Binding characteristics of sigma2 receptor ligands

Características estruturais de ligantes do receptor sigma2

Abstracts

Sigma (sigma) receptors, once considered a type of opioid receptor, are now recognized as representing a unique receptive entity and at least two different types of sigma receptors have been identified: sigma1 and sigma2 receptors. Evidence suggests that these receptors might be targeted and exploited for the development of agents potentially useful for the treatment of several central disorders. This review primarily describes some of our efforts to understand those structural features that contribute to sigma2 receptor binding, and some recent work by other investigators is also included. Despite an inability to formulate a unified pharmacophore model for sigma2 binding due to the diversity of structure-types that bind at the receptor, and to the conformational flexibility of these ligands, significant progress has been made toward the development of some very high-affinity agents.

sigma2 receptor; sigma2 ligand structural features; sigma2 pharmacophore model

Receptores sigma (sigma), considerados como um tipo de receptor opióide, sigma ão hoje considerados como uma entidade receptora singular. Pelo menos dois subtipos desses receptores foram identificados: sigma1e sigma2. Há evidências de que esses receptores devam ser explorados como alvo para o desenvolvimento de agentes potencialmente úteis para o tratamento de várias disfunções centrais. Esta revisão descreve, principalmente, alguns dos nossos esforços para compreender as características estruturais que contribuem para a ligação no receptor sigma2 , e incluem-se alguns trabalhos recentes desenvolvidos por outros pesquisadores. Apesar da incapacidade de formular um modelo de farmacóforo único para ligação no receptor s 2, em razão da diversidade de estruturas que a ele se ligam e da flexibilidade conformacional desses ligantes, houve progresso significativo no desenvolvimento de agentes de alta afinidade.

Receptor opióide sigma2; Características estruturais do ligante sigma2; Modelo farmacóforo sigma2

REVIEW

Binding characteristics of s₂ receptor ligands

Características estruturais de ligantes do receptor s ₂

Richard A. Glennon

Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA

^{Correspondence}

ABSTRACT

Sigma (s) receptors, once considered a type of opioid receptor, are now recognized as representing a unique receptive entity and at least two different types of s receptors have been identified: s₁ and s₂ receptors. Evidence suggests that these receptors might be targeted and exploited for the development of agents potentially useful for the treatment of several central disorders. This review primarily describes some of our efforts to understand those structural features that contribute to s₂ receptor binding, and some recent work by other investigators is also included. Despite an inability to formulate a unified pharmacophore model for s₂ binding due to the diversity of structure-types that bind at the receptor, and to the conformational flexibility of these ligands, significant progress has been made toward the development of some very high-affinity agents.

Uniterms: s₂ receptor. s₂ ligand structural features. s₂ pharmacophore model.

RESUMO

Receptores sigma (s), considerados como um tipo de receptor opióide, s ão hoje considerados como uma entidade receptora singular. Pelo menos dois subtipos desses receptores foram identificados: s₁e s₂. Há evidências de que esses receptores devam ser explorados como alvo para o desenvolvimento de agentes potencialmente úteis para o tratamento de várias disfunções centrais. Esta revisão descreve, principalmente, alguns dos nossos esforços para compreender as características estruturais que contribuem para a ligação no receptor s₂ , e incluem-se alguns trabalhos recentes desenvolvidos por outros pesquisadores. Apesar da incapacidade de formular um modelo de farmacóforo único para ligação no receptor s ₂, em razão da diversidade de estruturas que a ele se ligam e da flexibilidade conformacional desses ligantes, houve progresso significativo no desenvolvimento de agentes de alta afinidade.

Unitermos: Receptor opióide s₂. Características estruturais do ligante s₂. Modelo farmacóforo s₂.

INTRODUCTION

The possible existence of putative sigma (s) opioid receptors was proposed by William Martin in the mid 1970s to account for the binding of benzomorphans such as N-allylnormetazocine (NANM; SKF 10,047; 1) and pentazocine (2). It soon became evident that various non-opioids (e.g. haloperidol; 3) bind at these receptors and that some benzomorphans bind at phencyclidine (PCP) binding sites; the sites were subsequently termed s /PCP receptors. Due to differences in brain localization, and because of affinity differences in ligand binding at s versus PCP sites, it became apparent that s binding sites and PCP binding sites were distinct receptor types. Identification of agents such as ditolylguanidine (DTG; 4) led to the final realization that s sites and PCP sites are distinct (Scherz et al., 1990). Eventually, at least two major populations of s receptors were identified: s₁ and s₂ (reviewed: Bowen, 2000). These two receptor populations differed in their tissue distribution and subcellular localization. The benzomorphan (+)pentazocine displays several hundred-fold selectivity for the former whereas DTG binds nearly equally well at both populations. The s₁ receptor has been recently cloned from several sources including human brain; s₂ receptors have yet to be cloned (reviewed: Guitart et al., 2004). A very recent review (Guitart et al., 2004) describes the potential involvement of s receptors in schizophrenia, movement disorders, depression, anxiety, drug abuse, and pain. For general reviews of early investigations with s receptors and s receptor ligands, the reader is referred to: Abou-Gharbia et al., 1993; Chavkin, 1990; Domino and Kamenka, 1988; Itzhak, 1994; Itzhak and Stein, 1990; Junien and Leonard, 1989; Musacchio et al., 1989; Quirion et al., 1987; Snyder and Largent, 1989; Walker et al., 1990.

Binding character of s₂ receptor ligands

One goal of our work has been the development of high-affinity s -selective ligands, and as the foundation for such an effort we have attempted to identify a pharmacophore for the binding of ligands at s receptors. Because our studies were begun in the mid 1980s prior to the discovery of s₁ and s₂ receptors, our conclusions required modification once two distinct s receptor types were described. That is, the discovery of s₁ and s₂ receptors necessitated a re-evaluation of some initial findings. Although our primary focus was on s₁ receptors, nearly all of the compounds we prepared were also evaluated at s₂ receptors. Hence, a by-product of our work was the formulation of structure-affinity relationships for the binding of these ligands at s₂ sites. We have not previously reviewed these latter findings and take this opportunity to do so. That is, this review is based on ligands we reported in a series of articles published over the past 15 years (e.g. Ablordeppey et al., 1991; Ablordeppey et al., 1992a; Ablordeppey et al., 1992b; Ablordeppey et al., 1993; Ablordeppey et al., 1998; Ablordeppey et al., 2000; Ablordeppey et al., 2002; El-Ashmawy et al., 1992; Glennon et al., 1991a; Glennon et al., 1991b; Glennon et al., 1991c; Glennon et al., 1994; Glennon, 2000; Glennon, and Fischer 2000; Glennon et al., 2004); these papers can be consulted for the synthesis and physicochemical properties of most of the compounds described here. Sigma-2 receptor binding data were obtained using guinea pig brain homogenates and the nonselective [³H]DTG in the presence of cold (+)pentazocine to block s₁.

One of the first sigma ligands we reported was R(-)PPAP (5R); the structure might be viewed as an N-phenylpropyl derivative of a ring-opened benzomorphan. R(-)PPAP was found to bind at s₁ sites (Ki = 11 nM) with slightly higher affinity than it displayed for s₂ sites (Ki = 61 nM; Table I). However, because selectivity is not a requirement for pharmacophore development or structure-affinity studies, we used R(-)PPAP as the basis for a more detailed structure-affinity investigation.

PPAP showed little stereoselectivity of binding with s (+)PPAP (Ki = 38 nM) binding with only about twice the affinity of it enantiomer. Chain length was extended from propyl to n-butyl (i.e. 6) and n-pentyl (i.e., 7) with relatively little change in affinity (Table I). Nevertheless, it was curious that with the longer-chain compounds (i.e., 7) the R(-) isomers displayed slightly higher affinity than their S(+)enantiomers.

Next examined was the effect of aryl substituents on binding. Table II shows that neither electron withdrawing nor electron donating substituents had much impact on affinity. First one, then the other, phenyl group of PPAP was replaced by either a 1-naphthyl or 2-naphthyl group (i.e. 13-16; Ki = ca 200 nM) indicating that such changes were not beneficial to affinity. N-Monomethylation of S(+)PPAP (i.e., 17; Ki = 5 nM) resulted in about 7-fold enhanced affinity, however the N-benzyl analog 18 (Ki = 470 nM) displayed >10-fold reduced affinity.

Due to the apparent reversal in stereoselectivity seen upon extension of chain length, and because the butyl and pentyl analogs 6 and 7 retained the affinity of PPAP, the a-methyl group was removed and chain-length on both sides of the amine was investigated (Table III). Comparing the phenylethyl derivatives 23-25, (Ki = 90 nM, 120 nM, and 15 nM, respectively) it seems that a pentyl chain (i.e., 25) is optimal among the three; furthermore, comparing 25 with 29, it also seems that the phenylethyl moiety can be replaced with a phenylpropyl chain. As was seen with PPAP, N-monomethylation induced a slight enhancement of affinity. The overall result is that phenylethyl and phenylpropyl compounds 25 (Ki = 15 nM) and 29 (Ki = 9.8 nM) bind with fairly similar affinity, and their N-monomethyl tertiary amine counterparts 26 (Ki = 5.0 nM) and 30 (Ki = 6.3 nM) bind with slightly higher affinity.

Removal of the phenylpentyl phenyl group of 29 (i.e. replacement of the phenyl group by H) afforded 32 (Ki = 240 nM) which binds with nearly 25-fold reduced affinity; in contrast, removal of the phenylpropyl phenyl group of 30 (i.e., 33; Ki = 40 nM) decreased affinity only by about 4-fold. Further shortening of the propyl chain of 33 to a methyl group (34; Ki = 965 nM) or replacement by H (35; Ki = 7,900 nM) resulted in dramatic decreases in affinity. On the other hand, cyclization of the alkyl substituents of 33 (Ki = 40 nM) to a five- (36; Ki = 70 nM) or six-membered (37; Ki = 50 nM) ring had much less impact on affinity. Replacement of the phenylpentyl phenyl ring with a cyclohexyl moiety had varying effects on affinity comparing 34 with 38 (Ki = 195 nM), and 35 with 39 (Ki = 350 nM).

Other modification of des-methyl PPAP that were examined included conformational constraint, aryl substitution, and certain side chain modifications. For example, compound 40 (Ki = 170 nM) is an analog of an extended PAPP compound that possesses an aminotetralin moiety similar to that found in the benzomorphans; yet 40 binds with >10-fold reduced affinity relative to its ring-open counterpart 25 (Ki = 15 nM).

The trifuoromethylphenyl compound 41 (Ki = 14 nM) binds with an affinity similar to that of 25, but its positional isomer 42 (Ki = 3.6 nM) binds with several-fold enhanced affinity. Compounds 43 (Ki = 1.3 nM) and racemate 44 (Ki = 3.0 nM) suggest that polar substituents are tolerated in the side chain. Additional compounds of this type require examination.

Cyclic compound 36 (Ki = 70 nM) was ring-opened to 45 (Ki = 90 nM) but, interestingly, introduction of a polar carbonyl oxygen atom decreased affinity (46; Ki = 750 nM). A second phenyl ring was tolerated (47; Ki = 50 nM), but here too, introduction of a polar hydroxyl substituent resulted in decreased affinity (48; Ki = 800 nM).

Gem-diphenyl substitution was also tolerated by 25 (i.e., 49; Ki = 32 nM); however here, rather than enhancing affinity N-monomethylation decreased affinity by 3-fold (i.e., 50; Ki = 100 nM).

Focusing on the piperidine ring of 37, 4-position substitution was investigated. Introduction of both a 4-methyl group (51; Ki = 7.1 nM) or a 4-benzyl group (52; Ki = 2.8 nM) resulted in about a 10-fold increase in affinity.

The benzyl group of 52 was moved to the 3-position (53; Ki = 4.2 nM) and 2-position (54; Ki = 10 nM), where it was shown to be tolerated at each of the three positions; nevertheless, the 3- and 4-substituted derivatives displayed the highest affinity. Both the 3- (55; Ki = 5.3 nM) and 2- phenyl (56; Ki = 4.7 nM) derivatives also retained high affinity.

At this point, the role of carbonyl derivatives, aryl substitution, and the importance of the piperidino phenyl group was reinvestigated. Compound 57 (Ki = 3.1 nM) binds with high affinity; introduction of a 3-chloro substituent (59; Ki = 1.6 nM) has little effect on affinity as does moving the 3-chloro substituent to the 4-position (61; Ki = 1.0 nM). But in both of the latter cases, removal of the piperidino phenyl group decreases affinity by about 20-fold (i.e. 58 and 60; Ki = 33 and 25 nM, respectively). In contrast, removal of the carbonyl oxygen atom of 61 (62; Ki = 2.1 nM) indicates that it likely does not participate in binding.

What emerged from these studies is that the s₂ receptor likely consists of an amine binding site flanked by two hydrophobic sites; in fact, there is striking similarity to what we have previously proposed for s₁ binding requirements (and, indeed, most compounds bind both at s₁ and s₂ receptors).

Subsequently, the phenylpentyl chain of 52 was shortened to a phenylbutyl (63: Ki = 3.1 nM) and phenylpropyl (64; Ki = 3.3 nM) chain; affinity was retained independent of the length of the chain. In the phenylbutyl series, the benzyl group could be replaced with a benzoyl group (65; Ki = 11 nM), and the benzoyl group could be reduced to its corresponding racemic alcohol (66; Ki = 13 nM). However, the gem diphenyl analog 67 (Ki = 235 nM) displayed reduced affinity.

Interesting is that 4-benzylpiperidine derivatives 52, 63, and 64, which vary only with respect to the length of their N-alkyl chain, bind with similar high affinity (Ki = 2.8 to 3.3 nM). This is in contrast to the affinities of N-substituted phenylethylamines 23-25 where the N-pentyl analog 25 (Ki = 15 nM) binds with 8-fold higher affinity than its N-butyl counterpart 24 (Ki = 120 nM). This same type of inconsistency was observed with piperazine 68 (Ki = 11 nM) where shortening of the alkyl chain by a single methylene group (i.e., 69; Ki = 8.2 nM) had negligible effect on affinity. However, in the absence of the benzylic phenyl group, pentyl analog 70 (Ki = 79 nM) displayed 10-fold higher affinity than its butyl counterpart 71 (Ki = 900 nM).

These inconsistencies argue for different modes of binding. This is especially germaine to piperazine derivatives where either one of the two basic nitrogen atoms might interact with the amine binding site. Because a benzylic carbonyl group seems to be tolerated by the receptor (e.g. comparing 63 with 65), it was reasoned that the affinity of 69 should remain unchanged following reduction of the basicity of the N_a nitrogen atom if it is the N_b nitrogen atom that interacts with the amine binding site; however, the reduced affinity of 72 (Ki = 965 nM) suggests that the N_a, not the N_b, nitrogen atom of 69 might be the more important. But, comparing 70 (Ki = 965 nM) with its des-amino analogs 51 (Ki = 7.1 nM) and 73 (Ki = 97 nM), it would seem that interaction of N_b with the amine binding site leads to higher affinity. Evaluation of a number of related compounds produced results that are equally difficult to interpret. Similar inconsistencies were observed in an earlier investigation of compounds at s₁ receptors. To account for this we suggested that multiple modes of binding are possible. That is, we proposed two different modes of binding for piperidine derivatives, and four possible modes of binding for piperazine derivatives (Ablordeppey et al., 2000), depending upon the presence of one or two basic nitrogen atoms, the length of the alkyl chain, and substituents that might be present in aryl portions of the chain. A similar argument can be made here for the binding of these ligands at s₂ receptors (Figure 1).

Figure 1

Turning to Figure 1, we further examined the existence of two possible hydrophobic binding regions. It would appear that occupation of one of these regions, in addition to interaction at the amine site, is insufficient to impart high affinity. For example, compound 79 (Ki >10,000 nM) which, in theory, should be accommodated by Hydrophobic Region A and the amine site, lacks significant affinity. Likewise, phenylpentylamine compound 35 (Ki = 7,900 nM; Table IV) binds only with low affinity. However, comparison of a series of 5-(phenyl)pentylamines showed that as the lipophilicity (bulk?) of the amine substituent increased, affinity increased. If it is assumed that the common phenyl moiety interacts with Hydrophobic Region B, it would appear that at least four carbon atoms are required (in the diection of Hydrophobic Region A) to achieve optimal affinity (to wit: compare 37 with 51, Table IV). The necessity of an aromatic ring to interact with Hydrophobic Region A does not seem to be a requirement. Nevertheless, such a ring is accommodated by the receptor (in a region of bulk tolerance?). It is proposed that there exists two binding regions (tentatively termed hydrophobic regions) flanking an amine site. Hydrophobic Region A is situated such that it optimally accommodates four carbon atoms. Hydrophobic Region B is situated such that it seems capable of accommodating somewhat longer chains. But the semi-symmetrical nature of the binding site makes it very difficult to determine exactly how compounds bind. For example, if the 5-(phenyl)pentyl chain is shortened by a single methylene group, the phenyl ring might now bind at Hydrophobic Region A rather than Hydrophobic Region B. This might be further influenced by any substituents that might be present on the phenyl ring. Of course, this is further complicated when the ligand possesses a piperidine or piperazine ring (see Figure 1). Evidence for the possibility of "reverse" modes of binding might be that S(+)PPAP (5S) binds with twice the affinity of its enantiomer 5R, whereas for the corresponding pentyl homolog 7R binds with twice the affinity of 7S, and for the butyl analog (i.e., 6) the two optical isomers bind with nearly identical affinity. Other such evidence might come from the observations that conversion of piperidine 52 (Ki = 2.8 nM) to its corresponding piperazine 68 (Ki = 11 nM), or piperidine 63 (Ki = 3.1 nM) to piperazine 69 (Ki = 8.2 nM) results in very small changes in affinity, whereas conversion of piperidine 80 (Ki = 13 nM) to piperazine 81 (Ki = 290 nM), or piperidine 82 (Ki = 12 nM) to piperazine 83 (Ki = 149 nM), lead to substantial decreases in affinity.

The proposed model, simplistic though it might be, provides a framework for further evaluation. Although it accounts for the binding of certain compounds, it is not particularly robust in explaining the binding of other agents. For example, it does not provide a satisfactory explanation for why chain extension of 83 to 84 (Ki = 20 nM) results in enhanced affinity, nor why compound 85 (Ki = 0.7 nM) binds with such high affinity.

There are relatively few agents that display significant selectivity for s₂versus s₁ receptors. Most of the compounds described herein bind with at least equivalent, and in most cases, with higher affinity at s₁ receptors than ats₂ receptors.Our interest in the above phthalimido analogs was heightened by the observation that introduction of a carbonyl group adjacent to an amine present in the alkyl chain showed a tendency to modulate selectivity. For example, amide 88 (Ki = 490 nM) displayed modest affinity and no selectivity for s₂ receptors (Table V); the corresponding amine 91 (Ki = 100 nM) showed 5-fold enhanced affinity for s₂ receptors, but was 50-foldselective for s₁ receptors. It was surmised that the basicity of the amine might be responsible for these effects. Accordingly, we investigated amide 92 and imides 93-95; these compounds displayed varying affinities for s₂ receptors but showed enhanced s₂ selectivity. Compound 83 (s₂ Ki = 149 nM, 87.9-folds₂ selectivity) displayed modest affinity but good selectivity. Conversion of the 1-phenylpiperazine 83 to 4-phenylpiperidine 82 enhanced affinity at both receptor populations but resulted in loss of selectivity. Replacement of the piperazine phenyl group of 83 with a benzyl group (i.e., 81) reduced both affinity and selectivity. Lengthening of the alkyl chain of 83 by a single methylene group (i.e. 84) enhanced s₂ affinity by about 7-fold, but reduced its selectivity by a corresponding amount. Among the compounds examined, compound 83 was a compromise between high affinity and selectivity.

Most of our studies were conducted in the mid to late 1990s. Since then, a number of exciting results have been reported by others; some of these will be described. Although benzomorphans do not typically bind with high affinity at s₂ receptors, May and co-workers (2000) have found that the s₂ receptor affinity of a series of (1R,5R,9R)-benzomorphans 96 increases as n is increased from 1-4 (Ki = 3,200 nM, 620 nM, 180 nM, and 80 nM, respectively). These results are consistent with those features we have found to be important for binding (Figure 1).

Maeda et al. (2002) prepared a series of bis(aralkyl)amines, such as those shown in Table III, and found they could be cyclized to tetrahydroisoquinolines; for example 97 (Ki = 57.3 nM) and 98 (Ki = 14.2 nM) bind with high affinity. However, 97 binds with 10-fold greater affinity at s₁ receptors than at s₂ receptors whereas 98 binds equally well at both population; on the basis of these and related studies they suggested that phenylpropyl derivatives, rather than phenylethyl derivatives, might provide leads to agents with greater s₂ selectivity. More recently, Mach et al. (2004) have reported on a very interesting series of tetrahydroisoquinolines. Compound 99 (Ki = 8.2 nM), for example, binds with high affinity, and displays 1,573-fold selectivity versus s₁ binding; interestingly, the related but shorter analog 100 (Ki = 89.4 nM) binds with lower affinity and is several-fold selective for s₁ receptors.

Piperidine and piperazine derivatives continue to receive considerable attention (e.g. Berardi et al., 1998; Berardi et al., 2004; Fujimura et al., 1997; Kawamura et al., 2003; Mach et al., 2004; Maeda et al., 2002; Maier and Wunsch, 2002; Marrazzo et al., 2001; Matsumoto et al., 2004). Of particular interest is a series of substituted tetralins bearing a gem-dimethyl piperidine. Compound 101 (n = 4; IC₅₀ = 0.016 nM) is a very high affinity s₂ ligand with >100,000-fold selectivity over s₁ receptors; remarkably, when n=5 (IC₅₀ = 0.03 nM) the compound binds only with 21-fold selectivity. Also remarkable is that removal of the methoxy group from the latter compound (i.e., des-methoxy 101, n = 5; IC₅₀ = 0.008 nM) once again results in >100,000-fold s₂-selectivity. The shorter relative 102 (IC₅₀ = 119 nM) binds with much lower affinity and with 1,340-fold s₁ selectivity (Berardi et al., 1998).

Kawamura et al. (2003) have also found that small structural differences have a major impact on affinity and selectivity. Compound 103 binds at s₂ receptors with low affinity and 106-fold selectivity for s₁ sites when R is a methyl group (s₂ Ki = 1,800 nM), but binds with higher affinity at, and nearly 3-fold selectivity for, s₂ sites when R is an ethyl group (s₂ Ki = 13 nM).

Some of the more structurally unusual compounds to be examined are steroids 104 and 105, and tropane 106. Curious as to just how far we might push the 5-(phenyl)pentylamine concept with respect to conformation and bulk, we prepared steroid analogs 104 and 105 (unpublished finding; Glennon, Ismaiel, Fischer). Both compounds possess an embedded 5-(phenyl)pentyl chain in their cyclic structure, with a different amine function appended. Compound 104 (Ki = 125 nM) binds with unexpectedly high affinity and with 6-fold selectivity over s₁ receptors. Compound 105 (Ki = 24 nM) binds with even higher affinity, but with 3-fold selectivity. Surprisingly, the affinity of 105 is not much unlike that of the structurally simpler 4-methyl-N-(5-phenyl)pentylpiperazine (51; Ki = 7.1 nM). Evidently, the receptors can tolerate considerable bulk.

SM-21 (106) has seen application as a s₂ antagonist. SM-21 was initially reported to bind at s₂ receptors (rat liver; Ki = 67.5 nM) with >14-fold selectivity over s₁ receptors (Mach et al., 1999). However, a more recent investigation demonstrated that SM-21 binds with somewhat lower affinity (guinea pig; s₂ Ki = 434 nM; s₁ Ki >1000 nM); in that same study, neither optical isomer retained the affinity of the racemate (s₂ Ki = 703 nM and 2,169 nM for the R(+) and S(-)isomers, respectively) (Prezzavento et al., 2002). The lower affinity of SM-21 in the latter study was attributed to differences in the tissue source that was used.

This review has attempted to highlight progress made in the identification of the binding character of s₂ ligands since the s₁/s₂ receptor concept was first proposed 15 years ago. It should now be evident that a pharmacophore model to account for the binding of ligands at s₂ receptors remains elusive. Nevertheless, outstanding progress has been made, despite lack of a pharmacophore model, towards the development of various high-affinity s₂ ligands. While s₂-selective ligands were not the intended focus of the review, it should be noted that several such agents also have been identified.

Important binding features common to many s₂ ligands are shown in Figure 1. The nearly symmetrical nature of these binding features presents problems as to exactly how specific compounds might bind at the receptors, and this is only further complicated when the ligands possess two basic amine groups (e.g. as with piperazine derivatives). To some extent, binding character is not unlike that proposed for s₁ ligands (Gilligan et al., 1992; Glennon et al., 1994; Ablordeppey et al., 2000); indeed, most compounds bind at both s receptor subtypes with, frequently, <10-fold selectivity. On the other hand, compounds such as 101-103 suggest that real differences exist — subtle though they may be. What is now required to better define pharmacophore models for s₁ and s₂ receptor binding are high-affinity, conformationally-constrained ligands. It would certainly not come as a surprise if multiple pharmacophores are eventually identified for one or both s receptor types.

ACKNOWLEDGMENTS

Dr. Abd Ismaiel and Dr. Ho Law are acknowledged for their contributions to this project.

Recebido para publicação em 27 de janeiro de 2005.

Aceito para publicação em 02 de fevereiro de 2005.

• ABLORDEPPEY, S. Y.; EL-ASHMAWY, M. B.; GLENNON, R. A. Analysis of the structure-activity relationships of sigma receptor ligands. Med. Chem. Res., v.1, p.425-438, 1991.
• ABLORDEPPEY, S. Y.; EL-ASHMAWY, M. B.; GLENNON R. A. Analysis of the structure-activity relationships of sigma receptor ligands. Med. Chem. Res., v.2, p.425-438, 1992a.
• ABLORDEPPEY, S. Y.; FISCHER, J. B.; GLENNON, R. A. Is a nitrogen atom an important pharmacophoric element in sigma ligand binding? Bioorg. Med. Chem.,v.8, p.2105-2111, 2000.
• ABLORDEPPEY, S. Y.; ASHMAWY, M.; FISCHER, J. B.; GLENNON, R. A. A CoMFA investigation of sigma receptor binding affinity: Reexamination of a spurious sigma ligand. Eur. J. Med. Chem., v.33, p.625-633, 1998.
• ABLORDEPPEY, S. Y.; FISCHER, J. B.; LAW, H.; GLENNON, R. A. Probing the proposed phenyl-A region of the sigma-1 receptor. Bioorg. Med. Chem, v.10, p.2759-2765, 2002.
• ABLORDEPPEY, S. Y.; ISSA, H.; FISCHER, J. B.; BURKE HOWIE, K. J.; GLENNON, R. A. Synthesis and structure-affinity relationship studies of sigma ligands related to haloperidol. Med. Chem. Res., v.3, p.131-138, 1993.
• ABLORDEPPEY, S. Y.; FISCHER, J. B.; BURKE HOWIE, K. J.; GLENNON, R. A. DESIGN, synthesis and binding of sigma receptor ligands derived from butaclamol. Med. Chem. Res, v.2, p.368-375, 1992b.
• ABOU-GHARBIA, M.; ABLORDEPPEY, S . Y.; GLENNON, R. A. Sigma receptors and their ligands: The Sigma Enigma. Ann. Rep. Med. Chem, v.28, p.1-10, 1993.
• BERARDI, F.; SANTORO, S; PERRONE, R.; TORTORELLA, V.; GOVONI, S; LUCCHI, L. N-[w-(Tetralin-1-yl)alkyl] derivatives of 3,3-dimethylpiperidine are highly potent and selective s₁ or s₂ ligands. J. Med. Chem., v.41, p.3940-3947, 1998.
• BERARDI, F.; FERORELLI, S.; ABATE, C.; COLABUFO, N. A.; CONTINO, M.; PERRONE, R.; TORTORELLA, V. 4-(Tetralin-1-yl)- and 4-(naphthalene-1-yl)alkyl derivatives of 1-cyclohexylpiperazine as s receptor ligands with agonist s₂ activity. J. Med. Chem, v.47, p.2308-2317, 2004.
• BOWEN, W. D. Sigma receptors: Recent advances and new clinical potentials. Helv. Pharm. Acta,v.74, p.211-218, 2000.
• Chavkin, C. The sigma enigma. Trends Pharmacol. Sci, v.11, p.213-215, 1990.
• DOMINO, E. F.; KAMENKA, J.-M. (Eds.) Sigma and Phencyclidine-like Compounds as Molecular Probes in Biology. Ann Arbor: NPP Books. 1988.
• EL-ASHMAWY, M.; ABLORDEPPEY, S. Y.; ISSA, H.; GAD, L.; FISCHER, J. B.; BURKE HOWIE, K. J.; GLENNON, R. A. FURTHER investigation of 5-phenylpentylamine derivatives as novel s receptor ligands. Med. Chem. Res, v.2, p.119-126, 1992.
• EL-ASHMAWY, M.; ABLORDEPPEY, S. Y.; ISSA, H.; GAD, L.; FISCHER, J. B.; BURKE HOWIE, K. J.; GLENNON, R. A. FURTHER, structure and quantitative structure-activity relationships of s receptor ligands, 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazines. Bioorg. Med. Chem, v.5, p.1675-1683, 1997.
• GILLIGAN, P. J.; CAIN, G. A.; CHRISTOS, T. E.; COOK, L.; DRUMMOND, S .; JOHNSON, A. L.; KERGAY, A. A.; MCELROY, J. F.; ROHRBACH, K. W.; SCHMIDT, W. K.; TAM, S . W. NOVEL piperidine s receptor ligands as potential antipsychotic drugs. J. Med. Chem., v.35, p.4344-4361, 1992.
• GLENNON, R. A. Sigma receptor ligands and the use thereof. U.S. Patent, v.6, p.057,371, May 2, 2000.
• GLENNON, R. A.; FISCHER, J. B. Sigma receptor ligands and the use thereof. U.S. Patent, v.6, p.087,346. July 11, 2000.
• GLENNON, R. A., SMITH, J. D., ISMAIEL, A. M., EL-ASHMAWY, M., BATTAGLIA, G., FISCHER, J. B. Identification and exploitation of the sigma opiate pharmacophore. J. Med. Chem, v.34, p.1094-1098, 1991a.
• GLENNON, R. A.; YOUSIF, M. Y.; ISMAIEL, A. M.; EL-ASHMAWY, M. B.; HERNDON, J. L.; FISCHER, J. B.; Server, A. C.; Burke-Howie, K. J. Novel 1-phenylpiperazines and 4-phenylpiperidines as high-affinity sigma ligands. J. Med. Chem, v.34, p.3360-3365, 1991b.
• GLENNON, R. A., ISMAIEL, A., SMITH, J. D., YOUSIF, M. Y., EL-ASHMAWY, M., HERNDON, J. L., FISCHER, J. B., BURKE HOWIE, K. J., SERVER, A. A. BINDING of substituted and conformationally restricted derivatives of N-(3-phenyl-n-propyl)- 1-phenyl-2-aminopropane at s receptors. J. Med. Chem, v.34, p.1855-1859, 1991c.
• ANAND, P.; TERENGHI, G.; WARNER, G.; KOPELMAN, P.; WILLIAMS-CHESTNUT, R.E.; SINICROPI Structural features important sigma-1 (s-₁) receptor binding. J. Med. Chem, v.37, p.1214-1219, 1994.
• GLENNON, R. A.; ISMAIEL, A. M.; ABLORDEPPEY, S.; EL-ASHMAWY, M.; FISHER, J. B. Thioxanthene-derived analogs as s₁ receptor ligands. Bioorg. Med. Chem. Lett, v.14, p-2217-2220, 2004.
• GUITART, X.; CODONY, X.; MONROY, X. Sigma receptors: Biology and therapeutic potential. Psychopharmacology, v.174, p.301-319, 2004.
• ITZHAK, Y. (ed.) Sigma receptors Academic Press, San Diego. 1994.
• ITZHAK, Y.; STEIN, I. Sigma binding sites in the brain: An emerging concept for multiple sites and their relevance for psychiatric disorders. Life Sci, v.47, p.1073-1081, 1990.
• JUNIEN, J. L.; LEONARD, B. E. Drugs acting on s receptors: A review of their nature, function, and possible therapeutic importance. Clin. Neuropharmacol, v.12, p.353-374, 1989.
• KAWAMURA, K.; ELSINGA, P. H.; KOBAYASHI, T.; ISHII, S.; WANG, W,-F.; MATSUNA, K.; VAALBURG, W.; ISHIWATA, K. Synthesis and evaluation of ¹¹C- and ¹⁸F-labeled 1-[2-(4-alkoxy-3-methoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazines as sigma receptor ligands for positron emission tomography studies. Nucl. Med. Biol., v.30, p.273-284, 2003.
• MACH, R. H.; WU, L.; WEST, T.; WHIRRETT, B. R.; CHILDERS, S. R. The analgesic tropane analogue (±)SM-21 has a high affinity for sigma₂ receptors. Life Sci, v.64, PL131-137, 1999.
• MACH, R. H.; HUANG, Y.; FREEMAN, R. A.; WU, L.; VANGVERAVONG, S.; LUEDTKE, R. R. Conformationally-flexible benzamide analogues as dopamine D₃ and s₂ receptor ligands. Bioorg. Med. Chem. Lett., v.14, p.195-202, 2004.
• MAIER, C. A.; WUNSCH, B. Novel spiropiperidines as highly potent and subtype selective s-selective ligands. J. Med. Chem, v.45, p.438-448, 2002.
• MARRAZZO, A.; PREZZAVENTO, O.; PASQUINUCCI, L.; VITTORIO, F.; RONISVALLE, G. Synthesis and pharmacological evaluation of potent and enantioselective s₁ and s₂ ligands. Farmaco, v.56, p.181-189, 2001.
• MATSUMOTO, R.; POTELLERET, F. H.; MACK, A.; POUW, B.; ZHANG, Y.; BOWEN, W. D. Structure-activity comparison of YZ-069, a novel s ligand, and four analogs in receptor binding and behavioral studies. Pharmacol. Biochem. Behav., v.77, p.775-781, 2004.
• MAY, E. M.; JACOBSON, A. E.; MATTSON, M. V.; TRAYNOR, J. R.; WOODS, J. H.; HARRIS, L. S.; BOWMAN, E. R.; ACETO, M. D. Synthesis and in vitro and in vivo activity of (-)-(1R,5R,9R)- and (+)-(1S,5S,9S)-N-alkenyl, N-alkynyl, and N-cyanoalkyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan homologues. J. Med. Chem., v.43, p.5030-5036, 2000.
• MAEDA, D. Y.; WILLIAMS, W.; KIM, W. E.; THATCHER, L. N.; BOWEN, W. D.; COOP, A. N-Arylalkylpiperidines as high-affinity sigma-1 and sigma-2 receptor ligands: Phenylpropylamines as potential leads for selective sigma-2 agents. Bioorg. Med. Chem. Lett, v.12, p.497-500, 2002.
• MUSACCHIO, J. M.; KLEIN, M.; CANOLL, P. D. Dextromethorphan and sigma ligands: Common site but diverse effects. Life Sci, v.45, p.1721-1732, 1989.
• PREZZAVENTO, O.; GUALTIERI, F.; MARRAZZO, A.; ROMANELLI, M. N.; RONSISVALLE, G.; TEODORI, E. Sigma receptor binding profile of a series of analgesic tropane derivatives. Arch. Pharm, v.335, p.39-43. 2002.
• QUIRION, R.; CHICHEPORTICHE, R.; CONTRERAS, P. C.; JOHNSON, K. M.; LODGE, D.; TAM, S. W.; WOODS, J. H.; ZUKIN, S. R. Classification and nomenclature of phencyclidine and sigma sites. Trends Neurol. Sci,v.11, p.444-446, 1987.
• SCHERZ, M. W.; FIALEIX, M.; FISCHER, J. B.; REDDY, N. L.; SERVER, A. C.; SONDERS, M. S.; TESTER, B. C.; WEBER, E.; WONG, S. T.; KEANA, J. F. W. Synthesis and structure-activity relationships of N,N-di-o-tolylguanidine analogues: High-affinity ligands for the haloperidol-sensitive s receptor. J. Med. Chem, v.33, p.2421-2429, 1990.
• SNYDER, S. H.; LARGENT, B. L. Receptor mechanisms in antipsychotic drug action: Focus on sigma receptors. J. Neuropsychiat, v.1, p.7-15, 1989.
• WALKER, J. M.; BOWEN, W. D.; WALKER, F. O.; MATSUMOTO, R. R.; DECOSTA, B.; RICE, K. C. Sigma receptors: Biology and function. Pharmacol. Rev, v.42, p.355-404, 1990.

Publication Dates

• Publication in this collection
  25 Oct 2006
• Date of issue
  Mar 2005

History

• Received
  27 Jan 2005
• Accepted
  02 Feb 2005