity, papers reporting alterations in glutamate levels of strong open-channel blockers with slow off-rates, blood and cerebrospinal fluid (CSF) in patients with such as ketamine, exert antidepressant effects MDD (Mauri et al., 1998; Mitani et al., 2006). whereas low-affinity, weak open channel blockers There is also a positive correlation between plasma with fast off-rates, such as memantine, are glutamate levels and severity of depressive ineffective (Tsai, 2007). However, Kollmar et al. symptoms in patients with MDD (Mitani et al., (2008) reported the successful treatment of a patient 2006). Glutamate is also known to regulate with MDD using a two-step therapeutic regimen neurogenesis, synaptogenesis, and neuron survival in consisting of two infusions of ketamine followed by the developing and adult mammalian brain oral administration of memantine. Still, the (Mattson, 2008). Stress during childhood and antidepressant effects of memantine remain adolescence has been implicated in the extent of unproven. depression at adulthood. Stressful events lead to the The NMDA receptors containing the NR2B regression of synapses with the loss of synaptic subunit are localized primarily in the forebrain spines and in some cases whole dendrites of including hippocampus, a region implicated in the pyramidal neurons in the prefrontal cortex, a process pathophysiology of MDD (Campbell and P-48 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012

Macqueen, 2004). Considering the acute methanonemethanesulfonate), is another potent and psychotomimetic side effects of ketamine, the highly subtype-selective mGluR1 antagonist that has selective antagonists of the NR2B subtype of NMDA antidepressant-like effects in the rat forced-swim and receptors appear to pose little risk. The NR2B the mouse tail-suspension tests (Belozertseva et al., antagonist Ro 25-6981 had antidepressant-like 2007). Several studies have demonstrated that the properties in the forced-swim test (Maeng et al., selective mGluR5 antagonists, MPEP, and the more 2008). Moreover, a recent double-blind, randomized, selective and metabolically stable analog MTEP, placebo-controlled study demonstrated that the have antidepressant-like effects in animal models of selective NR2B antagonist traxoprodil had depression. Administration of MPEP or MTEP significant antidepressant effects in patients with decreased immobility in the tail-suspension test in treatment-resistant MDD (Preskorn et al.,2008). mice (Belozertseva et al., 2007; Pałucha et al., Therefore, the selective NR2B antagonists may be a 2005). fruitful target for the development of a new Group II mGlu receptors (mGluR2/3) exhibit antidepressant with more robust effects and a faster moderate to high expression in brain regions (e.g., onset compared with those currently available. hippocampus, prefrontal cortex, and amygdala) that Recent findings suggest the emerging role of are associated with MDD. The mGluR2/3 AMPA receptors in the treatment and etiology of antagonists, as LY341495 and MGS0039, exhibit mood disorders (Mathew et al., 2008; Alt et al., antidepressant-like effects in behavioral animal 2006). Where, it was reported that ketamine might models of depression (Sanacora et al., 2008; Pilc et exert its rapid antidepressant-like effects by al., 2008). Administration of MGS0039 or enhancing AMPA receptors relative to NMDA LY341495 reportedly increased firing rates of receptors throughout critical neuronal circuits serotonergic dorsal raphe neurons, and that (Maeng and Zarate, 2007; Maeng et al., 2008). MGS0039 increased extracellular serotonin levels in This results raise the possibility that the the medial prefrontal cortex (Kawashima et al., combination of AMPA receptor potentiators with 2005). In addition, repeated administration of even lower doses of NMDA receptor antagonists MGS0039 for 14 days increased cell proliferation in might be useful in the treatment of major depression. the adult mouse hippocampus (Yoshimizu and Positive modulators of AMPA receptors do not Chaki, 2004), which is implicated in the activate AMPA receptors themselves but slow the pathophysiology of MDD as well as in the rate of receptors desensitization and/or deactivation underlying mechanisms of antidepressants (Sahay in the presence of antagonist. Several positive and Hen, 2007). However , till now no clinical modulators (piracetam, aniracetam, cyclothiazide, studies have been conducted to explore the CX516, CX614, LY392098, LY404187, LY451395, antidepressant efficacy of mGluR2/3 antagonists in LY503430) of AMPA receptors have shown patients with MDD (Sanacora et al., 2008; Pilc et antidepressant-like effects in animal models of al., 2008). depression (Alt et al., 2006; O'Neill and Witkin, On the other hand, selective group III mGlu 2007). receptor agonist ACPT-1 showed antidepressant- Lavreysen et al. (2004) demonstrated that like effects in a forced-swim test (Pałucha et al., JNJ16259685; 3-4-Dihydro-2H-pyrano[2,3- 2004). The effects of ACPT-1 were antagonized by b]quinolin-7-yl-(cis-4-methoxy-cyclohexyl)- the group III mGluR antagonist CPPG (Kłak et al., methanone is a highly potent, selective, and 2007). Furthermore, administration of mGlu8 systemically active mGluR1 antagonist produced a receptor agonist (R,S)-4-phosphonophenylglycine significant reduction of offensive behaviors (e.g., ((R,S)-PPG) showed dose dependent antidepressant- threat and attack) without affecting immobility. This like effects in the forced-swim test in rats (Pałucha suggest that mGlu1 receptors are involved in et al., 2004). Moreover, Palucha et al. (2007) aggression regulation (Navarro et al., 2008). reported that the first selective and bio-available EMQMCM, (JNJ16567083): 3-ethyl-2-methyl- mGluR7 agonist N,N′-dibenzylhydryl-ethane-1,2- quinolin-6-yl-(4-methoxycyclohexyl)- diaminedihydrochloride (AMN082) showed P-49 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 antidepressant-like effects in the forced-swim test agonistm D-cycloserine, the full agonists glycine and and in the tail-suspension test. These results D-serine, and the glycine transporter-1 inhibitor suggested that group III mGlu receptor agonists sarcosine. D-serine and sarcosine, both of which might show antidepressant-like effects. increase NMDA receptor activities, have reportedly improved cognitive impairment in rodent models and 4.2. Schizophrenia in schizophrenic patients (Karasawa et al., 2008; Schizophrenia is characterized by positive Coyle and Tsai, 2004). Though administration of (hallucinations and delusions), negative (anhedonia direct agonists, such as D serine and glycine, are of and poverty of speech), cognitive, mood and motor therapeutic value, such treatments require large symptoms (Tandon et al., 2009). In addition to the doses and exhibit difficulties in penetrating the well-established “dopamine hypothesis of blood–brain-barrier (Labrie and Roder, 2010). schizophrenia”, abnormalities in glutamate Consequently, agents targeting proteins involved in transmissions have been suggested to be involved in D-serine metabolism may be a more effective the pathophysiology of schizophrenia. The glutamate strategy. Inhibition of D-amino acid oxidase (DAO), hypothesis stemmed from the following findings: 1) the D-serine catabolic enzyme, activity in the brain is significantly lower levels of glutamate are found in of particular interest as it would circumvent any the cerebrospinal fluid (CSF) and postmortem brain nephrotoxicity associated with the catabolism of tissue of schizophrenic patients (Kim et al., 1980; high levels of systemic D-serine (Maekawa et Tsai et al., 1995); 2) CSF glutamate levels are al.,2005b). Development of DAO antagonists has inversely correlated with the severity of positive recently begun (Adage et al., 2008; Hashimoto et symptoms in unmedicated patients (Faustman et al., al., 2009). Intravenous injections of the DAO 1999);and 3) phencyclidine (PCP) and ketamine, inhibitor AS057278 were found to readily cross the two non-competitive NMDA receptor antagonists, blood-brain-barrier and enhance D-serine contents in produced transient psychosis and disrupted affect the rat brain (Adage et al., 2008). Chronic and cognitive impairment in healthy volunteers, administration of AS057278 in mice was shown to similar to the symptoms of schizophrenia (Javitt normalize PCP-induced deficits in behavioral tasks and Zukin, 1991; Lahti et al., 2001), and also led to relevant to the cognitive and positive symptoms of the profound exacerbation of preexisting symptoms schizophrenia (Adage et al., 2008). However, in schizophrenic patients (Lahti et al., 2001) and elevations in D-serine following DAO inhibition are indicated the NMDAR hypofunction hypothesis in considerably lower than with exogenous D-serine schizophrenia. This NMDAR hypofunction leads to treatments (Ferraris et al., 2008) Indeed, excessive release of glutamate, leading to coadministration of D-serine and a DAO antagonist overstimulation of glutamatergic neurotransmission were shown to produce greater ameliorative effects at AMPA/kainate receptors (Moghaddamet al., in animals treated with an NMDAR antagonist than 1997). Thus, glutamatergic dysfunction, particularly either compound applied alone (Hashimoto et al., the hypofunction of NMDA receptors may have an 2009). Thus, DAO inhibition in combination with D important role in the pathophysiology of serine administration may be a valuable therapeutic schizophrenia. approach for the treatment of schizophrenia.

Based on this NMDA receptor hypofunction Although the capacity of D-cycloserine to hypothesis, compounds that enhance NMDA improve negative symptoms of schizophrenia has receptor function could alleviate symptoms of this been replicated in some placebo-controlled studies disorder. In this case, the NMDAR D-serine/glycine (Heresco-Levy et al., 2002; Goff et al., 1999b), site has been proposed as a potential therapeutic evidence supporting the effectiveness of D- target, as increasing its activation offers a safer cycloserine in treatment of schizophrenia is weak alternative to elevations in glutamate levels that can according to several other clinical studies. promote neurotoxicity (Coyle, 2006). To date, (Tuominen et al., 2005, 2006; Buchanan et al., clinical trials have been conducted with the partial 2007). P-50 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012

2,3-dihydro-1H-isoindol-1-one (Satow et al., 2008, Several lines of evidence suggest that mGlu1 2009) were tested for their antipsychotic effect in the receptor positive allosteric modulators may have most commonly used animal models for potential for the treatment of positive and cognitive schizophrenia that involve the measurement of symptoms of schizophrenia. This is because; first, hyperactivity and increased stereotypic behaviors in compounds that activate mGlu1receptors are response to amphetamine, MK-801, ketamine or documented to facilitate NMDA and AMPA receptor phencyclidine. However, the data with mGluR1 responses. As mGluR1 are expressed in regions that antagonists were not very consistent. play a crucial role in schizophrenia: the cortex, hippocampus and basal ganglia (Simonyi et al., Antagonists of mGluR5 can be also used for 2005), and it facilitate NMDA receptor-induced treatment of schizophrenia. Activation of currents in cortical neurons (Lindemeyer et al., presynaptic mGluR5 facilitates synaptic glutamate 2006), the CA3 region of the hippocampus release whereas postsynaptic mGluR5 increase (Benquetet al., 2002), and in the thalamus (Salt and neuronal excitability by facilitating NMDA currents. Binns, 2000), as revealed in electrophysiological Consequently, a reduction of the hyperglutamatergic recordings of synaptic plasticity (Anwyl, 2009). PFC state could be achieved with drugs like Second, mGluR1 levels are altered in brains of acamprosate which attenuate the excitatory effect of schizophrenic patients. Where, mGlu1 receptor mGluR5 on presynaptic glutamate release and by expression is increased in the prefrontal cortex of decreasing NMDA-dependent postsynaptic schizophrenic patients, which has been interpreted as excitability. Acamprosate, interfere with mGluR5- a compensatory change to the NMDA receptor dependent regulation of glutamate release (De Witte hypofunction (Gupta et al., 2005). And third, et al., 2005). Additionally, preclinical studies mGlu1 receptors can modulate dopamine release. suggest that acamprosate normalizes glutamate Although few studies have investigated whether release and NMDA receptors function without mGlu1 receptor scan modulate dopamine release, but altering the normal glutamatergic neurotransmission glutamate spillover from the corticostriatal synapse (De Witte et al., 2005). On the other hand, mGluR5 could not only activates glutamate receptors on regulates non-synaptic release of glutamate from glia medium spiny neurons, but may also activate and astrocytes via stimulation of the cystine– presynaptic mGlu1 receptors on neighboring glutamate antiporter (Melendez et al., 2005). dopaminergic substantia nigra afferents, to inhibit Accordingly, acamprosate would prevent activation electrically-evoked dopamine release (Zhang and of this antiporter by antagonizing mGluR5, which in Suzler, 2003). These may all add to the rationale in turn would reduce the non-synaptic extracellular support of mGlu1 receptor positive allosteric glutamate. modulators as potential therapy for the treatment of schizophrenia. However, for our knowledge, there is In addition, clinical reports documented that no mGlu1 receptor selective agonist published, and activation of mGluR2/3 receptors provides the effect of the mGlu1 positive allosteric symptomatic improvements in schizophrenic patients modulators in animal models of schizophrenia has without major adverse effects (Patil et al., 2007). not been reported (Sheffler and Conn, 2008). Recent results of a phase 2 clinical trial examining LY2140023, an mGlu2/3 receptor agonist, showed In contrast, several reports have been describing the improvements in both positive and negative effects of mGlu1 receptor antagonists in animal symptoms of schizophrenia. Importantly, patients models that pick up antipsychotic-like activity. taking LY2140023 did not show the typical side Different mGluR1 antagonist as ; FTIDC , 4-[1-(2- effects associated with medications targeting Fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl] dopamine receptors, such as extrapyramidal -N-isopropyl-N-methyl-3,6 dihydropyridine-1(2H)- syndrome or elevated serum prolactin levels; carboxamide; and CFMTI, 2-cyclopropyl-5-[1-(2- furthermore, unlike olanzapine, which has negative fluoro-3-pyridinyl)-5- methyl-1H-1,2,3-triazol-4-yl]- metabolic side effects such as weight gain, P-51 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012

LY2140023 did not increase body weight rather, it Glycine site antagonists could have some resulted in a loss of body weight (Patil et al., 2007). advantages over NMDA channel blockers such as Therefore, mGlu2/3 receptor agonists might be lower potential for inducing psychotomimetic side superior to the antipsychotics currently used for the effects. However, they have not yet been tested in treatment of schizophrenia. clinical trials for epilepsy most likely due to numerous pharmacokinetic problems such as low 4.3. Epilepsy solubility potentially resulting in kidney damage due Epileptic syndromes have very diverse primary to crystallization (e.g. ACEA 1021), low penetration causes, which may be genetic, developmental or to the CNS, short half-life, and last but not least by acquired (McNamara, 1994). During an epileptic doubtful efficacy in kindled seizure models (Wlaz seizure, large populations of neurons in selected and L¨oscher, 1998). Paradoxically, the best pre- portions of the central nervous system abandon their clinical data for modulating the glycine site have normal activity and begin to fire in periodic come from D-cycloserine, a partial agonist synchronous discharges. This pathological (LiSscher et al., 1994). synchronized activity is transmitted from one neuron Felbamate is one of NR2B selective antagonists to the next primarily through excitatory that has been under development for epilepsy (Harty glutamatergic transmission (Doherty and and Rogawski, 2000). It has favorable profile in Dingledine, 2002). Regardless of the primary cause, animal models including kindling (Wlaz and synaptically released glutamate acting on ionotropic L¨oscher, 1997). However, felbamate had to be and metabotropic receptors appears to play a major subsequently withdrawn due to the occurrence of role in the initiation and spread of seizure activity aplastic anaemia cases connected with the drug use (Chapman, 2000; Meldrum, 1994). (Pennell et al., 1995). Conantokin G which also Epilepsy was one of the early targets for NMDA preferentially interacts with NR2B subunit is still receptor antagonists (Czuczwar and under development for epilepsy, as it is in phase I Meldrum,1982). Despite being effective in some clinical trials (Donevan and McCabe, 2000; White animal models, those NMDA receptor antagonists et al., 2000). that have been tested in man have not been proven AMPA/kainate receptor antagonists had been or effective. The first NMDAR channel blocker to be are still under development for treatment of tested in epileptic patients was(+)MK-801 epilepsy. However, competitive AMPA antagonists (dizocilpine) which showed no efficacy at doses show several obstacles such as low solubility in producing appearance of side-effect (Leppik et al., neutral pH, short half-life and weak anticonvulsive 1988). On the one hand, side effects have seriously effects. In fact most of these substances are either restricted the clinical trials of classical NMDA mixed antagonists of AMPA and other receptors antagonists and, some doubts have been cast on the such as kainate (NS-1209) or glycine (LU-73068) or use of global seizure models induced by chemicals act through noncompetitive, modulatory sites, e.g. and sound as predictors of activity in partial seizures, talampanel. (LiSscher and Schmidt, 2006). On the the greatest population of epilepsy patients (Dansysz other hand, the fundamental role of kainate in and Parsons, 1998). Kindled animals have been synaptic physiology, in particular in the balance suggested as a better model (LiSscher and Schmidt, between excitation and inhibition in many brain 1988). Some NMDA antagonists have been reported regions suggests that they may participate selectively to interfere with kindling (LiSscher and Honack, in some forms of epilepsy in humans (Vincent and 1993). ADCI (5-aminocarbonyl-lo,11-dihydro-5h- Mulle, 2009). In view of their role in the regulation dibenzo[a,d] cyclohepten-5,10-imine) is a low of hippocampal networks, kainite receptors affinity uncompetitive NMDA receptor antagonist antagonists may represent a promising showing anticonvulsive activity in various animal anticonvulsant. There is some growing evidence that models and a favorable side effect profile, however it GluR5 containing KARs represent a novel target for was discontinued in Phase I of clinical trials antiepileptic drugs development. Topiramate is a (Rogawski et al., 1995). new antiepileptic drugs that has been beneficial for P-52 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 the treatment of refractory epilepsy. Although there mediated pathways occurs early in the disease and in is clear evidence that topiramate affects the function a pattern that corresponds with the distribution of of GluR5-containing receptors, its mode of action plaques and tangles (Procter, 2000). needs to be better understood . On the other hand, there is also the intriguing possibility that in fact Pyramidal neuron loss is a feature of AD GluR5 agonists, by increasing the inhibitory tone, (Morrison and Hof, 1997), and glutamatergic might paradoxically be protective, under conditions pyramidal neurons account for many of the neurons that remain to be clarified (Khalilov et al., 2002). lost in the cerebral cortex and hippocampus in AD (Morrison and Hof, 1997). Similarly, a large It has been reported that the mGluR1 antagonist decrease in glutamate receptors has been observed in LY456236 and mGluR5 antagonist MPEP are the hippocampus (Greenamyre et al., 1987; effective as antiepileptic in mice (Barton et al., Procter et al., 1989) and cortex (Greenamyre et al., 2003; Shannon et al., 2005). Another mGluR1 1985) of the brains of AD patients presumably due in antagonist, BAY36-7620 has been shown to inhibit part to the accompanying neuronal loss described PTZ seizures but failed to provide protection against above. Subsequent reports of subunit-specific kindled seizures (Chapman et al., 2000; Spooren et abnormalities in the expression and pharmacological al., 2003). However, it should be pointed out that the properties of NMDA receptors (Hynd et al., 2004; use of either mGluR1 and mGluR5 antagonists may Procter et al., 1989) and mGluR (Albasanz et al., be connected with possible learning impairing 2005) suggests these changes do not simply reflect effects (Steckler et al., 2005). generalized cortical atrophy, but may indicate disease-specific processes. Abnormalities in AMPA Several reports indicate potential anticonvulsive receptor expression have also been observed in the utility of metabotropic group II agonists. The AD (Wakabayashi et al., 1999), while KA receptors orthosteric agonist LY354740 has been shown to seem to be unaffected (Cowburn et al., 1989). attenuate clonic convulsions produced by PTZ or picrotoxin, but not by NMDA (Klodzinska et al., In addition to the consequences of glutamatergic 2000). Moreover, the GluR2/3 agonists LY379268 cell loss there is evidence for dysfunction in and LY389795 inhibited sound-induced clonic remaining neurons. Where, the ability of glial cells seizures in mice (Moldrich et al., 2001). However, to remove glutamate from the synaptic cleft was these agonists did not inhibit sound induced seizures impaired in several brain regions (Procter et al., in genetically epilepsy-prone rats, but were even pro- 1988). Similarly there was a reduction in the convulsant following the sound stimulus (Moldrich vesicular glutamate transporter in parietal but not et al., 2001). Little is known about the role of group temporal cortex (Kirvell et al., 2006) and the III metabotropic receptors due to the very limited activity of this protein was lower in AD temporal number of selective ligands. In principle, cortex than in controls (Westphalen et al., 2003). As anticonvulsive effects could be expected from either a consequence of these alterations ,it has been agonists or positive modulators. ACPT-I proposed (Francis, 2003) that in AD there is (preferential mGluR4 agonist) inhibited sound inadequate removal of glutamate in the synaptic cleft convulsions in mice and rats (Chapman et al., 2001) between the pre and postsynaptic neuron, creating an which indicate that mGluR4 may be a candidate for excessive level of background “noise” at glutamate anticonvulsive therapy. receptors within the synapse and adversely affecting the ability of the NMDA receptor to generate LTP 4.4. Alzheimer’s disease (Danysz et al., 2000). This disruption of Alzheimer’s disease (AD) is an irreversible glutamatergic neurotransmission may contribute to neurodegenerative disease causing dementia severe cognitive impairment in AD (Francis, 2003). enough to hamper daily living. Both Furthermore, the pathologic glutamate acting at all neuropathological and neurochemical studies of the classes of glutamate receptors can cause neuronal AD brain have shown that degeneration of glutamate P-53 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 death or at least can be a contributory factor in AD. (Danysz et al., 2000). 4.5. Parkinson’s disease Parkinson’s disease (PD) is a common neurodegenerative disorder Several approaches to correct glutamatergic characterized by severe motor impairments such as dysfunction in AD have been attempted, including bradykinesia, tremor and rigidity. These motor positive modulation of both AMPA and NMDA symptoms arise as a consequence of a progressive receptors. AMPAKines, which are considered to loss of dopaminergic neurons in the substantia nigra, work by increasing the sensitivity of these receptors, which project into the striatum regulating activity were in clinical trial for mild cognitive impairment through the basal ganglia (Hassler, 1938). (Johnson and Simmon, 2002), but no drugs have yet come to the clinic. Modulation of the NMDA Glutamatergic pathways to the striatum and basal receptor has been also attempted via the glycine co- ganglia output nuclei become overactive in agonist site with clear indication in preclinical Parkinson’s disease owing to the depletion of studies that the partial agonist D-cycloserine nigrostriatal dopamine. Glutaminergic neurons improved learning and memory (Myhrer and themselves do not appear to degenerate in Paulsen, 1997). Clinical studies have suggested Parkinson’s disease ,however NMDA receptors have some benefit but full-scale trials have not been been implicated in mediating excitotoxicity in the initiated (Schwartz et al., 1996). basal ganglia, a process that has been linked to dopaminergic neuronal cell death in PD. There is Since NMDARs are the primary mediators of some evidence that blocking glutamate input to the glutamate mediated excitotoxicity, one line of striatum with NMDA receptor antagonists reverses therapeutical research has focused on the akinesia (Uyama et al., 1991), improves development of NMDAR antagonists for treatment parkinsonian motor symptoms and improves of AD. One would normally consider that such an dyskinesia (Blanchett et al., 1996). approach , blockade of a receptor that would normally be activated in learning and memory , Amantadine, is an NMDA receptor antagonist, would be counter-intuitive. However, the most that is accepted for treatment of Parkinson’s disease. surprising development is the success of the non- Originally being found to be remarkably effective in competitive NMDA antagonist memantine (1-amino- treating the motor symptoms of the disorder in a 3,5-dimethyladamantane) in clinical trials in patient taking it as a flu prevention agent. A number moderate and severe AD (Parsons et al., 2007). of reports followed which described the benefit of Memantine could decrease pathological activation of the drug in terms of symptomatic improvement, time NMDA receptors without affecting physiological of response to the medication, and the coprescribing NMDA receptor activity (Scarpini et al., 2003). As of L-DOPA (Schwab and England, 1995; Factor this molecule acts like magnesium ions, able to et al., 1998). Where improvement in levodopa- prevent background activation of the NMDA induced dyskinesias were reported (Blanchet et al., receptor (“noise”), whilst allowing activation of this 1998),but no studies specifically examined receptor for LTP formation (Francis, 2003; Parsons cognition. Side effects of the drug include ankle et al., 2007). Most importantly, clinical trials have edema, insomnia, nausea, restlessness and in some shown that memantine treatment leads to substantial cases psychosis. There have also been some reports increases in cognitive function relative to placebo in of worsening of cognition and withdrawal delirium AD patients with severe dementia (Winblad and with the use of amantadine in PD (Cash et al., Poritis, 1999; Kirby et al., 2006), and it is well 1987). tolerated (Winblad and Poritis, 1999). On the basis of successful clinical trials, the use of memantine in Pharmacological studies using NR2B receptor the modulation of glutamatergic function may antagonists in several animal models further support therefore represent a novel approach for the a role for this subtype in Parkinson’s disease (Nash treatment of AD. et al., 2004). Ifenprodil showed efficacy in a P-54 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 reserpine-treated rat model of Parkinson’s disease antagonists, such as GYKI-47261 and the non- (Nash et al., 1999). However, a small clinical trial in competitive inhibitor talampanel, have entered into which ifenprodil was used as an add-on therapy with clinical trials as potential neuroprotectants in PD. L-DOPA in Parkinson’s disease patients failed to Conversely, several strategies have been used to demonstrate significant therapeutic benefit potentiate AMPA receptor function, with a view to (Montastruc et al., 1992). Traxoprodil has been providing cognitive enhancement and neurotrophic shown to reduce rigidity and akinesia in both rodent effects (O’Neill et al., 2004b). and non-human primate Parkinson’s disease models (Steece-Collier et al., 2000). These preclinical data, 4.6. CNS injury taken together with results from clinical studies of Primary traumatic brain injury is a direct result of NMDA antagonists, suggest that NR2B-selective the initial insult, that is complete at the time of antagonists hold therapeutic utility as presentation, and cannot be altered. Secondary antiparkinsonian agents. traumatic brain injury is an alteration of brain tissue, either anatomic or physiologic, which occurs Targeting mGlu receptors is another interesting subsequent to the primary injury (Leonard and possibility for treatment of PD. Recent evidence Kirby, 2002). Secondary injury may include edema suggests that profound alterations in depotentiation, and elevations of intracranial pressure (Chen and a process that probably utilizes mGlu receptors could Swanson, 2003). Traumatic brain injury has been underlie dyskinesia (Picconi et al., 2003). The shown to cause marked elevation in glutamate mGlu4 orthosteric agonist LSP1-2111 has concentrations, which is responsible through demonstrated efficacy in rodent models of PD, excitotoxicity for neuronal injury or death, making specifically reversal of haloperidol-induced secondary injury as potentially lethal as primary catalepsy and 6- hydroxydopamine-induced motor injury (Leonard and Kirby, 2002). Recently, deficits (Beurrier et al., 2009). This has been linked growing evidence has suggested that apoptosis to the inhibition of striato-pallidal GABAergic significantly contributes to central neuronal death transmission through mGlu4 activation (Cuomo et following head trauma. NMDA receptor activation al., 2009). However, positive allosteric modulators as well as AMPA receptor activation have been have several advantages over orthosteric agonists. N- implicated in the initiation of apoptosis following phenyl-7-(hydroxylimino) cyclopropa[b]- chromen- trauma (Bullock et al., 1998; Wada et al., 1999). 1a-carboxamide (PHCCC) was the first selective Sustained intracranial pressure elevations and poor mGlu4 positive allosteric modulator with high patient outcome have been significantly associated selective potentiation on mGluR4, and with no direct with high levels of CNS glutamate in humans agonist activity and no potentiator activity at any (Bullock et al., 1998). It was proposed that failure of other mGluR receptor subtype (Marino et al., 2003). the high affinity uptake system of glutamate is the This compound was originally identified as an cause for its high concentrations following trauma to allosteric antagonist of mGluR1. PHCCC increases the nervous tissue (Bullock et al., 1998). Essentially, the potency of glutamate in recombinant systems as transporter-mediated glutamate homeostasis fails well as at several synapses including the striato- dramatically in ischaemia: instead of removing pallidal synapse (Marino et al., 2003; Valenti et al., extracellular glutamate to protect neurons, 2005). Moreover, PHCCC decreases reserpine- transporters release glutamate, triggering neuronal induced akinesia (Marino et al., 2003). Clearly, death (Rossi et al., 2000). Several studies using there is much promise for the development of mGlu4 tissue cultures or intact animals provided evidence positive allosteric modulator as novel therapeutics that the accumulation of synaptically released for PD. glutamate was responsible for anoxic cell death, and that the removal of glutamatergic excitatory input Another prime target in treating PD is the AMPA reduced ischaemic damage. receptor, which mediates most fast excitatory Blockade of NMDA receptors attenuates synaptic transmission in the brain. AMPA receptor ischaemic damage in the brain (Simon et al., 1984). P-55 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012

Studies showing that high levels of glutamate are accompanying cardovascular interactions. maintained for many hours during prolonged focal Traxoprodil and Ro 25-6981 exhibit greater ischemia and that NMDA receptor antagonists are selectivity for NR2B over other receptor subtypes protective when administered either before or during and ion channels, suggesting a reduced probability of focal ischaemic insult support this hypothesis cardiovascular side effects (Chenard and Menniti, (Parsons et al., 1998). For example, the non- 1999; Mutel etal., 1998). Clinical trial data for competitive NMDA open channel blocker traxoprodil show that it is well tolerated, with none memantine was recently shown to be neuroprotective of the side effects typically seen with non-selective without adverse side-effects in animal models of NMDA antagonists (Saltarelli et al., 2004). CNS ischaemia (Rao et al., 2001). Additionally, However, the efficacy results for traxoprodil in the NMDA receptor antagonist MK-801, was effective acute ischemic cortical stroke trial were somewhat in ameliorating the effects of CNS trauma (Yum and disappointing (Saltarelli et al., 2004). Faden, 1990). Based on these very positive, if in hindsight misleading (Gladstone et al., 2002), Owing to the signal transduction coupling and preclinical data, where NMDA antagonists proved to synaptic localization of mGluR subtypes, be very effective neuroprotective drugs in vitro and antagonizing the postsynaptic excitatory group I in animal models of stroke, traumatic brain injury mGluRs should have a protective effect whereas and spinal-cord injury, clinical trials of NMDA activation of the presynaptic inhibitory group II or antagonists were initiated. However, sequentially the III mGluRs should be required. Indeed, this concept clinical trials were terminated based on efficacy and has been demonstrated with several orthosteric group side effects (Kemp and McKernan, 2002; Muir, I mGluR antagonists. After spinal cord contusion 2006). Failure may be due to deficient injury, injections of the mGluR group I antagonist pharmacokinetics with the plasma levels achieved in AIDA into the lesion site improved early locomotor studies consistently below those needed for maximal recovery (Mills et al., 2002a). mGluR1 antagonists neuroprotection in animal models (Kemp and have also proved protective in traumatic brain injury McKernan, 2002). Moreover, NMDA antagonists models. AIDA administration after lateral fluid have a number of mechanism-based adverse CNS percussion in rats significantly improved neuro- effects, including hallucinations, a centrally scores (Faden et al., 2001), as well as reducing mediated increase in blood pressure and, at high overall neuronal cell death (Lyeth et al., 2001). doses, catatonia which have limited the doses used Furthermore, the mGluR1 antagonist YM-202074 is clinically (Kemp and McKernan, 2002). Together, neuroprotective after cerebral ischemia (Kohara et it seems unlikely that nonselective channel blockers al., 2008). will ever pass the safety hurdles to receive approval for widespread use (Kemp and McKernan, 2002; Additionally, mGluR5 agonists have shown Muir, 2006). antiapoptotic properties in neuronal cultures (Vincent et al., 1999; Allen et al., 2000). Although However, several NR2B receptor selective a number of reports indicate that treatment with the antagonists have been evaluated in animal models of specific mGluR5 agonist CHPG is neuroprotective in ischaemic brain injury, and it was proven to be vitro and in vivo (Lea et al., 2002; Deng et al., effective. Several studies using rat, cat and mouse 2004), treatment with the mGluR5 antagonist MPEP middle cerebral artery occlusion models show that may also provide neuroprotection. The fact that the ifenprodil reduces infarct volume in a dose-related group I receptors mGluR1 and mGluR5 have similar manner in the absence of hypothermia (Wang and signaling pathways and intracellular effects led to the Shuaib, 2005). However, ifenprodil and its analogue theory that inhibition of mGluR5, similar to eliprodil are also antagonists of α1-adrenergic mGluR1, would be neuroprotective. Indeed, receptors, serotonin receptors and calcium channels, administration of MPEP significantly reduced suggesting that the therapeutic effectiveness of these neuronal death after glutamate or NMDA exposure compounds might be compromised by (O’Leary et al., 2000). This apparent confusion P-56 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 regarding mGluR5 agonists and antagonists was spinal sensitization and secondary hyperalgesia in resolved by work of Lea et al., 2005 who first degree burn models can be prevented by definitively showed that neuroprotective actions of pretreatment with intrathecal AMPA/kainate the mGluR5 antagonists MPEP or MTEP do not receptor antagonists NBQX or CNQX (Pogatzki et reflect actions at the mGluR5 receptor. Instead, al., 2000; Nozaki-Taguchi and Yaksh, 2002). MPEP acts to directly inhibit NMDA receptor Agents that selectively block calcium permeable signaling, and application of the antagonists in AMPA/kainate receptors, such as philathotoxins or cultures lacking the mGluR5 receptors (mGluR5 joro spider toxin, indicate also a role for this type of knockouts) yields the same neuroprotective effects receptor in secondary mechanical allodynia resulting as in cultures from wild-type animals. from thermal injury (Sorkin et al., 1999), and incisional pain (Pogatzki et al., 2003). The Moreover, group II and III mGluRs provide involvement of these may extend to neuropathic pain neuroprotection against models of CNS damage, models such as the chronic constriction injury such as spinal cord injury, traumatic brain injury, or model, where intrathecal AMPA/kainite receptor excitotoxic injections (Mills et al., 2002b). As antagonists appear to block nerve-induced thermal activation of group II and III receptors reduces hyperalgesia and mechanical allodynia (Garry et al., glutamate release and GABAergic transmission in 2003). All of these data suggest a potential role for neurons (Pinheiro and Mulle, 2008). Thus this receptor in pathological pain signaling and the potentially reducing excitotoxic cell death. The potential utility of AMPA receptor antagonists as group II agonist LY379268 reduced neuronal loss in therapeutic treatments for chronic pain conditions. A the hippocampus after global ischemia and key challenge to this therapeutic approach will be application of LY379268 up to 2 h after occlusion dissociating the well-known side-effects of AMPA was neuroprotective in a rat model of focal ischemia receptor antagonists, including ataxia and sedation, (Bond et al., 1999). from their analgesic actions. When considering allosteric modulators, the In addition to the animal data for the role of positive mGluR4 modulator, PHCCC has also shown NMDA antagonist in pain some clinical observations neuroprotection in vitro (Maj et al. 2003) but it with medicines that are known to block NMDA should be kept in mind that this compound also receptor activation are observed. Thus, low-dose antagonize group I mGluRs.. ketamine reduced chronic pain associated with spinal cord injury (Eide et al., 1995) and could reduce pain 4.7. Pain in patients with peripheral nerve injury and with Chronic pain is now thought to involve plastic peripheral vascular disease (Felsby et al., 1996; changes resulting from sustained electrical activity. Eisenberg and Pud, 1998). Amantadine was proven An accumulating body of evidence supports the to significantly reduce pain in cancer patients and in notion that modulation of glutamate receptors may those with trauma-induced neuropathic pain (Pud et have potential for therapeutic utility in several al., 1998). On the other hand, NR2B subunit- categories of persistent pain, including neuropathic selective compounds as, Ifenprodil, traxoprodil and pain resulting from injury and/or disease of central Ro 25-6981 are effective in inflammatory and/or (e.g., spinal cord injury) or peripheral nerves (e.g., neuropathic pain models in animals at doses that are diabetic neuropathy) and inflammatory or joint- not accompanied by motor effects (Chizh and related pain (e.g., rheumatoid arthritis, osteoarthritis) Headley, 2005). In addition, traxoprodil (Dougherty and Willis, 1991). demonstrated efficacy in a randomized, double- Evidence in support of a therapeutic potential for blind, placebo-controlled crossover trial in patients AMPA receptor antagonists in chronic pain states with neuropathic pain (spinal cord injury) without comes from studies implicating a role for AMPA producing side effects typically associated with non- receptors in nociceptive signaling, as well as the selective NMDA antagonists (Sang et al., 2003). For actions of selective compounds in animal models of that NR2B antagonists hold promise for therapeutic persistent pain. For example, the development, of intervention in pain states, particularly given their P-57 Pharmaceutical Science Pharmacology Review rticle ISSN 2250-0480 Vol 2/Issue 1/Jan-Mar 2012 potential for efficacy with reduced liability of persistent inflammatory pain conditions. For psychomotor effects. example, local infusion of the selective group I mGlu In addition to NMDA receptor inhibitors, the receptor antagonists (AIDA or LY367385) into the prominence of functional kainate receptors and the spinal cord attenuates the development and GluR5 subunit in dorsal root ganglia suggests that maintenance of thermal hyperalgesia induced by this might also be a target for chronic pain. A kaolin/carrageenan injection into the knee joint selective GluR5 antagonist LY382884 that has poor (Zhang et al., 2002). In addition, intrathecal affinity for AMPA receptors and for GluR6 showed administration of selective mGlu5 receptor analgesic activity in the rat formalin model (Palecek antagonists reduces mechanical hypersensitivity to et al., 2004). Another decahydroisoquinoline, subdermal hindpaw injection of capsaicin in rats LY466195, has also been shown to be effective in (Soliman et al., 2005). Collectively, these data these animal models of migraine (Weiss et al., demonstrate that group I mGlu receptor antagonists 2006). can have analgesic effects in multiple models of Also antagonism of mGlu1 receptors may provide inflammatory pain. a useful therapeutic strategy for treatment of

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