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Home , Acetylcholine receptor, Adrenergic antagonist, Altanserin, Amperozide, BIMU8, Chlorophenylbiguanide

DRIVING RESEARCH FURTHER

, - 3 2+ 2 , receptors. 3 1F adrenoceptor). 2 , and 5-HT β 1e , 5-ht 1D and the 4 receptors), RNA editing (the 5-HT (the editing RNA receptors), 7 Numerous 5-HT receptor families Receptor Family , 5-HT 1 1 1B receptor, receptor and the Zn , 5-HT A and 5-HT and 1A 4 receptor), and the putative formation of homo- and heterodimers (5‑HT The 5-HT This family consists of five separate gene products: 5-HT a Cys-loop -gated channel (LGIC) that in evolutionary terms arose independent of the GPCR 5-HT receptors along with other receptor, nicotinic the (e.g. members superfamily of this GABA is generated through alternative splicing (e.g. 5-HT 5-HT nervous systems, and also gastrointestinal as the including a tissues, local other numerous in tract, the cardiovascular system and immune cells. This multiplicity of function implicates 5-HT in a vast array of physiological and pathological processes. This plethora of roles has consequently encouraged the development of many compounds of therapeutic , various including value, and . Part of the ability of 5-HT to mediate a wide range of actions arises from the imposing HT number of receptors. 5- and subtypes have evolved. Currently, are recognized 18 as being responsible genes for 14 distinct mammalian 5-HT receptor divided subtypes, into 7 which families, are all members of the G-protein coupled receptor (GPCR) but one of which superfamily. The are exception is the 5-HT activated receptor). Further receptor heterogeneity Introduction 5-hydroxytryptamine ) (5-HT, is an ancient biochemical manipulated through evolution utilized to be extensively throughout plant the kingdoms. animal Mammals within and employ the central 5-HT and peripheral as a 2 2 3 3 3 4 4 5 5 5 7 8 9 1 1 2 11 10 12 13 10 Tocris Bioscience Scientific Review Series Department of University , of Washington, 98104 Seattle, USA. WA 2 and John F. Neumaier and John F...... Neuronal 5-HT 5-HT Neuronal . 1 ...... Receptors and SERT and Receptors Receptors Receptor Receptor Receptor Receptor Family Receptor Family 6 7 3 4 2 1 Receptors Receptors Receptors Receptors Receptors Receptors Receptors Receptors 5 Receptors 2A 2B 2C 1D 1F 1A 1B 1e 5-HT 5-ht 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT Cellular and Molecular Research Group, Section of Neuropharmacology and

References 5-HT Receptor Compounds The 5-HT Transporter (SERT) The 5-HT Transporter Conclusion The 5-HT The 5-ht The 5-HT The 5-HT The 5-HT The 5-HT Introduction The 5-HT Contents Sciences and Director of the Division of at the University of Washington. His research concerns the behavior. role of serotonin receptors in emotional Correspondence: [email protected] and [email protected] Correspondence: Nicholas Barnes is Professor of Neuropharmacology at the University of Birmingham Medical School, and focuses on serotonin receptors and the . John Neumaier is Professor of Psychiatry and Behavioural 1 Edgbaston, Birmingham, of University School, Medical The Medicine, Experimental and Clinical Neurobiology, Birmingham B15 2TT UK and Nicholas M. Barnes Nicholas M. Tocris Bioscience Scientific Review Series

Previously, some of these were thought to be species- ligands include some of the atypical , specific homologs (e.g. 5-HT1B receptor in and which have partial or neutral antagonist

5-HT1D receptor in ), but the genes for each activity and , a that is used of these receptors are now known to be present in for generalized anxiety disorder. 5-HT1A receptor every mammalian species examined so far. Each is partial are clinically useful encoded by a single, intron-less reading frame and drugs and may act on the to reduce they share considerable sequence homology. All activity, whereas 5-HT1A receptors of these receptors couple to Gi/o to inhibit adenylyl in the have been implicated in the cyclase and reduce cAMP levels, but additional signal mechanism of antidepressant action (by facilitating transduction mechanisms have also been described. ) and in regulating the hypothalamic- While their gene structure and molecular properties pituitary-adrenal axis. Other physiological effects of are similar, important cellular differences and distinct CNS 5-HT1A receptor activation include hypothermia, 1 patterns of regional expression in the body underlie hyperphagia, and . 5-HT1A divergent physiological features. Several of these receptor knockout mice have heightened anxiety and receptors are well known as autoreceptors that may exhibit diminished -like features.4,5 As regulate the excitability of serotonin and the with the other serotonin receptors this may involve release of serotonin,3 but also they are expressed receptor actions during early development as in nonserotonergic neurons, where they can have well as during processing of emotional experience analogous effects on other . in the adult. A number of highly selective ligands for 5-HT receptors have been developed, although it 5-HT Receptors 1A 1A should also be noted that some of these share affinity 5-HT1A receptors are distributed broadly in the CNS, for 5-HT7 receptors (e.g. 8-OH-DPAT) and others found in the soma, and in some cases for other 5-HT or 5-HT receptors. WAY 100635 the hillock of neurons, and the cell body and 1 2 has often been used as a highly selective 5-HT1A processes of . This receptor is expressed receptor neutral antagonist. and S-14506 by all serotonin neurons (as autoreceptors) and by are selective agonists. many nonserotonergic neurons (as ).

The electrophysiological effect of 5-HT1A receptor 5-HT1B Receptors activation on neurons is generally inhibitory and 5-HT1B receptors are also distributed broadly in the acts by reducing neuronal firing rate. A number of CNS in serotonergic and nonserotonergic neurons; highly selective ligands have been developed, and these receptors are predominantly translocated to they range from full agonists to partial agonists, axon terminals, so there is an anatomical mismatch antagonists, and inverse agonists. 5-HT1A receptors between the localization of mRNA and mature 5‑HT1B are thought to be therapeutic targets for several receptor protein. Historically the 5-HT1B receptor was neuropsychiatric disorders including anxiety, thought to be the analog of 5-HT1D receptors, but depression, and . Clinically used it is now clear that both receptors are present in all mammalian species examined and their regional distributions differ.6 β- antagonists have high affinity for 5-HT receptors in some but not all Figure 1A | 5-HT1A subtype-selective compounds 1B species. 5-HT1B autoreceptors have been found to

O reduce 5-HT synthesis and release and enhance H OH via the serotonin transporter. 5-HT N 1B N heteroreceptors inhibit the release of a range of N H O N N different neurotransmitters, depending on the N types that express them. Systemic administration of 5-HT receptor agonists have several behavioral 8-Hydroxy-DPAT (0529) (2854) 1B effects including increased locomotion, changes 5-HT1A agonist 5-HT1A partial agonist in brain reward mechanisms, and decreased , whereas selective antagonists may have F O 7,8 H some procognitive potential. The expression of O tBu OMe N N H these receptors in diverse and potentially competing N N sets of neurons may impact their utility as a clinical

target, although several 5-HT1B/D receptor agonists are H2N O effective as antimigraine treatments. 5-HT1B receptor knockout mice have been tested extensively and NAD 299 (3282) (S)-WAY 100135 (1253) have a distinct phenotype characterized by increased

5-HT1A antagonist 5-HT1A antagonist aggression and, in most cases, predisposition for -like behaviors. Their phenotype may

 | Neuronal 5-HT Receptors

however depend on compensatory changes in the 5-ht1e Receptors system during development rather than The lower case letters denote that this receptor has being due to decreased 5-HT1B receptor signaling in not been confirmed to have meaningful physiological adults. Several moderately selective agonists have functions in vivo. The existence of this receptor been developed, including CP 93129 and the more was originally postulated based on brain-penetrant CP 94253, and antagonists such as binding studies using brain homogenates, indicating

SB 224289 are used commonly to identify 5-HT1B that a 5-HT1-like receptor with low affinity for receptor-mediated responses. 5‑carboxamidotryptamine could be demonstrated. 5-HT Receptors It is now clear that several binding sites might have 1D contributed to this observation. The gene sequence 5-HT receptors are expressed at more modest 1D for the 5-ht receptor has been cloned from a levels than 5-HT receptors in the brain, but the 1e 1B placental library and guinea pig brain genomic DNA largest extent of expression seems to be in the raphe but was undetectable in rat and mouse.12 There have nuclei. Similarly, 5-HT receptor binding sites are 1D been few pharmacological studies of this receptor in present at a lower level than 5-HT receptor binding 1B rodents or in human tissue, but it was detected by sites in most brain areas.9 Most evidence, using RT-PCR in various brain regions of guinea pig and in 5‑HT receptor knockout mice as controls, indicates 1B the human and monkey brain by in situ hybridization.6 that terminal serotonin activity in the Furthermore, no highly selective ligands have been forebrain is of the 5-HT receptor type,10 but there 1B developed, although a number of typical 5-HT may be somatodendritic 5-HT autoreceptors that 1 1D receptor agonists and antagonists display modest regulate serotonin release within the .11 affinity at these receptors in heterologous expression The dilemma for most putative selective 5‑HT 1D systems. A recent method for labeling 5-ht binding receptor ligands is that they have high affinity for 1e sites in guinea pig was recently described and may more than one receptor, usually either the 5-HT 1B be a useful strategy for modeling human 5-ht or 5-HT receptors, but often not both, allowing 1e 1A receptors.13 The physiological significance of this combinations of drugs to achieve conditions that receptor therefore remains uncertain. are reasonably selective for activation or inhibition of 5‑HT1D receptors. Interestingly, has 5-HT1F Receptors

~100‑fold higher affinity for human 5-HT1D than The 5-HT1F receptor has been detected in multiple 5‑HT1B receptors, but it has the highest affinity for species and has been cloned from human, rat, guinea 5-HT2A receptors. pig, and mouse genomes. Like other members

of the 5-HT1 receptor family, this receptor inhibits

via a Gi-dependent mechanism. It is expressed at modest levels in the CNS in both Figure 1B | 5-HT1 subtype-selective compounds serotonergic and nonserotonergic cell bodies where it acts as both an autoreceptor and , respectively. Like 5-HT receptors, 5-HT is F 1B 1F

H expressed in trigeminal ganglion and vestibular Me2N N N nuclei neurons and has a high affinity for N O O N drugs that are useful for the treatment of H MeHN OMe . The relative contribution of each of these O two receptors to pain relief in migraine has not been resolved. It is possible that less selective agonists LY 344864 (2451) PNU 109291 (2556) that can potentially activate multiple 5-HT1 receptors 5-HT1F agonist 5-HT1D agonist (e.g. 5-HT1B/D/F subtypes, such as the ‘’) may relieve migraine via multiple mechanisms; therefore, more selective drugs may Me N have distinct clinical and profiles. Me O For example, the relatively selective 5-HT1F receptor N agonist LY 334370, which has ~100-fold higher N O affinity for 5-HT1F over 5-HT1B receptors, is active in O NH animal models of anti-migraine activity but seems to O N act on the trigeminal nucleus rather than through a N 14 Me N vascular mechanism. To date, no selective 5-HT H 1F antagonists have been identified. SB 224289 (1221) CP 94253 (1317)

5-HT1B antagonist 5-HT1B agonist

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Table 1 | Summary of the structure, and function of mammalian 5-HT1 receptors

Receptor 5-HT1A 5-HT1B 5-HT1D 5-ht1e 5-HT1F Human Gene 5q11.2–q13 6q13 1p34.3–36.3 6q14–q15 3q11 Structure GPCR GPCR GPCR GPCR GPCR ↓cAMP Transduction System ↓cAMP ↓cAMP ↓cAMP ↓cAMP G-protein coupled- K+ current 8-OH-DPAT Sumatriptan LY 344864 Agonists (R)-UH301 PNU 109291 - L 694247 LY 334370 U 92016A L694247 WAY 100 635 GR 55562 BRL 15572 Antagonists (S)-UH301 SB 224289 - - SB 714786 NAD 299 () SB 236057 ↓5-HT ↑Acetylcholine ↓Acetylcholine Effect on ↑Noradrenaline ↓Glutamate - - ↓Glutamate ↑Dopamine ↓Dopamine Depression Depression Anxiety/stress Anxiety Therapeutic Target Panic Aggression Migraine - Migraine Aggression Migraine Cognition addiction

The 5-HT2 Receptor Family structural conformations which have been resolved by X-ray crystallography in some cases. Structure- The 5-HT2 family has three members, 5-HT2A, 5‑HT2B activity models have also been tested using site and 5-HT2C receptors. Their pharmacological significance is substantial due to both the clinical directed mutagenesis. A great deal of biophysical importance and complex pharmacological features information has been generated using molecular strategies and heterologous expression of 5-HT of these receptors. 5-HT2 receptors were originally 2A posited based on an important study by Gaddum and receptors. Furthermore, simultaneous analysis of Picarelli in 1957.15 Using a guinea pig ileum multiple mechanisms in cell contraction bioassay, they observed two classes of culture systems has shown that the same ligand ‘’ receptors (namely ‘M’ and ‘D’) that may have differing degrees of for the activation of different second systems correspond to 5-HT3 and 5-HT2 receptors in current by the same population of 5-HT receptors.17 This nomenclature. Constituents of the 5-HT2 receptor 2A family share similar sequence homology, structural motifs, and overlapping pharmacology, although considerable ligand development has occurred and Figure 2A | 5-HT2A subtype-selective compounds highly selective ligands are available.16 Some of the notable features of these receptors include the prominence of inverse agonists, multiple signal OMe O transduction pathways, agonist-directed signaling NH2 O and important clinical roles in neuropsychiatric N Br .HBr N F conditions. Like 5-HT1 receptors, 5-HT2 receptors OMe have a seven-transmembrane domain motif but N O H couple to phospholipases C and A2. The relative efficiency of coupling to these effectors varies TCB-2 (2592) Ketanserin (0908) depending on the cell type being examined. 5-HT2A agonist 5-HT2A antagonist

5-HT2A Receptors

5-HT2A receptors are densely expressed in the HO2C O forebrain, especially the cortex, and are expressed O in both interneurons and pyramidal neurons. Various N O NMe OMe ligands display complex pharmacological patterns 2 of activity at 5-HT2A receptors, ranging from full to OH partial agonism, and from neutral antagonism to MDL 11,939 (0870) (3739) inverse agonistic behavior. These different activities 5-HT2A antagonist 5-HT2A antagonist are thought to reflect ligand stabilization of multiple

 | Neuronal 5-HT Receptors further supports the notion of complex and dynamic Figure 2B | 5-HT2B subtype-selective compounds structure-activity relationships for 5-HT2A and 5-HT2C receptors. 5-HT has relatively low affinity for the 5-HT receptor 2A Me H compared to other 5-HT receptors, with a Kd in the low N Me N N O NH2 micromolar range. It can be argued however that the S Me O high affinity, active conformational state has roughly O N N Cl H ten-fold higher affinity for 5-HT2A. Several agonists, such as DOI and LSD, have high affinity for 5-HT 2A BW 723C86 (1059) SB 242084 (2901) receptors and others demonstrate selective 5-HT2B agonist 5-HT2C antagonist for stimulating one signal transduction pathway over another (e.g. TCB-2). These, however are not CF3 particularly selective as they also bind to other 5-HT2 O H2N N receptors. Several well-characterized antagonists O S O N display high selectivity for 5-HT2A receptors, including HN O N ketanserin and MDL 100907. A number of others MeO OMe NH have high affinity but their specificity is not fully HN described. Some 5-HT2A receptor agonists produce O F effects (most famously LSD), and RS 102221 (1050) RS 127445 (2993) therefore several antipsychotic are high 5-HT2C antagonist 5-HT2B antagonist affinity 5-HT2A receptor antagonists.

5-HT2B Receptors

5-HT2B receptors are sparsely expressed in discrete date as those described also have affinity for other subregions of CNS, but are heavily expressed in , 5‑HT2 receptors. displays some selectivity , and the fundus of the . This for the 5-HT2C receptor, although there are no readily pattern of expression differs from 5-HT2A and 5-HT2C available sources for this molecule outside of custom receptors, which are expressed at relatively higher synthesis.20 levels in the CNS. They share affinity for many of The 5-HT3 Receptor the same drugs, but a few highly selective 5-HT2B receptor antagonists have been described, including The 5-HT3 receptor is the only 5-HT receptor that is RS 127445. The physiological role of 5-HT receptors a member of the Cys-loop ligand-gated 2B 21 is still unclear, but they have been implicated in family. The receptor complex is thought to be cardiac function, morphogenesis, and anxiety. 5-HT pentameric which is consistent with other Cys- 2B 22 receptors have similar signal transduction coupling loop LGIC family members. This complex may be formed by a combination of up to 5 different to other 5-HT2 receptors in vitro, but less evidence has accumulated for endogenous receptors. subunits, named 5-HT3A-E, although at present only the 5-HT3A and 5-HT3B subunits have been

5-HT2C Receptors studied in detail. The 5-HT3 receptor complex is a 5-HT2C receptors are strongly expressed throughout non-selective cation channel (most permeable to the CNS but are expressed at lower levels outside Ca2+, Na+ and K+ ) that mediates fast synaptic the brain. They are unique among the 5-HT receptors depolarizing neurotransmission in the brain and is because the mRNA transcript can be edited, leading prone to rapid desensitization. Recent attention has to subtle changes in coding sequence that can focused on the combination of subunits forming the have functionally relevant impacts on the mature functional channel in native tissue. Expression of 18 receptor protein. 5-HT2C receptor knockout mice the 5-HT3A subunit alone in recombinant systems have been generated which interestingly develop produces a functional receptor that displays many mid-life , glucose intolerance and seizures.19 characteristics of native receptors. The caveat is

The pharmacology of 5-HT2C receptors is similar that homomeric 5-HT3A receptors do not generate a to the other 5-HT2 receptors; they display complex relatively high single channel conductance receptor, interactions with signal transducing mechanisms, something that is evident in some populations of agonist directed signaling and inverse agonism by native neuronal receptors. Most significantly, co- some atypical antipsychotics. Evidence from animal expression of the 5-HT3A and 5-HT3B subunits models indicates that 5-HT2C receptors may impact results in a heteromeric receptor that mimics the high anxiety, appetite, addiction, and antipsychotic drug single channel conductance of some populations of 23,24 actions. SB 242084 is a fairly selective 5-HT2C native receptors more faithfully. In addition to 5‑HT, with anxiolytic activity. There 5‑HT3 receptor action is modulated allosterically by 25,26,27 are no highly selective 5-HT2C agonists developed to volatile and . The actions

www.tocris.com |  Tocris Bioscience Scientific Review Series of these compounds may, however, depend on the The majority of compounds investigated so far subunit composition of the receptor.28 appear unable to discriminate between molecular isoforms of the 5-HT receptor. A notable exception is Within the brain, the highest densities of 5-HT 3 3 , which displays weak (micromolar) affinity receptors are associated with the nuclei but good selectivity (approx. 100 -fold for homomeric encompassing the trigger zone; mouse 5-HT A versus heteromeric mouse 5‑HT AB namely the dorsal motor nucleus of the , 3 3 receptors).32 This has been demonstrated in functional and nucleus tractus solitarius.29 The recordings and the molecular interaction is likely to 5-HT receptor is also expressed in human forebrain 3 be a channel blockade of the 5-HT receptor rather regions including the hippocampus, and 3 than competition at the 5-HT . caudate-.30 Of note, expression within the extrapyramidal system (caudate-putamen [] Whilst the search continues for the identification and ) is not readily detectable in of compounds that discriminate readily between other species (such as rodents and/or non-human 5‑HT3 receptor molecular isoforms, a large number primates). of ligands exist that display high selectivity for the 5-HT receptor versus other neurotransmitter The 5-HT binding site within the 5-HT receptor 3 3 receptors. Initial examples of selective antagonists complex is constructed by two adjacent N-termini with nanomolar affinity arose in the 1980s with from neighboring subunits in the pentameric complex. compounds such as , and Structural analysis has identified that three (although the latter also has micromolar loops (designated A, B and C) contribute from the affinity for the 5-HT receptor). All three of these ‘principal’ subunit and a further three peptide loops 4 compounds were subsequently approved as drugs to from the ‘complementary’ subunit (D, E and F) reduce emesis ( and ). Subsequently participate in ligand binding. Hence, the initial report second generation compounds have been developed concerning the stoichiometry of the heteromeric such as and . These have 5‑HT AB receptor (with a subunit composition B- 3 very high affinity for the 5-HT receptor and have A-B-B-A) generated much debate concerning the 3 also gained regulatory approval as medicines; the potential to identify pharmacological compounds that former for (IBS), whilst the would discriminate homomeric 5-HT A receptors from 3 latter appears to display particularly long-lasting anti- heteromeric 5-HT AB receptors. The binding sites of 3 emetic actions. Indeed this long duration of action of the former would arise from A-A interfaces, whereas palonosetron would appear to be considerably more this structural interface was absent in heteromeric than would be predicted from its metabolic half-life 5‑HT3AB receptors. Recently, however, the B-A-B-B- 31 and some evidence suggests that this antagonist A stoichiometry has been questioned. 33 induces internalization of 5-HT3 receptors.

Table 2 | Summary of the structure, pharmacology and function of mammalian 5-HT2-3 receptors

Receptor 5-HT2A 5-HT2B 5-HT2C 5-HT3 11q23.1-23.2 (A) Human Gene 13q14–q21 2q36.3–2q37.1 Xq24 11q23.1 (B) 3q27 (C/D/E) Structure GPCR GPCR GPCR LGIC Ion conductance (K+, Na+, Transduction System ↑PLC ↑PLC ↑PLC Ca2+) DOI DOI 2-methyl 5-HT Agonists DOI BW 723C86 Ro 600175 SR 57227 Ro 600175 Lorcaserin m-chlorophenyl-biguanide RS 127445 Granisetron Ketanserin SB 242084 Antagonists SB 200646 Ondansetron MDL 100907 RS 102221 SB 204741 Tropisetron ↑5-HT ↑Glutamate Effect on Neurotransmission ?↓Dopamine ↑Dopamine ↑Dopamine ↓Acetylcholine Depression Emesis Anxiety Depression Anxiety Anxiety Schizophrenia Anxiety Cognition Therapeutic Target Obesity Cognition Sleep Disorder Drug Addiction Cognition Eating Disorders Migraine Analgesia Sleep Disorder Chronic Fatigue Syndrome

 | Neuronal 5-HT Receptors

In addition to antagonists, there are also high Figure 3 | 5-HT selective compounds affinity and selective agonists for the 5-HT3 receptor, 3 although these tend to be partial agonists similar to the non-selective exogenous agonist, 2-methyl-5‑HT. Some examples of partial agonists are pumosetrag O N (DDP733), PBG and mCPBG; SR 57227A is a good N Cl N N example of an exogenous near full agonist. NH2 N

Activation of the 5-HT3 receptor modulates release of various neurotransmitters, including a facilitation SR 57227 (1205) Ondansetron (2891) of dopamine, GABA and 5-HT release, although 5-HT3 agonist 5-HT3 antagonist the receptor is not thought to be expressed by 5‑HT 34,35 neurons. Conversely, the 5-HT3 receptor has O an inhibitory effect on acetylcholine release in the N O 36,37 cortex. This is likely to be mediated via GABAergic N N MeN 37,38 interneurons. N O N H H A number of 5-HT3 receptor ligands – including odansetron, granisetron, tropisetron and (2459) palonosetron – have now been exploited for Granisetron (2903) Tropisetron 5-HT3 antagonist 5-HT3 antagonist therapeutic benefit from their ability to alleviate the nausea and vomiting resulting from anticancer chemo- and radiotherapy and also post-operative emesis particularly evident following procedures predicted prokinetic action of a 5-HT3 receptor partial involving the abdomen.39 agonist, DDP733, was assessed; unfortunately the compound displayed relatively high levels of agonist A further therapeutic utility of 5-HT3 receptor ligands activity (intrinsic activity) such that the compound concerns the symptomatic relief from IBS. IBS is a caused emesis in some patients (predictable for 5- recognized heterogeneous condition, which, although HT3 receptor agonists with high intrinsic activity). not life-threatening, presents a considerable health and economic burden. The potent and selective The potential efficacy of 5-HT3 receptor antagonists to reduce behaviors likely to be mediated via the 5‑HT3 receptor antagonist, alosetron, displays clear efficacy in reducing the symptoms of IBS-d (IBS forebrain (for example anxiety, cognitive dysfunction, presenting with diarrhea). Marketing approval for this and -induced reward) is not fully understood. was withdrawn due to rare occurrences Indeed the initial potential of antagonists as therapies of potentially fatal ischemic colitis. This side-effect for these effects failed to translate in consistent was also noted – again at a relatively low incidence clinical findings. A potential explanation for this is the considerable differences apparent in the cellular – in the aborted trials of another 5-HT3 receptor antagonist, , suggesting this side-effect is and regional expression of the 5-HT3 receptor when not an ‘off-target’ phenomenon. The relatively high comparing laboratory animals (rodents and New World primates) with humans. Interestingly, some number of patients that have received 5-HT3 receptor antagonists to control emesis – without a single report effects of 5-HT3 receptor antagonists have been of ischemic colitis - suggests this side effect results identified in humans without prior identification in animal models including and chronic from the combination of 5-HT3 receptor antagonism and the IBS condition. fatigue syndrome.

Significantly, patient pressure assisted the The 5-HT4 Receptor reinstatement of alosetron, albeit with limited Consistent with other GPCRs, a functional 5-HT4 availability. In Japan, however, regulatory approval receptor protein arises from a single gene. Arising exists for the use of a very low dose of the mRNA, however, can can be alternatively spliced selective 5-HT3 receptor antagonist, within the region corresponding to the extracellular with a maximum daily dose of 10 µg. This very link between the fourth and fifth transmembrane low dose presumably reduces the occurrence of domain and the region corresponding to the ischemic colitis by limiting the degree of blockade C‑terminus. This produces ten isoforms – 5-HT4(a‑g), of the 5-HT3 receptor, although the levels of efficacy 5-HT4(hb), 5‑HT4(i) and 5-HT4(n) – although it is possible achieved by these low doses are open to question. that even more will become apparent. With the

An alternative pharmacological strategy targeting exception of the 5-HT4d receptor isoform, 5-HT4 the 5-HT3 receptor has also been evaluated for receptor transcripts are expressed in the brain. With IBS‑c (IBS presenting with ). Here the the role of the C‑terminus to facilitate subcellular

www.tocris.com |  Tocris Bioscience Scientific Review Series localization and to communicate receptor activation peptide that facilitates neuronal growth and enhances rather than impact pharmacology of the orthosteric functions in behavioral paradigms and site, it is not surprising that 5-HT4 receptor isoforms also ablates the cellular associated with do not tend to differ pharmacologically, although excessive transmission that can result 42 functional differences are apparent. in cognitive impairment. In addition, the 5-HT4 receptor may also enhance cognitive performance Expression of the 5-HT receptor is evident in 4 through of pyramidal cells within the the brain, gut and cardiovascular tissues. Within CA1 field of the hippocampus and hence promote the brain, protein and mRNA tend to colocalize the induction of hippocampal long-term potentiation indicating a post-synaptic location. Maximal levels (LTP), a cellular phenomenon regarded as a of expression are in the , including the neurophysiological basis of memory.43 substantia nigra, , , putamen, , hippocampus (CA1 The 5-HT4 receptor may also have a role in the 40 and subiculum) and cortex. generation of anxiety. 5-HT4 receptor antagonists have been shown to exhibit anxiolytic properties, The 5-HT receptor is positively coupled to adenylyl 4 whilst the 5-HT receptor knockout mouse exhibited cyclase via G , with receptor activation resulting 4 s abnormal responses to stress, whereby stress- in neuronal excitability, although coupling to ion induced hypophagia was attenuated in the knockout channels is also evident. Excitatory 5-HT receptors 4 mouse compared with the wild-type strain.44,45 enhance the release of a number of neurotransmitters Consistent with the dogma associating excessive including cortical acetylcholine, nigral-striatal 5‑HT function with anxiety, 5-HT receptor antagonists dopamine and hippocampal 5-HT. 4 decrease hippocampal 5-HT release. The 5-HT receptor is believed to have a role in 4 A number of drug tools are available to either learning and memory. Many studies have shown that antagonize or activate 5-HT receptors. Selective high 5-HT receptor activation improves performance in 4 4 affinity antagonists include GR 113808, SB 204070 various behavioral paradigms of cognitive function.41 and RS 100235, whereas non‑tryptamine selective The beneficial effects of 5-HT receptor activation may 4 agonists include RS 67506, ML 10302 and BIMU8. The be mediated by facilitation of acetylcholine release in tryptamine derivative agonist, 5-methoxytryptamine the . An alternative relevant process is also a potent, but non-selective agonist of the attributed to the 5-HT receptor relates to amyloid 4 5‑HT receptor. Some derivatives, such precursor protein (APP) . 5-HT receptors 4 4 as , display agonist actions. Cisapride promote secretion of sAPPα, a neuroprotective was marketed as a gastro-prokinetic before it was withdrawn due to cardiovascular side-effects,

consistent with the expression of 5-HT4 receptors

in atria. A further 5-HT4 receptor agonist, ,

Figure 4 | 5-HT4 and 5-ht5 compounds developed for IBS-c was withdrawn for similar reasons.

The 5-ht5 Receptors O F The 5-ht5 receptor subfamily contains two gene O O N products; the 5-ht5a and 5-ht5b receptors. Despite N OMe NHSO2Me Cl H being discovered nearly 20 years ago, they remain

NBu the most poorly understood 5-HT receptor subtypes. H2N OMe There is no conclusive evidence as to how they elicit second messenger responses in native tissue, RS 67333 (0989) GR 125487 (1658) despite their structural classification as GPCRs. The 5-HT4 partial agonist 5-HT4 antagonist lack of clear physiological roles for these receptor subtypes has necessitated lower-case appellation to emphasize their current status as merely gene NMe2 N products, contrasting with the upper-case notation O of a receptor with known cellular functions in native H N cells or tissues. O NH2 Of the two subtypes, the 5-ht receptor has received H2N 5a more attention, since the human 5-ht receptor N 5b H gene sequence is likely to be a pseudogene as it 5-CT (0458) SB 699551 (3188) contains stop codons within its open reading frame. 5-ht agonist 5-ht antagonist 5a 5a If the resulting truncated protein were expressed it

 | Neuronal 5-HT Receptors

46 is likely that it would lack functionality. The rodent The 5-ht5a receptor has also been implicated in

5-ht5b receptor, however, would appear capable of the regulation of rodent , although functional expression although little evidence has limited pharmacological tools to probe this receptor 53 been generated. 5-ht5b receptor mRNA in the rat brain complicates interpretation. The most promising is evident in the hippocampus, , entorhinal compound, SB 699551-A,54 displays a 30-fold 47 and piriform cortices, and the . selectivity for the human 5-ht5a receptor over other 5-HT receptor subtypes and other neuronal targets, Within heterologous expression systems, the aside from the serotonin transporter, which it impacts 5‑ht receptor may inhibit adenylyl cyclase activity, 5a at only 10-fold higher concentrations.54 Unfortunately, presumably via G,48,49 although other reports have i SB 699551-A displays inter-species variation in detected no such response.50 Alternative transduction affinity for the 5-ht receptor and displays relatively processes impacted by this receptor may include an 5a low affinity for rodent 5-ht receptors (pK = 6.3), increase in intracellular Ca2+ mobilization51 or coupling 5a i which further limits the utility of this compound to to an inwardly rectifying .50 investigate 5-ht5a receptor function through the The lack of suitable selective ligands has hampered common rodent paradigms. autoradiographic study of the 5-ht receptor. 5a 5-HT Receptors 5‑ht5a receptor protein expression in the rat brain 6 is associated with neurons, and is evident in the The 5-HT6 receptor is coupled to Gs to activate , raphe nuclei, , adenylyl cyclase and shows moderate affinity for horizontal nucleus of the diagonal band and amygdala, serotonin. It is strongly and selectively expressed in with more moderate immunoreactivity in the cerebral CNS but has species-specific patterns of expression cortex (particularly ), hippocampus, with rat and human showing intense expression in lateral habenula, substantia nigra, ventral tegmental striatum and hippocampus but about 1/10 of the area, pons and . In situ hybridization using expression level in mice and litter regional variation 55 tissue has demonstrated 5-ht5a receptor in different areas of the mouse brain. A 5-HT6 transcripts in the cortex, hippocampus, amygdala receptor knockout mouse has been developed but and cerebellum.52 the phenotypic relevance is unclear given the low levels of 5-HT receptor expression in wild-type mice Although no definitive role for native 5-ht receptors 6 5a as compared to rat or human.56 The rat and human has been identified, a few studies have suggested 5-HT receptor are more similar pharmacologically to putative functions. For instance, 5-ht receptor 6 5a each other than to the mouse receptor. The 5-HT knockout mice display enhanced exploratory 6 receptor has been found in animal models to offer behavior in response to a novel environment.46 promise as a target for cognitive enhancement and

Table 3 | Summary of the structure, pharmacology and function of mammalian 5-HT4-7 receptors

Receptor 5-HT4 5-ht5a 5-ht5b 5-HT6 5-HT7 2q11–13 Human Gene 5q31–q33 7q36 1p35–36 10q21–q24 (Non-functional) Structure GPCR GPCR GPCR GPCR GPCR ?↓cAMP Transduction System ↑cAMP ?Ca2+ mobilization Not Known ↑cAMP ↑cAMP ?K+ current BIMU 8 Agonists RS 67506 5-CT 5-CT - 8-OH-DPAT ML 10302 GR 113808 Ro 630563 SB 258719 Antagonists SB 204070 SB 699551-A - SB 271046 SB 269970 RS 100235 SB 357134 SB 656104 ↑Acetylcholine ↓Acetylcholine Effect on Neurotransmission ↑Dopamine Not Known Not Known ↓Dopamine ?↑↓5-HT ↑5-HT ↓Glutamate Cognition Depression Schizophrenia Schizophrenia Cognition Depression Therapeutic Target Not Known Not Known Sleep Disorder Anxiety Anxiety/Stress Epilepsy Cognition Obesity

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The 5-HT transporter (SERT) Figure 4 | 5-HT and selective compounds 6 7 The 5-HT transporter (SERT or 5-HTT) is a Na+/Cl- dependent biogenic transporter whose family includes the dopamine (DAT) and noradrenaline (NET) NH Cl transporters.61 SERT is critical to the functioning of Cl HN O O the 5-HT system, limiting 5-HT neurotransmission by N S N Cl removing synaptic neurotransmitter through transport H N OMe 62 H MeO across the presynaptic membrane. Following the original sequencing of rat SERT,63 subsequent EMD 386088 (2382) SB 399885 (3189) studies have indicated that the functional complex 64,65 5-HT6 agonist 5-HT6 antagonist may exist as an oligomer. Within the brain SERT is located throughout 5-HT MeN N O Me neurons, and hence displays a distribution at the O Me Me S protein level that closely matches the regions N N HO receiving 5-HT neuron innervation. Indeed, the protein offers a phenotypic marker for 5-HT neurons.66 NMe 2 Consistently, in situ hybridization studies AS 19 (1968) SB 269970 (1612) 5-HT agonist 5-HT antagonist demonstrate that SERT transcript expression is 7 7 associated with the cell bodies of 5-HT neurons.67 In the developing mouse brain however, expression possibly weight loss.57 EMDT, EMD 386088, and of the transporter occurs transiently in glutamatergic

WAY 181,187 are relatively selective 5-HT6 receptor thalamocortical afferents that lack the ability to agonists, and a number of selective antagonists synthesize 5-HT.68,69 These neurons may therefore have also been developed including SB 399885, sequester 5-HT, enabling the afferents to mediate SB 258585 and Ro 4368554. The less selective serotonergic transmission during brain ligands tend to also have high affinity for 5-HT2A development. and D2 receptors. A number of clinically important More than one form of SERT protein appears to antipsychotic and antidepressant drugs also share be present in vivo. Shigematsu and colleagues high affinity for this receptor along with their other conducted immunohistochemical studies on targets. the mouse brain with two selective antibodies, raised against different epitopes within the C- and The 5-HT7 Receptor N‑terminus.70 They observed that immunoreactivity 5-HT7 receptors also couple to Gs (activating adenylyl cyclase) and are widely distributed in with the N-terminal antibody was absent in the CA3 the brain.58 Several splice variants with different field of the hippocampus, whereas the C-terminal patterns of distribution within the CNS have been antibody indicated SERT expression. This implies identified,59 although they do not show meaningful that SERT may contain variable N-terminal domains, pharmacological distinctions in human isoforms.60 potentially though alternative splicing of exon 1. Several and antidepressant Further molecular diversity appears to be apparent drugs have sufficient affinity for this receptor and will in human immune cells, where SERT may function to deliver 5-HT to other immune cells across the occupy it at commonly used dosages. Some ligands 71 traditionally associated with other 5-HT receptors also immunological . bind to 5-HT7 receptors, especially those associated The efficacy of a range of antidepressant drugs, with 5-HT1A, 5-HT2A, and 5-HT6 receptors. A particular in particular the selective serotonin reuptake compound to note is the agonist, 8-OH-DPAT, a full inhibitors (SSRIs), has encouraged elucidation of agonist that has only about ten-fold higher affinity the physiological roles of SERT in the brain. It is for 5-HT1A than 5-HT7 receptors. 5-HT7 receptors indisputable that the transporter has an effect upon have been implicated in a variety of behavioral and depression, though its precise function is still debated. physiological processes, including affective behavior, Further evidence comes from the genetic variation circadian rhythmicity and . 5-HT7 receptor that occurs upstream of the SERT coding sequence, knockout mice have reduced immobility in the forced the so-called 5-HTT gene-linked polymorphic region swim test consistent with the pharmacological data (5-HTTLPR). A series of repeated units incorporated suggesting that blockade of this receptor can produce within this sequence forms a promoter region antidepressant effects. Several moderately selective regulating SERT expression.72,73 One common agonists have been reported, including AS 19 and polymorphism within this region is a 44 base pair LP 12; SB 258719 and SB 269970 are very selective deletion, denoted as a short form (S) for the gene, antagonists at 5‑HT7 receptors. along with two variations of a long form (LG and

10 | Neuronal 5-HT Receptors

LA). The short form allele reduces SERT expression field continues to expand both scientifically and and function relative to the long forms.72,74 It has commercially. Over the last sixty years, considerable been reported however, that LG may result in SERT physiological and pharmacological processes expression comparable with the short form variant75 involving 5-HT receptors and the 5-HT transporter and the short allele may not be associated with have been identified. The consecutive discovery of reduced SERT levels in the adult brain,76 complicating the 6 classes of G-protein coupled 5‑HT receptors the research area. Individuals carrying at least one (5-HT1,2,4-7) and their subclasses along with the short form allele appear predisposed to depressive ligand-gated ion channel 5-HT3 has provided an episodes. In further support from in vivo imaging, exciting research platform that holds promise for 77 SERT expression is reduced within the brainstem, future drug discovery. Both 5-ht5 and 5-ht1e receptors amygdala and midbrain78 in patients presenting with are relatively uncharacterized and the generation of depression. selective ligands for these receptors may well aid our understanding of their functions in vivo. One A number of reports correlate SERT expression of the most significant problems in this field has with the of victims although this area been the absence of sufficiently selective ligands to remains controversial.79 SERT knockout mice do identify the relative contribution of multiple serotonin however display behavioral abnormalities related to receptors to complex behavioral and physiological depression and anxiety.80,81 phenomena mediated by serotonin. As new In contrast to SERT being a molecular therapeutic molecular and pharmacological tools become target, it is also a target for various drugs of abuse, available, targeting specific 5-HT receptors should including MDMA (‘ecstasy’) and . MDMA, to the development of many compounds of for example, blocks 5-HT reuptake and enhances therapeutic value that will reduce the potential for 5-HT release.82,83 Whilst cocaine is predominantly undesired side effects. The future holds the promise considered to act upon DAT, SERT interaction for a new generation of serotonergic drugs that appears to contribute to the rewarding actions of may be useful as antidepressant, antipsychotic, cocaine.84 procognitive, and antiemetic treatments. It can be Conclusion anticipated that 5-HT receptor research will continue to progress and yield exciting results in the years to From the initial discovery of serotonin in the mid- come. twentieth century, the 5-HT receptor research

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12 | Neuronal 5-HT Receptors

65. Kilic and Rudnick (2000) Oligomerization of serotonin transporter and 76. Parsey et al (2006a) Effect of a triallelic functional polymorphism of the its functional consequences. Proc.Natl.Acad.Sci. USA 97 3106. serotonin transporter-linked promoter region on expression of serotonin 66. Qian et al (1995) Identification and characterization of antidepressant- transporter in the human brain. Am.J.Psychiatry 163 48. sensitive serotonin transporter proteins using site- specific antibodies. 77. Malison et al (1998) Reduced brain serotonin transporter availability J.Neurosci. 15 1261. in major depression as measured by [123I]-2β-carbomethoxy-3β-(4- 67. Fujita et al (1993) Cellular localization of serotonin transporter mRNA iodophenyl) and single photon emission computed tomography. in the rat brain. Neurosci.Lett. 162 59. Biological Psychiatry 44 1090. 68. Lebrand et al (1996) Transient uptake and storage of serotonin in 78. Parsey et al (2006b) Lower serotonin transporter binding potential in developing thalamic neurons. Neuron 17 823. the human brain during major depressive episodes. Am.J.Psychiatry 69. Bruning and Liangos (1997) Transient expression of the serotonin 163 52. transporter in the developing mouse thalamocortical system. Acta. 79. Purselle and Nemeroff (2003) Serotonin transporter: a potential Histochem. 99 117. substrate in the biology of suicide. Neuropsychopharmacology 28 613. 70. Shigematsu et al (2006) Novel non-uniform distribution of serotonin 80. Lira et al (2003) Altered depression-related behaviors and functional transporter in the mouse hippocampus and revealed by N- changes in the dorsal raphe nucleus of serotonin transporter-deficient and C-terminal domain-specific immunohistochemistry. Brain Res.1075 mice. Biol.Psychiatry 54 960. 110. 81. Zhao et al (2006) Insertion mutation at the C-terminus of the serotonin 71. Chamba et al (2008) Characterisation of the endogenous human transporter disrupts brain serotonin function and emotion-related peripheral serotonin transporter SLC6A4 reveals surface expression behaviours in mice. Neuroscience 140 321. without N-glycosylation. J.Neuroimmunol. 204 75. 82. Pletscher et al (1963) Decrease of cerebral 5-hydroxytryptamine and 72. Lesch et al (1996) Association of anxiety-related traits with a 5-hydroxyindolacetic acid by an arylalkylamine. Life Sciences 2 828. polymorphism in the serotonin transporter gene regulatory region. 83. Rudnick and Wall (1992) The molecular mechanism of “ecstasy” [3,4- Science 274 1527. methylenedioxymethamphetamine (MDMA)]: Serotonin transporters are 73. Greenberg et al (1999) Genetic variation in the serotonin transporter targets for MDMA-induced serotonin release. Proc.Natl.Acad.Sci. USA promoter region affects serotonin uptake in human blood platelets. 89 1817. Am.J.Med.Genet. 88 83. 84. Rocha et al (1998) Cocaine self-administration in dopamine transporter 74. Little et al (1998) Cocaine, ethanol, and genotype effects on human knockout mice. Nature Neurosci. 1 132. serotonin transporter binding sites and mRNA levels. Am.J.Psychiatry 155 207. 75. Hu et al (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive compulsive disorder. Am.J.Hum. Genet. 78 815.

5-HT Receptor Compounds Available from Tocris

5-HT1 Receptors 0553 NAN-190 hydrobromide 5-HT1A 5-HT antagonist Agonists 1A 0994 0556 BP-554 maleate 5-HT antagonist. Also β- Selective 5-HT agonist 1A/1B 1A 1060 (S)-(-)-Pindolol 1006 BMY 7378 dihydrochloride 5-HT antagonist. Also β-adrenergic antagonist. More active 5-HT partial agonist 1A/1B 1A enantiomer of pindolol (Cat. No. 0994) 0962 Buspirone hydrochloride 1516 SDZ 21009 5-HT partial agonist 1A β-adrenoceptor antagonist. Also 5-HT antagonist 0529 8-Hydroxy-DPAT hydrobromide 1A/1B 0631 Selective 5-HT agonist. Also has moderate affinity for 5-HT 1A 7 5-HT antagonist 1080 (R)-(+)-8-Hydroxy-DPAT hydrobromide 1A 1253 (S)-WAY 100135 dihydrochloride Selective 5-HT agonist. More active enantiomer of 8-Hydroxy-DPAT 1A Potent, selective 5-HT antagonist hydrobromide (Cat. No. 0529) 1A 0797 8-Hydroxy-PIPAT oxalate 5-HT1B High affinity 5-HT1A agonist Agonists 2399 hydrochloride 0703 Anpirtoline hydrochloride 5-HT1A, 5-HT1B and 5-HT2C agonist Highly potent 5-HT agonist. Also 5-HT antagonist 1869 1B 3 0638 CGS 12066B dimaleate Selective 5-HT1A agonist 5-HT agonist 0411 1B MDL 73005EF hydrochloride 1032 CP 93129 dihydrochloride Potent and selective 5-HT1A partial agonist 5-HT agonist 1746 1B 1317 CP 94253 hydrochloride Highly potent D2-like antagonist. Also 5-HT1A agonist Potent, selective 5-HT agonist 0912 1B RU 24969 hemisuccinate 3665 hydrochloride 5-HT1B/1A agonist 5-HT agonist 1771 1B/1D S 14506 hydrochloride 3862 hydrochloride Highly potent 5-HT1A agonist; displays unique binding mechanism Orally active, selective 5-HT agonist 2854 1B/1D Tandospirone hydrochloride 1860 hydrochloride Selective 5-HT1A partial agonist 5-HT receptor agonist/partial agonist 2739 1 U 92016A 2399 Indorenate hydrochloride Selective 5-HT1A agonist 5-HT , 5-HT and 5-HT agonist 1772 1A 1B 2C hydrochloride 0901 5-Nonloxytryptamine oxalate α 1 antagonist. Also 5-HT1A receptor agonist Selective 5-HT agonist 2491 1B Xaliproden hydrochloride 0912 RU 24969 hemisuccinate Orally active, high affinity 5-HT1A agonist 5-HT1B/1A agonist Antagonists Antagonists 2806 hydrochloride 0993 hemifumerate 5-HT1A antagonist 5-HT antagonist. Also β-adrenergic antagonist 3346 1A/1B ATC 0175 hydrochloride 1054 GR 55562 dihydrochloride MCH1 antagonist; also 5-HT2B antagonist and partial antagonist of 5-HT antagonist 5-HT 1B 1A 1477 GR 127935 hydrochloride 0993 Cyanopindolol hemifumerate Potent, selective 5-HT antagonist 5-HT antagonist. Also β-adrenergic antagonist 1B/1D 1A/1B 0992 hemifumarate 0933 MM 77 dihydrochloride 5-HT antagonist 5-HT (postsynaptic) antagonist 1B 1A 3350 LY 393558 3282 NAD 299 Dual 5-HT1B/1D antagonist and 5-HT re-uptake inhibitor Selective, high affinity 5-HT1A receptor antagonist

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1413 NAS-181 1985 PNU 142633

Selective rat 5-HT1B antagonist. Active in vivo Highly selective 5-HT1D agonist 0994 Pindolol Antagonists 5-HT1A/1B antagonist. Also β-adrenergic antagonist 1207 BRL 15572 hydrochloride 1060 (S)-(-)-Pindolol Selective human 5-HT1D antagonist 5-HT1A/1B antagonist. Also β-adrenergic antagonist. More active 1477 GR 127935 hydrochloride enantiomer of pindolol (Cat. No. 0994) Potent, selective 5-HT1B/1D antagonist 1242 SB 216641 hydrochloride 3078 LY 310762 hydrochloride Selective human 5-HT1B antagonist 5-HT1D-preferring antagonist 1221 SB 224289 hydrochloride 3350 LY 393558 Selective 5-HT1B antagonist Dual 5-HT1B/1D antagonist and 5-HT re-uptake inhibitor 1516 SDZ 21009

β-adrenoceptor antagonist. Also 5-HT1A/1B antagonist 5-ht1e 5-HT 1129 BRL-54443 1D Potent 5-ht1e/5-HT1F agonist Agonists 3783 CP-135807 5-HT1F Selective 5-HT agonist 1129 BRL-54443 1D Potent 5-ht /5-HT agonist 3665 Donitriptan hydrochloride 1e 1F 5-HT agonist 3079 LY 334370 hydrochloride 1B/1D Selective 5-HT agonist 3862 Eletriptan hydrobromide 1F Orally active, selective 5-HT agonist 2451 LY 344864 hydrochloride 1B/1D Potent, selective 5-HT agonist 0864 GR 46611 1F 5-HT agonist 1D 5-HT1 0781 L-694,247 General 5-HT agonist 1D 0458 5-Carboxamidotryptamine maleate 2640 L-703,664 succinate 5-HT agonist. Also has high affinity for 5-ht and 5-HT Selective 5-HT receptor agonist 1 5A 7 1D 3586 Sumatriptan 2556 PNU 109291 5-HT1 receptor agonist Potent and selective 5-HT1D agonist

5-HT2 Receptors Antagonists 5-HT2A Agonists 3346 ATC 0175 hydrochloride MCH1 antagonist; also 5-HT antagonist and partial antagonist of 2643 DOI hydrochloride 2B 5-HT Mixed 5-HT agonist 1A 2A/2C 3077 LY 272015 hydrochloride 2201 PNU 22394 hydrochloride High affinity 5-HT antagonist, orally active 5-HT agonist and 5-HT partial agonist 2B 2C 2A/2B 2993 RS 127445 hydrochloride 2592 TCB-2 Selective, high affinity 5-HT antagonist Potent, high affinity 5-HT agonist 2B 2A 1371 SB 200646 hydrochloride Antagonists 5-HT2C/2B antagonist 1809 hydrochloride 1372 SB 204741 5-HT receptor antagonist 2A Potent, selective 5-HT2B antagonist 0444 1661 SB 206553 hydrochloride with some D selectivity. Also 5-HT 4 2A/2C Potent, selective 5-HT2C/5-HT2B antagonist. Orally active antagonist 1379 SB 221284 2645 Potent, selective 5-HT2C/2B antagonist 5-HT2A antagonist. Also D4 antagonist 1375 SB 228357 0523 4F 4PP oxalate 5-HT2C/2B antagonist/inverse agonist Selective 5-HT2A antagonist 1255 SDZ SER 082 fumarate 0908 Ketanserin tartrate Selective 5-HT2B/2C antagonist Selective 5-HT2A antagonist. Also antagonist at 5-HT1D 0870 MDL 11,939 5-HT2C

5-HT2A antagonist Agonists 2495 hydrochloride 3041 CP 809101 hydrochloride

5-HT2A/D2 receptor antagonist; neuroleptic Potent and selective 5-HT2C agonist 1644 hydrochloride 0875 m-CPP hydrochloride

5-HT2A and 5-HT2C antagonist. Also partial agonist 5-HT2B/2C receptor agonist 2777 hydrochloride 2643 DOI hydrochloride

5-HT2A antagonist and 5-HT uptake inhibitor. Antidepressant Mixed 5-HT2A/2C agonist 2735 PNU 06415E 1860 Eltoprazine hydrochloride

D4 and 5-HT2A antagonist; antipsychotic 5-HT1 receptor agonist/partial agonist 1742 R-96544 hydrochloride 2399 Indorenate hydrochloride

Potent, selective 5-HT2A antagonist 5-HT1A, 5-HT1B and 5-HT2C agonist 2865 3017 1-Methylpsilocin

5-HT2A antagonist Potent and selective 5-HT2C agonist 3739 Sarpogrelate hydrochloride 0941 MK 212 hydrochloride

Selective 5-HT2A antagonist 5-HT2C agonist 0995 hydrochloride 3585 Org 12962 hydrochloride

5-HT2A antagonist. Also D2-like antagonist Selective 5-HT2C agonist 3085 hydrochloride 2201 PNU 22394 hydrochloride

5-HT2A/D2 antagonist; atypical antipsychotic 5-HT2C agonist and 5-HT2A/2B partial agonist 3996 1854 Ro 60-0175 fumarate

5-HT2A/D2 antagonist; atypical antipsychotic Potent, selective 5-HT2C agonist 0925 SCH 23390 hydrochloride 5-HT2B Standard selective D1-like antagonist. Also 5-HT2C agonist Agonists 2173 WAY-629 hydrochloride 1059 BW 723C86 hydrochloride Selective 5-HT2C agonist 5-HT2B agonist 1801 WAY 16503 hydrochloride 0875 m-CPP hydrochloride Potent, selective 5-HT2C agonist 5-HT2B/2C receptor agonist 0557 α-Methyl-5-hydroxytryptamine maleate

5-HT2B agonist

14 | Neuronal 5-HT Receptors

Antagonists 5-HT2 0444 Clozapine General 5-HT antagonist. Also with some D selectivity 2A/2C 4 0524 AMI-193 1007 N- Selective 5-HT antagonist 5-HT antagonist 2 2C 2746 hydrochloride 1644 Mesulergine hydrochloride Atypical antipsychotic; high affinity 5-HT ligand 5-HT and 5-HT antagonist. Also dopamine receptor partial agonist 2 2A 2C 0460 hydrochloride 1050 RS 102221 hydrochloride Selective 5-HT antagonist Selective 5-HT antagonist 2 2C 2863 DOB hydrochloride 1371 SB 200646 hydrochloride Selective 5-HT agonist 5-HT antagonist 2 2C/2B 0590 1661 SB 206553 hydrochloride 5-HT antagonist. Also 5-HT antagonist and 5-HT ligand. Has Potent, selective 5-HT /5-HT antagonist. Orally active 2 1 1D 2C 2B moderate affinity for 5-HT and high affinity for 5-HT 1379 SB 221284 6 7 0997 hydrochloride Potent, selective 5-HT antagonist 2C/2B 5-HT antagonist. Has moderate affinity for 5-ht 1375 SB 228357 2 6 2018 Mirtazepine 5-HT antagonist/inverse agonist 2C/2B Potent 5-HT antagonist. Also 5-HT , H and α -antagonist. 2901 SB 242084 2 3 1 2 Antidepressant Selective 5-HT antagonist; brain penetrant 2C 1955 1255 SDZ SER 082 fumarate Potent 5-HT2 antagonist Selective 5-HT2B/2C antagonist

5-HT3-7 Receptors

5-HT3 1795 hydrochloride Highly potent 5-HT receptor antagonist. Also 5-HT agonist Agonists 3 4 0440 m- hydrochloride Antagonists

Potent and specific 5-HT3 agonist 1322 GR 113808 0558 2-Methyl-5-hydroxytryptamine hydrochloride Potent, selective 5-HT4 antagonist

5-HT3 agonist/potent 5-HT6 ligand 1658 GR 125487 sulfamate 0566 N-Methylquipazine dimaleate Potent, selective 5-HT4 antagonist. Active in vivo

5-HT3 agonist 0728 RS 23597-190 hydrochloride 0969 1- hydrochloride 5-HT4 antagonist

5-HT3 agonist 0991 RS 39604 hydrochloride 0629 dimaleate 5-HT4 antagonist

5-HT3 agonist 0785 SB 203186 hydrochloride 0988 RS 56812 hydrochloride 5-HT4 antagonist

5-HT3 partial agonist 2037 SDZ 205-557 hydrochloride 1205 SR 57227A hydrochloride 5-HT4/5-HT3 receptor antagonist

Potent, selective 5-HT3 agonist 5-ht5 Antagonists Agonists 0666 3-AQC 0458 5-Carboxamidotryptamine maleate 5-HT antagonist 3 5-HT agonist. Also has high affinity for 5-ht and 5-HT 2759 B-HT 920 1 5A 7 Antagonists D2 receptor agonist. Also α2 agonist and 5-HT3 antagonist 2903 Granisetron hydrochloride 3188 SB 699551 Selective 5-ht5A antagonist 5-HT3 antagonist 0640 MDL 72222 5-HT6 5-HT3 antagonist 2018 Mirtazepine Agonists 2382 EMD 386088 hydrochloride Potent 5-HT2 antagonist. Also 5-HT3, H1 and α2-antagonist. Antidepressant Potent 5-HT6 agonist 2844 citrate Antagonists

5-HT4 agonist and 5-HT3 antagonist 3326 BGC 20-761

2891 Ondansetron hydrochloride High affinity 5-HT6 antagonist

Selective 5-HT3 antagonist 3904 WAY 208466

2037 SDZ 205-557 hydrochloride Selective, high affinity 5-HT6 agonist

5-HT4/5-HT3 receptor antagonist 2911 Ro 04-6790

0641 Tropanyl 3,5-dimethylbenzoate Potent and selective 5-HT6 antagonist

5-HT3 antagonist 3885 Ro 630563

2459 Tropisetron hydrochloride Selective, high affinity 5-HT6 antagonist

Potent 5-HT3 receptor antagonist; orally active 1961 SB 258585 hydrochloride

0380 Y-25130 hydrochloride Potent, selective 5-HT6 antagonist

Potent, selective 5-HT3 antagonist 3368 SB 271046 hydrochloride

1795 Zacopride hydrochloride Orally active, selective 5-HT6 antagonist

Highly potent 5-HT3 receptor antagonist. Also 5-HT4 agonist 3189 SB 399885 hydrochloride

Potent and selective 5-HT6 antagonist 5-HT4 3688 SGS 518 oxalate

Agonists Selective 5-HT6 antagonist 1695 Cisapride 5-HT 5-HT4 agonist; stimulates intestinal ACh release 7 3089 CJ 033466 Agonists

Selective 5-HT4 partial agonist 1968 AS-19

3499 ML 10302 hydrochloride Reported potent 5-HT7 agonist

Potent and selective 5-HT4 partial agonist 2925 LP 12 hydrochloride

2844 Mosapride citrate 5-HT7 agonist

5-HT4 agonist and 5-HT3 antagonist 2534 LP 44

0736 2-[1-(4-Piperonyl)piperazinyl] High affinity 5-HT7 agonist 5-HT4 agonist. Also 5-HT3 antagonist Antagonists 0989 RS 67333 hydrochloride 1523 LY 215840 5-HT4 partial agonist 5-HT2/5-HT7 antagonist 0990 RS 67506 hydrochloride

5-HT4 partial agonist

www.tocris.com | 15 2726 SB 258719 hydrochloride 2148 (±)-McN 5652

Selective 5-HT7 antagonist Potent, orally active 5-HT uptake inhibitor. Also inhibits noradrenalin 1612 SB 269970 hydrochloride and dopamine uptake in vitro

Potent selective 5-HT7 antagonist. Brain penetrant 3027 MDMA hydrochloride Inhibitor of 5-HT and dopamine uptake; hallucinogenic 5-HT Transporters 3286 hydrochloride 5-HT and noradrenalin re-uptake inhibitor (SNRI) 2341 A 80426 mesylate 2777 Nefazodone hydrochloride High affinity α antagonist. Also 5-HT uptake inhibitor 2 5-HT antagonist and 5-HT uptake inhibitor. Antidepressant 2322 BTS 54-505 hydrochloride 2A 2141 maleate Potent SNRI; active metabolite of (Cat. No. 2290) Highly potent and selective 5-HT uptake inhibitor 1427 hydrobromide 2742 Highly potent and selective 5-HT uptake inhibitor Inhibitor of vesicular monoamine transport 0457 hydrochloride 2395 hydrochloride 5-HT re-uptake inhibitor 5-HT re-uptake inhibitor 2833 Cocaine hydrochloride 2290 Sibutramine hydrochloride Inhibitor of monoamine transporters 5-HT and noradrenalin re-uptake inhibitor (SNRI) 2695 hydrochloride 2175 5-HT re-uptake inhibitor. Also stimulates 5-HT release Potent inhibitor of vesicular monoamine transport; depletes dopamine 3428 DMT stores Endogenous σ ligand. Also 5-HT agonist 1 2A 2917 hydrochloride 0927 hydrochloride Dual serotonin/noradrenalin re-uptake inhibitor 5-HT re-uptake inhibitor 1767 Zimelidene hydrochloride 1033 maleate Selective 5-HT uptake inhibitor 5-HT re-uptake inhibitor 1588 hydrochloride 5-HT Potent 5-HT uptake inhibitor. Also inhibits dopamine and noradrenalin General uptake 3991 NPEC-caged-serotonin 2545 Caged serotonin 5-HT and noradrenalin re-uptake inhibitor (SNRI) 3547 Serotonin hydrochloride 3350 LY 393558 Endogenous 5-HT receptor agonist Dual 5-HT1B/1D antagonist and 5-HT re-uptake inhibitor

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Tocris Reviews No. 34 ©2011 Tocris Cookson

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