Synthesis and characterization of selective dopamine D₂ receptor ligands using aripiprazole as the lead compound

A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D(?-like) dopamine receptors. These compounds also share structural elements with the classical D(?-like) dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D? receptor subtype with high affinity (K(i) values < 0.3 nM), (b) exhibit >50-fold D? versus D? receptor binding selectivity and (c) be partial agonists at both the D? and D? receptor subtype.     

Conformationally-flexible benzamide analogues as dopamine D3 and sigma 2 receptor ligands

A series of conformationally-flexible analogues was prepared and their affinities for D2-like dopamine (D2, D3 and D4) were determined using in vitro radioligand binding assays. The results of this structure-activity relationship study identified one compound, 15, that bound with high affinity (K(i) value=2nM) and moderate selectivity (30-fold) for D3 compared to D2 receptors. In addition, this series of compounds were also tested for affinity at sigma1 and sigma2 receptors. We evaluated the affinity of these dopaminergic compounds at sigma receptors because (a) several antipsychotic drugs, which are high affinity antagonists at dopamine D2-like receptors, also bind to sigma receptors and (b) sigma receptors are expressed ubiquitously and at high levels (picomoles per mg proteins). It was observed that a number of analogues displayed high affinity and excellent selectivity for sigma2 versus sigma1 receptors. Consequently, these novel compounds may be useful for characterizing the functional role of sigma2 receptors and for imaging the sigma2 receptor status of tumors in vivo with PET.     

Synthesis and D(2)-like binding affinity of new derivatives of N-(1-ethyl-2-pyrrolidinylmethyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxamide and related 4H-[1]benzothiopyrano[4,3-b]pyrrole and 5,6-dihydro-4H-benzo[6,7]cyclohepta[b]pyrrole-3-carboxamide analogues

Various new derivatives and structural analogues of N-(1-ethyl-2-pyrrolidinylmethyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxamide (2a), a representative term of a series of 2-aminomethylpyrrolidinyl derived 4,5-dihydrobenzo[g]indolcarboxamides with good D(2)-like affinity, were synthesized and evaluated for their ability to bind to dopamine D(2)-like receptors in vitro. The structural contribution to D(2)-like receptor binding of the 4,5-dihydrobenzo[g]indole portion of the molecule was examined. From these studies, compound 2k, 2-chloro-N-(1-ethyl-2-pyrrolidinylmethyl)-5,6-dihydro-4H-benzo[6,7]cyclohepta[b]pyrrole-3-carboxamide, was found to possess a potent affinity for D(2)-like receptors. Behavioural tests in rats have shown that this compound reduces the hyperactivity induced by amphetamine, a property shared by all antipsychotic drugs, at a dose which failed to induce catalepsy, an effect which is predictive of extrapyramidal side effects in humans. The other compounds demonstrated moderate (2c, 2h, and 2j) or no affinity for D(2)-like receptors.     

Synthesis of novel lactam derivatives and their evaluation as ligands for the dopamine receptors, leading to a D(4)-selective ligand

The preparation of some lactam (cyclic amide) derivatives bearing various phenylpiperazinylbutyl side chains attached to the amide nitrogen together with their dopamine receptor affinity study is described. The synthesis of the target compounds involved the preparation of the intermediate bromobutyl derivatives of the appropriate lactam followed by N-alkylation of the appropriate phenylpiperazines with these intermediates. Radioligand binding studies at D(2)-D(5) receptor subtypes and a functional calcium assay of the target compounds at D(2) and D(5) receptor subtypes were performed. All compounds, except 12a and 12b, showed selectivity towards the D(2)-like receptor subtypes. Selectivity of the indolinone derivatives 11a-d at the D(4) receptors was observed. Compound 11b exhibited a remarkable affinity to hD(4) receptors with K(i) value of 0.04+/-0.02 nm and was >43,000-fold selective over the hD(2) receptor. In the functional assay, all the active compounds were of antagonistic activity.     

Synthesis and characterization of selective dopamine D2 receptor antagonists. 2. Azaindole,benzofuran, and benzothiophene analogs of L-741,626

A series of indole, 7-azaindole, benzofuran, and benzothiophene compounds have been prepared and evaluated for affinity at D_2-like dopamine receptors. These compounds share structural elements with the classical D_2-like dopamine receptor antagonists haloperidol, N-methylspiperone and benperidol. Two new compounds, 4-(4-iodophenyl)-1-((4-methoxy-1H-indol-3-yl)methyl)piperidin-4-ol (6) and 4-(4-iodophenyl)-1-((5-methoxy-1H-indol-3-yl)methyl)piperidin-4-ol (7), were found to have high affinity to and selectivity for D₂ versus D₃ receptors. Changing the aromatic ring system from an indole to other heteroaromatic ring systems reduced the D₂ binding affinity and the D₂ versus D₃ selectivity.     

Molecular Cloning,Stable Expression and Desensitization of the Human Dopamine D1B / D5 Receptor

Abstract

The sub-family of dopamine D1-like receptors is now known to be comprised of at least two members: the originally cloned D1 receptor (herein referred to as the D1a receptor) and a related receptor referred to as the D1b, D1β or D5 dopamine receptor (herein referred to as the D1b/D5 receptor). Here, we characterize the D1b/D5 receptor expressed transiently in COS-7 cells and permanently in Ltk^? cells.

Transiently expressed human D1b/D5 receptors bind the D1 specific ligand [¹²⁵I]SCH 23982 saturably and with high affinity (K_D = 500 _pM). Competition for [¹²⁵I]SCH 23982 binding to rat D1b/D5 and human D1a and D1b/D5 receptors supports the contention that the two D1b/D5 receptors are species homologues. Furthermore, in COS-7 cells, as previously observed, dopamine competes for the binding of [¹²⁵I]SCH 23982 to human D1b/D5 receptors with a higher affinity than that seen at the human D1a receptor. These results are similar to those seen in Ltk^? cells permanently transfected with the human D1b/D5 receptor. In these cells, dopamine competition for [¹²⁵I]SCH 23982 binding is complex, sensitive to guanine nucleotides and of a higher affinity than that observed for dopamine binding to the human D1a receptor expressed in these same cells. In both D1a and D1b/D5 expressing Ltk^? cells, dopamine stimulates adenylyl cyclase with an EC₅₀ of = 200 nM. Furthermore, preincubation of Ltk^? cells expressing the D1a and D1b/D5 receptors with dopamine results in desensitization of the response of adenylyl cyclase to subsequent agonist stimulation.     

The dopamine D(2) receptor is expressed and sensitizes adenylyl cyclase activity in airway smooth muscle

Dopamine receptors are G protein-coupled receptors that are divided into two subgroups, "D(1)-like" receptors (D(1) and D(5)) that couple to the G(s) protein and "D(2)-like" receptors (D(2), D(3), and D(4)) that couple to G(i). Although inhaled dopamine has been reported to induce bronchodilation in patients with asthma, functional expression of dopamine receptor subtypes has never been described on airway smooth muscle (ASM) cells. Acute activation of G(i)-coupled receptors inhibits adenylyl cyclase activity and cAMP synthesis, which classically impairs ASM relaxation. In contrast, chronic activation of G(i)-coupled receptors produces a paradoxical enhancement of adenylyl cyclase activity referred to as heterologous sensitization. We questioned whether the dopamine D(2)-like receptor is expressed on ASM, whether it exhibits classical G(i)-coupling, and whether it modulates ASM function. We detected the mRNA encoding the dopamine D(2) receptor in total RNA isolated from native human ASM and from cultured human airway smooth muscle (HASM) cells. Immunoblots identified the dopamine D(2) receptor protein in both native human and guinea pig ASM and cultured HASM cells. The dopamine D(2) receptor protein was immunohistochemically localized to both human and guinea pig ASM. Acute activation of the dopamine D(2) receptor by quinpirole inhibited forskolin-stimulated adenylyl cyclase activity in HASM cells, which was blocked by the dopamine D(2) receptor antagonist L-741626. In contrast, the chronic pretreatment (1 h) with quinpirole potentiated forskolin-stimulated adenylyl cyclase activity, which was inhibited by L-741626, the phospholipase C inhibitor U73122, or the protein kinase C inhibitor GF109203X. Quinpirole also stimulated inositol phosphate synthesis, which was inhibited by L-741626 or U73122. Chronic pretreatment (1 h) of the guinea pig tracheal rings with quinpirole significantly potentiated forskolin-induced airway relaxation, which was inhibited by L-741626. These results demonstrate that functional dopamine D(2) receptors are expressed on ASM and could be a novel therapeutic target for the relaxation of ASM.     

Characterization of [3H]LS‐3‐134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand

LS‐3‐134 is a substituted N‐phenylpiperazine derivative that has been reported to exhibit: (i) high‐affinity binding (K_i value 0.2 nM) at human D3 dopamine receptors, (ii) > 100‐fold D3 versus D2 dopamine receptor subtype binding selectivity, and (iii) low‐affinity binding (K_i > 5000 nM) at sigma 1 and sigma 2 receptors. Based upon a forskolin‐dependent activation of the adenylyl cyclase inhibition assay, LS‐3‐134 is a weak partial agonist at both D2 and D3 dopamine receptor subtypes (29% and 35% of full agonist activity, respectively). In this study, [³H]‐labeled LS‐3‐134 was prepared and evaluated to further characterize its use as a D3 dopamine receptor selective radioligand. Kinetic and equilibrium radioligand binding studies were performed. This radioligand rapidly reaches equilibrium (10–15 min at 37°C) and binds with high affinity to both human (K_d = 0.06 ± 0.01 nM) and rat (K_d = 0.2 ± 0.02 nM) D3 receptors expressed in HEK293 cells. Direct and competitive radioligand binding studies using rat caudate and nucleus accumbens tissue indicate that [³H]LS‐3‐134 selectively binds a homogeneous population of binding sites with a dopamine D3 receptor pharmacological profile. Based upon these studies, we propose that [³H]LS‐3‐134 represents a novel D3 dopamine receptor selective radioligand that can be used for studying the expression and regulation of the D3 dopamine receptor subtype.     

Substituted 1-phenyl-2-cyclopropylmethylamines with high affinity and selectivity for sigma sites

A series of 1-phenyl-2-cyclopropylmethylamines structurally related to (+)- and (-)-MPCB were synthesized and their binding affinities for sigma1, sigma2, opioid and dopamine (D2) receptors were evaluated. Substitution of the cis-N-normetazocine with different aminic moieties provided compounds with high affinity and selectivity for sigma binding sites with respect to opioid and dopamine (D2) receptors. The observed increase in sigma2 affinity as compared to the parent (+)-MPCB, supports the idea that the particular stereochemistry of (+)-cis-N-normetazocine affects sigma1 selectivity but does not affect sigma1 affinity. The (+/-)-cis isomers of methyl 2-[(1-adamantylamino)methyl]-1-phenylcyclopropane-1-carboxyl ate (18) displayed a higher affinity and selectivity for the sigma1 and sigma2 receptor subtypes compared to the (+/-)-trans 19. Interestingly, the enantiomer (-)-cis 18 displayed a preference for sigma1 receptor subtype whereas the (+)-cis 18 did for sigma2. These results prompt us to synthesize compounds with modification of nitrogen and carboxyl groups. The compounds obtained showed high affinities and selectivity for sigma sites. Moreover, modifications of carboxyl groups provided compounds with the highest affinities in the series. In particular, compound 25 with reverse-type ester showed a Ki of 0.6 and 4.05 nM for sigma1 and sigma2 binding sites, respectively.     

Distinct function of the cytoplasmic tail in human D1-like receptor ligand binding and coupling

To delineate the role of the cytoplasmic tail in the distinct binding and coupling properties of human dopamine D1-like receptors, chimeric receptors were generated in which the entire tail region of wild-type human D1A (or D1) and D1B (or D5) receptors was exchanged. The hD1A-D1BT, but not hD1B-D1AT, receptor expression was dramatically reduced compared with wild-type receptor expression. Swapping the cytoplasmic tail resulted in a full switch of dopamine binding affinity and constitutive activity, while dopamine potency decreased and agonist-mediated maximal activation of adenylyl cyclase increased for both chimeras. Hence, the cytoplasmic tail plays a crucial role in D1-like receptor expression, agonist binding affinity and constitutive activation but regulates in a distinct fashion the formation of D1A and D1B receptor active states upon dopamine binding.     

Differential regulation of sigma and PCP receptors after chronic administration of haloperidol and phencyclidine in mice

The existence of multiple receptor sites for the psychotomimetic agents phencyclidine (PCP) and some opiate-benzomorphans such as (+)N-allylnormetazocine ([+]SKF 10,047) in the mammalian central nervous system is well documented. These are: 1) sigma/PCP (sigma p) site, which binds both PCP and psychotomimetic opiates but not antipsychotics such as haloperidol, 2) PCP site, which selectively binds PCP analogs, and 3) sigma/haloperidol (sigma h) site, for which certain antipsychotics and (+)SKF 10,047, but not PCP analogs, display high affinity. In this study we examined the regulation of these receptor sites after chronic treatment of mice with either PCP or haloperidol. The following radiolabeled ligands were used to assess binding to the various receptor subtypes: [3H]-1-[1-[3-hydroxyphenyl)cyclohexyl]piperidine ([3H]PCP-3-OH; sigma p and PCP sites), [3H]thienyl-phencyclidine ([3H]TCP; PCP site), (+)-[3H]SKF 10,047 (sigma p and sigma h sites), and [3H]haloperidol (sigma h and D-2 dopamine receptors). Treatment of mice for 1, 7, 14, and 21 days with PCP (10 mg.kg-1.day-1) failed to induce variations in sigma p, sigma h, and PCP receptor binding. However, similar treatment with haloperidol (4 mg.kg-1.day-1) induced: 1) complete elimination of the binding to sigma h sites, 2) up-regulation of D-2 dopamine receptors, and 3) no change in sigma p and PCP receptor binding after 14 or 21 days of treatment. However, a single day of haloperidol treatment or in vitro incubation of mouse brain membranes with haloperidol failed to alter receptor binding. This study suggests that prolonged treatment of mice with haloperidol induces a loss in sigma h receptors that are presumably associated with certain psychotomimetic effects. This phenomenon is accompanied by an up-regulation of D-2 dopamine receptors.     

Chemical modification of apomorphine to discover sigma ligands: 6H-dibenzo[b,d]pyran and carbazole analogues.

It seems that many sigma ligands have been designed from known sigma ligands. We focused on a difference in structural flexibility between haloperidol and apomorphine, and studied chemical modification of apomorphine, a compound with high affinity for dopamine D2 receptors but not for sigma receptors, for discovery of sigma ligands. The first modification yielded good results with 6H-dibenzo[b,d]pyran analogues with weak affinity for sigma receptors but not D2 receptors. Furthermore, carbazole analogues, compounds designed from 6H-dibenzo[b,d]pyran analogues, potentially acted at sigma receptors with high selectivity. This paper describes the design, synthesis and sigma/D2 selectivity of 6H-dibenzo[b,d]pyran and carbazole analogues.     

Functional Differentiation of Multiple Dopamine D1-Like Receptors by NNC 01-0012

Abstract: Although members of the multiple vertebrate/mammalian dopamine D1 receptor gene family can be selectively classified on the basis of their molecular/phylogenetic, structural, and tissue distribution profiles, no subtype-specific discriminating agents have yet been identified that can functionally differentiate these receptors. To define distinct pharmacological/functional attributes of multiple D1-like receptors, we analyzed the ligand binding profiles, affinity, and functional activity of 12 novel NNC compounds at mammalian/vertebrate D1/D1A and D5/D1B, as well as vertebrate D1C/D1D, dopamine receptors transiently expressed in COS-7 cells. Of all the compounds tested, only NNC 01-0012 displayed preferential selectivity for vertebrate D1C receptors, inhibiting [³H]SCH-23390 binding with an estimated affinity (∼0.6 n M ) 20-fold higher than either mammalian/vertebrate D1/D1A or D5/D1B receptors or the D1D receptor. Functionally, NNC 01-0012 is a potent antagonist at D1C receptors, inhibiting to basal levels dopamine (10 µ M )-stimulated adenylyl cyclase activity. In contrast, NNC 01-0012 (10 µ M ) exhibits weak antagonist activity at D1A receptors, inhibiting only 60% of maximal cyclic AMP production by dopamine, while acting as a partial agonist at vertebrate D1B and D1D receptors, stimulating adenylyl cyclase activity by ∼33% relative to the full agonist dopamine (10 µ M ), an effect that was blocked by the selective D1 receptor antagonist NNC 22-0010. These data clearly suggest that the benzazepine NNC 01-0012, despite lacking the N -methyl residue in the R3 position, is a selective and potent D1C receptor antagonist. Moreover, the differential signal transduction properties exhibited by NNC 01-0012 at these receptor subtypes provide further evidence, at least in vertebrates, for the classification of the D1C receptor as a distinct D1 receptor subtype.     

Phenylpiperazinylmethylindolecarboxylates and derivatives as selective D(4)-ligands

Novel phenylpiperazinylmethylindolecarboxylates were synthesized for evaluation as potential D(4)-ligands. Test compounds showed high affinity for the human dopamine D(4) receptor and great selectivity over the other receptor subtypes. Intrinsic effects of indole derivatives, which indicated most promising binding properties, were investigated in a mitogenesis assay.     

Synthesis and in vitro binding of N-phenyl piperazine analogs as potential dopamine D3 receptor ligands

A series of N-(2-methoxyphenyl)piperazine and N-(2,3-dichlorophenyl)piperazine analogs were prepared and their affinities for dopamine D(2), D(3), and D(4) receptors were measured in vitro. Binding studies were also conducted to determine if the compounds bound to sigma (sigma(1) and sigma(2)) and serotonin (5-HT(1A), 5-HT(2A), 5-HT(2B), 5-HT(2C), 5-HT(3), 5-HT(4), 5-HT(5), 5-HT(6), and 5-HT(7)) receptors. The results of the current study revealed a number of compounds (12b, 12c, 12e, and 12g) having a high affinity for D(3) (K(i) at D(3) receptors ranging from 0.3 to 0.9 nM) versus D(2) (K(i) at D(2) receptors ranging from 40 to 53 nM) receptors and a log P value indicating that they should readily cross the blood brain barrier (log P = 2.6-3.5). All of the compounds evaluated in this study had a high affinity for serotonin 5-HT(1A) receptors. These compounds may be useful as probes for studying the behavioral pharmacology of the dopamine D(3) receptor, as well as lead compounds for the development of radiotracers for studying D(3) receptor regulation in vivo with the functional imaging technique, positron emission tomography.     

Pharmacological characterization of mammalian D1 and D2 dopamine receptors expressed in Drosophila Schneider-2 cells

Mammalian D1 and D2 dopamine receptors were stably expressed in Drosophila Schneider-2 (S2) cells and screened for their pharmacological properties. Saturable, dose-dependent, high affinity binding of the D1-selective antagonist [3H]SCH-23390 was detected only in membranes from S2 cells induced to express rat dopamine D1 receptors, while saturable, dose-dependent, high affinity binding of the D2-selective antagonist [3H]methylspiperone was detected only in membranes from S2 cells induced to express rat dopamine D2 receptors. No specific binding of either radioligand could be detected in membranes isolated from uninduced or untransfected S2 cells. Both dopamine D1 and D2 receptor subtypes displayed the appropriate stereoselective binding of enantiomers of the nonselective antagonist butaclamol. Each receptor subtype also displayed the appropriate agonist stereoselectivities. The dopamine D1 receptor bound the (+)-enantiomer of the D1-selective agonist SKF38393 with higher affinity than the (-)-enantiomer, while the dopamine D2 receptor bound the (-)-enantiomer of the D2-selective agonist norpropylapomorphine with higher affinity than the (+)-enantiomer. At both receptor subtypes, dopamine binding was best characterized as occurring to a single low affinity site. In addition, the low affinity dopamine binding was also found to be insensitive to GTPgammaS and magnesium ions. Overall, the pharmacological profiles of mammalian dopamine D1 and D2 receptors expressed in Drosophila S2 cells is comparable to those observed for these same receptors when they are expressed in mammalian cell lines. A notable distinction is that there is no evidence for the coupling of insect G proteins to mammalian dopamine receptors. These results suggest that the S2 cell insect G system may provide a convenient source of pharmacologically active mammalian D1 and D2 dopamine receptors free of promiscuous G protein contaminants.     

Dopaminergic Inhibition of Catecholamine Secretion from Chromaffin Cells: Evidence that Inhibition Is Mediated by D4 and D5 Dopamine Receptors

Abstract: Previous studies have suggested that activation of D2-like dopamine receptors inhibits catecholamine secretion from adrenal chromaffin cells. The purpose of this study was to determine whether the activation of D1-like receptors on chromaffin cells affects either catecholamine release from the cells or the inhibition of secretion by D2-like dopamine receptors. Both D1- and D2-selective agonists inhibited secretion elicited by dimethylphenylpiperazinium (DMPP), veratridine, and high K⁺ levels. The D1-selective agonists 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Cl-APB) and SKF-38393 inhibited DMPP-stimulated catecholamine secretion in a concentration-dependent manner; 50% inhibition was obtained with ～10 µM Cl-APB and ～100 µM SKF-38393. Of the D2-selective agonists, bromocriptine was a more potent inhibitor of DMPP-stimulated catecholamine release than was quinpirole. The inhibition of secretion caused by Cl-APB or SKF-38393 was additive with the inhibition caused by bromocriptine. Pertussis toxin treatment (50 ng/ml, 18 h) attenuated the inhibitory effect of D2-selective, but not D1-selective, dopamine agonists. In addition, forskolin-stimulated adenylyl cyclase activity was inhibited by D2-selective, but not D1-selective, agonists. Neither D1- nor D2-selective agonists stimulated adenylyl cyclase activity in the cells, although cyclase activity was stimulated by forskolin, carbachol, and vasoactive intestinal peptide. DMPP-stimulated Ca²⁺ uptake was inhibited by both D1- and D2-selective dopamine agonists. PCR analysis was used to determine which of the dopamine receptor subtypes within the D1-like and D2-like subfamilies was responsible for the observed inhibition. PCR analysis indicated that mRNA for only D4 and D5 dopamine receptor subtypes was present in chromaffin cells. These combined data suggest that D1- and D2-selective agonists inhibit Ca²⁺ uptake and catecholamine secretion by activating D4 and D5 dopamine receptors on chromaffin cells.     

Insight into the mechanism of dopamine D1-like receptor activation. Evidence for a molecular interplay between the third extracellular loop and the cytoplasmic tail

A chimeric D1A dopaminergic receptor harboring the cytoplasmic tail (CT) of the D1B subtype (D1A-CTB) has been used previously to show that CT imparts high dopamine (DA) affinity and constitutive activity to the D1B receptors. However, the D1A-CTB chimera, unlike the D1B subtype, exhibits a significantly lower DA potency for stimulating adenylyl cyclase and a drastically lower maximal binding capacity (Bmax). Here, using a functional complementation of chimeric D1-like receptors, we have identified the human D1B receptor regions regulating the intramolecular relationships that lead to an increased DA potency and contribute to Bmax. We demonstrate that the addition of variant residues of the third extracellular loop (EL3) of the human D1B receptor into D1A-CTB chimera leads to a constitutively active mutant receptor displaying an increased DA affinity, potency, and Bmax. These results strongly suggest that constitutively active D1-like receptors can adopt multiple active conformations, notably one that confers increased DA affinity with decreased DA potency and Bmax and another that imparts increased DA affinity with a strikingly increased DA potency and Bmax. Overall, we show that a novel molecular interplay between EL3 and CT regulates multiple active conformations of D1-like receptors and may have potential implications for other G protein-coupled receptor classes.     

Sigma binding sites in the brain; an emerging concept for multiple sites and their relevance for psychiatric disorders

An increasing amount of evidence suggests the existence of specific binding sites for psychotomimetic drugs from the opiate-benzomorphan and arylcyclohexylamine series. The sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine and (+)pentazocine and also for some neuroleptics (e.g., haloperidol). The PCP receptor has preferential affinity for phencyclidine (PCP) analogs and other non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists. The physiological significance of the PCP receptor is associated with the blockade of the NMDA type of the glutamate receptor, implying a neuroprotective role of the PCP receptor. However, the significance of the sigma binding sites is less conspicuous. It is not only that drugs from distinct pharmacological classes display a certain degree of affinity for the "sigma/haloperidol" binding sites, but also that drugs which do not induce or block psychotomimetic activity, i.e., (+)3-(3-hydroxyphenyl)-N-(1-propyl) piperidine [(+)3-PPP] and 1,3-di-o-tolyl-guanidine (DTG), display relatively high affinity for the sigma binding sites. The diversity of the compounds which are proposed to interact with the sigma receptors and the variety of the responses elicited by these drugs suggest the existence of sigma receptor subtypes. The finding that the type A of monoamine oxidase (MAO) inhibitors, which are used in treatment of affective disorders, display high affinity for the sigma binding sites suggests their involvement in affective or schizoaffective disorders. Revealing the existence of sigma receptor subtypes may help to elucidate their association with various psychiatric disorders.