Copyright © 2003 by Institute of Pharmacology Polish Journal of Pharmacology Polish Academy of Sciences Pol. J. Pharmacol., 2003, 55, 923–934 ISSN 1230-6002 REVIEW POTENTIAL ANTIDEPRESSANT ACTIVITY OF SIGMA LIGANDS Gra¿yna Skuza Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland Potential antidepressant activity of sigma ligands. G. SKUZA. Pol. J. Pharmacol., 2003, 55, 923–934. Despite many years’ studies of antidepressant drugs (ADs), their mecha- nism of action still remains unclear. Recently, it has been postulated that sub- stances capable of reducing neurotransmission at the NMDA complex may represent a new class of ADs. Since several ADs have a high affinity for s receptors, the s binding site may be a relevant mechanism in antidepressant action. Moreover, s ligands are able to modulate the activity of the central neurotransmitter systems, including noradrenergic, serotonergic, dopaminer- gic and glutamatergic (NMDA) ones, which are seemingly important for the mechanism of action of known ADs. The existence of at least two different s s s subtypes of receptors, denoted 1 and 2 is now widely accepted. The se- lective agonists of both s receptor subtypes are available at present. In par- s ticular, a potential antidepressant activity of 1 receptor agonists has been postulated, since the antidepressive-like actions of these compounds have been shown in animal models. This article reviews the findings related to po- tential antidepressant activity of new, selective s ligands. Key words: sigma receptors, selective sigma ligands, antidepressant ac- tivity, animal models G. Skuza 3 Introduction Table 1. IC50 values for drugs competing with the [ H]ligands for s and phencyclidine (PCP) receptor binding sites (rat brain membranes) The term sigma (s) receptors was first proposed by Martin et al. [49] to explain, on the basis of in IC50 (nM) vivo experiments, the effects of benzomorphans, Compound (+)-[3H]SKF (+)-[3H]SKF [3H]TCP such as N-allyl-normetazocine (SKF 10,047), pen- 10,047 10,047 tazocine and cyclazocine which induced a charac- + TCP* + haloperidol teristic pattern of stimulation (“canine delirium”), (+)-SKF 10,047 55 320 405 differentiating these compounds from morphine- (–)-SKF 10,047 690 530 820 syndrome and ketocyclazocine- syndrome. Though (+)-3-PPP 45 > 50000 > 50000 s initially the receptors were considered to be Haloperidol 8 > 50000 > 50000 m k a type of opiate receptor (beside and ), later TCP 8330 25 10 studies (using more selective ligands and more pre- PCP 1450 48 66 cise techniques) convincingly demonstrated that Pentazocine 55 1520 3310 this opinion was not true. Further investigations have revealed that levorotatory form of SKF 10,047 * 1-[1-(2-thienyl)cyclohexyl]piperidine. According to [23] binds primarily to m and k opioid receptors, while its dextrorotatory analogue is distinguished by much s higher affinity for s site and considerable affinity affinity for site, binds to PCP receptor to much for phencyclidine (PCP) receptor. For these reasons, lesser extent (5–8 times) [23]. Martin et al. [49], who used (±)-SKF 10,047, ob- s served as well antinociceptive effects (resulting Characteristics and functions of receptor from the interaction with m and k opioid receptors The s receptors have been labeled and visualized mediated by (–)-SKF 10,047) as psychotomimetic with various radioligands using autoradiographic symptoms, believed to be an effect of (+)-SKF procedures. The numerous data demonstrate that s 10,047 binding to PCP receptors, not reversed by receptors are unevenly distributed in many brain an opiate antagonist, naloxone. areas and are quite abundant in various peripheral The lack of the selectivity shown by several tissues (the kidneys, lungs, intestine, muscles, and, compounds, including benzomorphans and PCP most of all, the liver). In the central nervous system, derivatives on the one hand, and similarities in bio- s receptors are concentrated in brainstem areas, chemical and behavioral effects of some s ligands certain limbic structures, some predominantly sen- and PCP on the other, suggested actions via the sory areas and brain regions associated with endo- same receptor site, so-called “s/PCP”. Further re- crine function [24, 55, 94]. sults (including autoradiographic studies using more Binding studies and in vivo or in vitro func- selective radioligands) demonstrated that s and tional bioassays led to the distinction of at least two s s s PCP receptors were distinct sites and their distribu- subpopulations of receptors, termed 1 and 2 [5, tion in brain regions was found to differ [23, 48, 55, 34, 65]. This classification is mostly based on dif- s 66]. ferences in binding of radioligands: 1 receptor is The use of nonselective ligands, including the able to distinguish between spatial isomers, show- prototypic agonist, N-allyl-normetazocine, to char- ing preference for dextrorotatory forms [(+)-penta- acterize s receptors resulted in an accumulation of zocine, (+)-SKF 10,047, dextrometorphan], whereas confusing and conflicting data which made the the levorotatory form of these compounds as well progress in this field more difficult. Table 1 pres- as haloperidol or 1,3-di-o-tolylguanidine (DTG) bind s s s ents differences in affinity of some ligands of and with high affinity also to the 2 receptors.The 1 PCP receptor sites. These data indicate that (+)-SKF sites are particularly concentrated in the hippocam- 10,047 shows 12.5 times higher affinity for s re- pal formation and other limbic areas (involved in ceptor than its levorotatory analogue, whereas both cognition and emotion), thus, they are suggested to forms exhibit the affinity for PCP receptor (dextro- play an important role in etiology and therapy of rotatory form is somewhat more potent) (Tab. 1). psychiatric disorders [13, 35, 36, 52, 94]. On the s On the other hand, pentazocine, having comparable other hand, the highest densities of 2 receptors 924 Pol. J. Pharmacol., 2003, 55, 923–934 POTENTIAL ANTIDEPRESSANT ACTIVITY OF SIGMA LIGANDS were revealed particularly in regions related to mo- Table 2. Affinities of some compounds for s1 and s2 receptor tor functions (e.g. the motor cortex area, cerebel- sites in the rat brain membranes lum) supporting their possible involvement in the modulation of posture and movements induced by Kd or Ki (nM) Compound s ligands [5, 94]. s s s 1 2 However, 2 binding sites are also likely to mo- dulate emotional responses, since Lu 28-179, a new Haloperidol 3.12 ± 0.23 55.0 ± 9.3 s (+)-Pentazocine 4.59 ± 0.26 1,052 ± 30 selective 2 receptor ligand, shows anxiolytic-like effects in mouse and rat black and white two-com- (–)-Pentazocine 7.41 ± 1.65 42.5 ± 1.7 partment box test, the rat social interaction test and DTG 17.9 ± 5.0 22.2 ± 3.5 the Vogel conflict test [71]. (+)-SKF 10,047 19.4 ± 4.6 2680 ± 444 Binding to s receptor is allosterically modu- 1 Progesterone 24.6 ± 6.6 15700 ± 100 lated by phenytoin and sensitive to the modulatory effects of guanosine triphosphate (GTP) and per- Testosteron 49.7 ± 11.7 > 50000 tussis toxin, which suggests its coupling to G pro- (–)-SKF 10,047 84.9 ± 10.7 1100 ± 170 s Dextrometorphan 85.5 ± 8.5 15800 ± 700 teins (Gi/o). It is thought that activation of 1 recep- tor implicates many second messenger cascades, Dizocilpine (MK-801) 47300 ± 3500 73600 ± 3300 including arachidonic acid cascade, protein kinase C translocation, modulation of the phosphorylation According to [56] state of specific proteins in the brain and phosphati- dyl inositol turnover [19, 26, 60, 94]. Moreover, an An electrophysiological in vivo model for studies s interaction between ligands and calcium channels of selective s receptor ligands has been proposed has been suggested [see: 94]. The findings of Brent by Debonnel et al. [2, 12, 13, 59]. Numerous results et al. [7] demonstrated that protein phosphorylation s 2+ from this laboratory demonstrated that several 1 (dependent on extracellular Ca ) may be one of ligands, e.g. (+)-pentazocine, when applied by mi- the important mechanisms through which s ligands croiontophoresis or administered iv at low doses, produce their effects. potentiated the neuronal response to N-methyl-D- The most commonly used selective s receptor 1 aspartate (NMDA) in the CA region of the rat dor- ligand is (+)-pentazocine, although new, more se- 3 sal hippocampus but did not modify kainate- nor lective compounds of this type have been synthe- quisqualate-induced activations. Only a few s li- sized in recent years (e.g. SA4503), while the DTG, s s s gands, including NE-100 (N,N-dipropyl-2-[4-me- mixed 1/ 2 receptor agonist, has been used as 2 receptor ligand or radioligand (in the presence of thoxy-3-(2-phenylethoxy)phenyl]ethylamine) and (+)-pentazocine). As mentioned above, a selective haloperidol, did not modify NMDA-induced firing s receptor ligand, siramesine, has been introduced activity but suppressed the potentiation of NMDA 2 s recently [71, 86]. The s receptor ligands used so response induced by agonists. Thus, they were s s s far showed low selectivity for its two subpopula- denoted antagonists. Similarly to 1 ligands, 2 tions and for other receptors, particularly dopamine agonists also potentiate the NMDA response [12]. s receptors. For instance, haloperidol, a typical neuro- A majority of agonists tested thus far generate s bell-shaped dose-response curves with respect to leptic, shows high affinity particularly for 1 sites s potentiation of NMDA response. It is worth em- and relatively lower for 2 sites. On the other hand, the aforementioned compound DTG binds with phasizing that this dose-response relationship s s seems characteristic of s receptor ligands, and was comparable potency to both 1 and 2 receptor sub- types (Tab. 2). Interestingly, some neurosteroids (e.g.