Neuropharmacological profile of a selective sigma ligand, igmesine: a potential antidepressant.

Igmesine is a selective sigma (sigma(1)) ligand that was reported to exert antidepressant action through an unknown mechanism of action. A number of neurochemical measures were taken in this study in efforts to understand its mode of action. Following 21-day drug treatments, the actions of igmesine on a number of neurochemical measures were investigated. Data obtained showed significant decreases in the densities of beta-adrenergic but not 5-HT(1A), sigma(1) and GABA(B) receptors in fluoxetine (18%), desipramine (DMI, 32%) and igmesine (20%)-treated groups when compared with control. Tyrosine hydroxylase (TH) activity was significantly (30-32%) reduced in all treated groups. Further, fluoxetine and DMI excluding the igmesine-treated groups showed 85 and 40% reductions in serotonin (5-HT) and noradrenaline (NE) neuronal uptake, respectively. Following acute treatment, igmesine lacked activity for monoamine oxidase (MAO) A or B (IC(50)>10 microM). In in vivo studies, at behaviorally active doses, igmesine showed weak effects on the NE uptake but lacked activity in altering 5-HT and DA synthesis or antagonizing selective drug-induced depletion of monoamine neuronal uptake. N-methyl-D-aspartate (NMDA)-induced increases in cGMP was blocked by igmesine indicating that igmesine may interfere with the NMDA receptor/nitric oxide synthase/cGMP pathway. Although it appears that part of the pharmacological actions of igmesine is mediated by the monoaminergic system, there is still need to explore other possible mechanisms of antidepressant action.

Stimulus-dependent modulation of [(3)H]norepinephrine release from rat neocortical slices by gabapentin and pregabalin.

Gabapentin (GBP; Neurontin) has proven efficacy in several neurological and psychiatric disorders yet its mechanism of action remains elusive. This drug, and the related compounds pregabalin [PGB; CI-1008, S-(+)-3-isobutylgaba] and its enantiomer R-(-)-3-isobutylgaba, were tested in an in vitro superfusion model of stimulation-evoked neurotransmitter release using rat neocortical slices prelabeled with [(3)H]norepinephrine ([(3)H]NE). The variables addressed were stimulus type (i.e., electrical, K(+), veratridine) and intensity, concentration dependence, onset and reversibility of action, and commonality of mechanism. Both GBP and PGB inhibited electrically and K(+)-evoked [(3)H]NE release, but not that induced by veratridine. Inhibition by these drugs was most pronounced with the K(+) stimulus, allowing determination of concentration-effect relationships (viz., 25 mM K(+) stimulus: GBP IC(50) = 8.9 microM, PGB IC(50) = 11.8 microM). R-(-)-3-Isobutylgaba was less effective than PGB to decrease stimulation-evoked [(3)H]NE release. Other experiments with GBP demonstrated the dependence of [(3)H]NE release inhibition on optimal stimulus intensity. The inhibitory effect of GBP increased with longer slice exposure time before stimulation, and reversed upon washout. Combination experiments with GBP and PGB indicated a similar mechanism of action to inhibit K(+)-evoked [(3)H]NE release. GBP and PGB are concluded to act in a comparable, if not identical, manner to preferentially attenuate [(3)H]NE release evoked by stimuli effecting mild and prolonged depolarizations. This type of modulation of neurotransmitter release may be integral to the clinical pharmacology of these drugs.

Thiazoloindans and thiazolobenzopyrans: a novel class of orally active central dopamine (partial) agonists.

The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5, 4-f]-[1]benzopyran (12) and 6-amino-2-(N, N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D(3) receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D(2) receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.

Synthesis and pharmacological evaluation of thiopyran analogues of the dopamine D3 receptor-selective agonist (4aR,10bR)-(+)-trans-3,4,4a,10b-tetrahydro-4-n-propyl-2H,5H [1]b enzopyrano[4,3-b]-1,4-oxazin-9-ol (PD 128907).

Benzopyranoxazine (+)-7 (PD 128907) is the most dopamine (DA) D3 receptor-selective agonist presently known. The only structural feature which distinguishes 7 from the analogous nonselective naphthoxazines is an oxygen atom in the 6-position. To extend this series of tricyclic DA agonists we used a classic bioisoster approach and synthesized thiopyran analogues of 7, which have a sulfur atom in the 6-position. We prepared trans-4-n-propyl-3,4,4a,10b-tetrahydro-2H,5H-[1]benzothiopyrano[4, 3-b]-1,4-oxazin-9-ol (9, trans-9-OH-PTBTO), its enantiomers ((+)-9 and (-)-9), the racemic cis-analogue (10), and the racemic trans-sulfoxide (11) and studied the potency and selectivity for DA receptors of these compounds. As with other rigid DA agonists, the highest affinity for DA receptors resided in one of the enantiomers, in this case the (-)-enantiomer of 9. On the basis of a single-crystal X-ray analysis of a key intermediate, the absolute configuration of (-)-9 was found to be 4aS,10bR, which is homochiral with (+)-(4aR,10bR)-7. In contrast to (+)-7 however, (-)-9 displayed no selectivity for any of the DA receptors. In addition, it has affinity for 5HT1A receptors. (+/-)-cis-4-n-Propyl-3,4,4a,10b-tetrahydro-2H,5H-[1]benzothiopyrano++ +[4,3-b]-1,4-oxazin-9-ol (10), which was expected to be inactive, displayed affinity and selectivity for the DA D3 receptor, whereas the sulfoxide 11 displayed some DA D3 selectivity, but with a lower affinity. Further pharmacological evaluation revealed that (-)-9 is a very potent full agonist at DA D2 receptors and a partial agonist at DA D3 receptors. The cis-analogue (+/-)-10 displayed the same profile, but with lower potency. These findings were confirmed in vivo: in reserpinized rats (-)-9 displayed short-acting activation of locomotor activity (DA D2 agonism) and also lower lip retraction and flat body posture, (5HT1A agonism). Compound (+/-)-10 had no effect on locomotor activity. In unilaterally 6-OH-DA lesioned rats, (-)-9 gave short-acting locomotor activation. Furthermore, in microdialysis studies in rat striatum, (-)-9 potently decreased DA release, confirming its activation of presynaptic DA D2 receptors.

PD 158771, a potential antipsychotic agent with D(2)/D(3) partial agonist and 5-HT(1A) agonist actions. I. Neurochemical effects.

The neurochemical effects of a novel dopamine (DA) D(2)-like and serotonin (5-HT) 5-HT(1A) agonist, PD 158771, are described. PD 158771 exhibited affinities for human D(2L), D(3) and D(4.2) receptors expressed in Chinese hamster ovary (CHO)-K1 cells with K(i) (nM) values of 5.2, 13.7 and 34.8 respectively. PD 158771 showed high affinity for cloned human 5-HT(1A) (K(i) = 2.6 nM) and rat hippocampal 5-HT(1A) receptors (K(i) = 3.5 nM). Weaker affinities were observed at alpha 1-adrenergic (K(i) = 43 nM), histamine H(1) (IC(50) = 30 nM), 5-HT(2A) (K(i) = 24.5 nM) and sigma (sigma) -1 binding sites (K(i) = 24.5 nM). In measures of in vitro functional activity, PD 158771 stimulated [(3)H]thymidine uptake in CHO p-5 cells transfected with hD(3) receptors with a maximal effect of 23% relative to quinpirole. In hD(2)L, the corresponding value was 60% with an EC(50) of 29 nM, again indicating partial DA agonist action of PD 158771. In vivo, PD 158771 produced a dose-related decrease in DA synthesis in the striatum and mesolimbic regions of rat brain treated with gamma-butyrolactone (GBL), indicating a DA autoreceptor agonist action. In animals not treated with GBL, PD 158771 produced a dose-related decrease in DA synthesis and extracellular DA. A decrease in 5-HT synthesis in several brain areas was observed consistent with an agonist response. Further support for DA autoreceptor agonist action is that PD 158771 produced a partial inhibition of the firing of substantia nigra zona compacta DA neurons, an effect reversed by haloperidol. In conclusion, PD 158771 exhibited affinities for DA and 5-HT receptors, appears to possess DA and 5-HT agonist actions; and it could provide improved antipsychotic profile with minimal side effects.

PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5-HT(1A) agonist actions. II. Preclinical behavioral effects.

PD 158771 has been described in receptor binding and biochemical tests as a partial agonist at dopamine (DA) D2 and D3 receptors as well as an agonist at serotonin (5-HT)(1A) receptors. The present studies describe the profile of PD 158771 in rodent and primate behavioral tests. PD 158771 reduced spontaneous locomotor activity in mice (ED(50)=0.38 mg/kg, i.p.) and rats (ED(50) = 1.2 mg/kg, i.p. and 0.16 mg/kg, s.c.), and reduced amphetamine-stimulated locomotion in mice (ED(50) = 0.13 mg/kg, i.p.). At relatively higher doses up to 3 mg/kg, s.c. in rats, PD 158771 did not produce locomotor stimulation or induce stereotypy, indicating a lack of postsynaptic DA agonist activity. PD 158771 reduced apomorphine stimulated locomotion in rats at a dose 4.6-fold greater than those that reduced spontaneous locomotor activity, indicating weak postsynaptic DA antagonist actions; results consistent with a partial agonist profile. PD 158771 produced anxiolytic-like effects in the water-lick (Vogel) conflict test, effects possibly due to the 5-HT(1A) activity. However, PD 158771 was inactive in the water wheel behavioral despair model in rats, indicating lack of antidepressant properties. Similar to known antipsychotics, PD 158771 produced a potent and long-lasting inhibition of conditioned avoidance responding in squirrel monkeys. In contrast to standard antipsychotics, and similar to clozapine, PD 158771 did not cause catalepsy in rats at a dose 20-fold higher than the ED(50) dose for locomotor inhibition. PD 158771 also had a somewhat lower liability than haloperidol to produce extrapyramidal dysfunction in squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. The data indicate that PD 158771 is a DA partial agonist with weak intrinsic activity that selectively activates brain DA autoreceptors. PD 158771 produced behavioral effects consistent with potential antipsychotic and anxiolytic efficacy, and has an improved profile in the extrapyramidal side effect model when compared to certain currently available antipsychotic agents.

A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with dopamine D4 antagonist activity: discovery of a potential atypical antipsychotic agent.

As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure-activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.

Design, synthesis, and evaluation of chromen-2-ones as potent and selective human dopamine D4 antagonists.

The discovery of a series of chromen-2-ones with selective affinity for the dopamine (DA) D4 receptor is described. Target compounds were tested for binding to cloned human DA D2L, D3, and D4.2 receptor subtypes expressed in Chinese hamster ovary K1 cells. Several compounds demonstrated high affinity (<20 nM, K(i)) and greater than 100-fold selectivity for DA D4.2 versus DA D2L receptors. The results of a SAR study are discussed within. In a DA D4 functional assay measuring [(3)H]thymidine uptake, target compounds showed antagonist activity at the D4.2 receptor. Compound 22, 7-[(2-phenylaminoethylamino)methyl]chromen-2-one, increased DOPA (L-3,4-dihydroxyphenylalanine) accumulation 51% in the hippocampus and 23% in the striatum of rat brains when dosed orally at 20 mg/kg.

Reduction of 3,4-diaminopyridine-induced biogenic amine synthesis and release in rat brain by gabapentin.

The anticonvulsant drug gabapentin has been shown recently to exhibit anxiolytic and analgesic actions in animals. Such actions have been postulated in part to reflect effects on biogenic amine neuronal activity. Therefore the effects of gabapentin on biogenic amine neuronal activity were assessed by measuring the synthesis of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in rat brain and on the release of [3H] NE from rat hippocampal slices both in the presence and absence of the depolarizing agent 3,4-diaminopyridine (DAP). Gabapentin (30 and 100 mg/kg, i.p.) did not alter the basal synthesis rates of NE and DA as assessed by the unchanged accumulation of L-dihydroxyphenylalanine (DOPA) in the NE-enriched hippocampus and cortex and in the DA-enriched striatum and mesolimbic areas. Gabapentin also did not alter 5-HT synthesis as determined by the unaltered accumulation of 5-hydroxytryptophan (5-HTP) in the same brain areas. DAP (2 mg/kg, i.p.) induced a modest but significant increase in DOPA accumulation in the hippocampal, mesolimbic and striatal regions. This DAP-induced increase in DOPA accumulation was antagonized significantly in the hippocampus and mesolimbic regions by gabapentin at 30 and 100 mg/kg and in striatum by 100 mg/kg; a 10 mg/kg dose was inactive. DAP increased selectively 5-HT synthesis in hippocampus and this effect was blocked by gabapentin. These findings indicate that the increased synthesis of biogenic amines induced by DAP is antagonized by gabapentin. In support of the in vivo studies, gabapentin was also shown to inhibit the DAP-evoked release of [3H]NE from hippocampal slices. Although the underlying mechanism for these effects is unclear, the present findings nevertheless demonstrate that gabapentin has inhibitory effects on stimulated NE, DA and 5-HT neurons that may be involved in explaining in part the CNS effects of this drug.

Pharmacological characterization of PD 152255, a novel dimeric benzimidazole dopamine D3 antagonist.

152255 (E-1,1'-(2-butene-1,4-diyl)bis[2-[4-[3-(1-piperidinyl)propoxy]-phe nyl]-1H-benzimidazole]) exhibited high affinity (Ki = 12.7 nM) for human dopamine (DA) D3 receptors expressed in CHO K1 cells but not for DA D2L receptors (Ki = 565 nM), DA D42 or DA D1 receptors (Ki > 3 microM) and a number of other neurotransmitter receptors. Affinity for human muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo. Antagonist activity at DA D3 receptors was demonstrated by blockade of quinpirole-stimulated [3H]-thymidine uptake in D3 transfected cells, an effect that was 28-fold more potent than in D2-transfected cells. Unlike classical DA D2 antagonists, PD 152255 did not increase rat brain DA synthesis and it increased locomotion in habituated rats. However, like antipsychotics, PD 152255 reduced locomotor activity in mice and reduced spontaneous and amphetamine-stimulated locomotion in nonhabituated rats. These results demonstrate that PD 152255 is a DA D3 antagonist that may have antipsychotic activity.

Isoindolinone enantiomers having affinity for the dopamine D4 receptor.

PD 108635 (1) was identified as a potent dopamine D4 ligand and we wanted to replace the benzylic alcohol with a metabolically more stable moiety. Investigations led to the discovery of a series of isoindolinones having D4 affinity.

Pyrazolo[1,5-a]pyrimidine CRF-1 receptor antagonists.

A series of 3-phenylpyrazolo[1,5-a]pyrimidines was prepared and found to have affinity for the human CRF-1 receptor. The 3-dimensional structure of one of the most potent analogs in this series, 10d, was determined by X-ray crystallography and suggests the spatial requirements for potent CRF-1 receptor binding affinity in this series.

(Aryloxy)alkylamines as selective human dopamine D4 receptor antagonists: potential antipsychotic agents.

The discovery of a series of novel (aryloxy)alkylamines with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. A number of compounds demonstrated subnanomolar Ki values for binding to the D4 receptor, with several 100-fold selectivities toward the D2 and D3 receptors. Several compounds with combined D3/D4 receptor binding selectivity were also identified. A limited structure-activity relationship study of this chemical series is discussed. In a mitogenesis functional assay, the effect of the test compounds on cellular uptake of [3H]thymidine in D4-transfected CHO 10,001 cells was measured and compared to the response of the full dopamine agonist quinpirole. The activity of the compounds varied from full antagonist to weak partial agonist activity (intrinsic activity of 0-19% in comparison to quinpirole).

Effects of the dopamine D3 antagonist PD 58491 and its interaction with the dopamine D3 agonist PD 128907 on brain dopamine synthesis in rat.

The dopamine (DA) D3 receptor antagonist PD 58491 [3-[4-[1-[4-[2-[4-(3-diethylaminopropoxy)phenyl]benzoimidazol++ +-1-yl-butyl]-1H-benzoimidazol-2-yl]phenoxy]propyl]diethylamine] bound with high affinity and selectivity to recombinant human DA D3 versus D2L and D4.2 receptors transfected into Chinese hamster ovary cells: Ki values of 19.5 nM versus 2,362 and >3,000 nM, respectively. In contrast, the putative DA D3 receptor antagonist (+)-AJ76 displayed low affinity and selectivity for D3 versus D2L and D4.2 receptors (91 nM vs. 253 and 193 nM, respectively). In vitro, PD 58491 (1 nM-1 microM) exhibited D3 receptor antagonist activity, reversing the quinpirole (10 nM)-induced stimulation of [3H]thymidine uptake in D3 CHOpro-5 cells, but did not have any significant intrinsic activity by itself in this assay. PD 58491 did not decrease the gamma-butyrolactone-induced increase in DA synthesis (L-3,4-dihydroxyphenylalanine accumulation) in rat striatum, indicating that the compound possessed no in vivo DA D2/D3 receptor agonist action at DA autoreceptors. PD 58491 (3-30 mg/kg, i.p.) generally did not alter DA or serotonin synthesis in either the striatum or mesolimbic region of rat brain. The D3-preferring agonist PD 128907 decreased DA synthesis in striatum and mesolimbic regions, and this effect was attenuated by pretreatment with PD 58491. These findings support the hypothesis that DA D3 autoreceptors may in part modulate the synthesis and release of DA in striatum and mesolimbic regions.

Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine.

The human dopamine D4 receptor (D4R) has received considerable attention because of its high affinity for the atypical antipsychotic clozapine and the unusually polymorphic nature of its gene. To clarify the in vivo role of the D4R, we produced and analyzed mutant mice (D4R-/-) lacking this protein. Although less active in open field tests, D4R-/- mice outperformed wild-type mice on the rotarod and displayed locomotor supersensitivity to ethanol, cocaine, and methamphetamine. Biochemical analyses revealed that dopamine synthesis and its conversion to DOPAC were elevated in the dorsal striatum from D4R-/- mice. Based on these findings, we propose that the D4R modulates normal, coordinated and drug-stimulated motor behaviors as well as the activity of nigrostriatal dopamine neurons.

Chromeno[3,4-c]pyridin-5-ones: selective human dopamine D4 receptor antagonists as potential antipsychotic agents.

The discovery of a series of chromeno[3,4-c]pyridin-5-ones with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. Several compounds demonstrated single digit nanomolar Ki values for binding to the D4 receptor with several hundred-fold selectivities toward the D2 and D3 receptors. A limited SAR study of this series is discussed. In a mitogenesis assay measuring [3H]thymidine uptake, the target compounds showed antagonist to weak partial agonist activity at the D4 receptor, with intrinsic activities ranging from 0 to 35%. Compound 6, 3-benzyl-8-methyl-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, increased DOPA (L-3,4-dihydroxyphenylalanine) synthesis 84% in the hippocampus and 10% in the striatum of rat brain when dosed orally at 10 mg/kg.

Cloning, expression and characterization of a human dopamine D4.2 receptor (CHO K1 cells) and various D4.2/D2L chimeras (COS-7 cells).

1. Using the gene splicing technique a synthetic human dopamine (DA) D4.2 gene was constructed and subsequently stably expressed in CHO K1 cells. 2. Binding of [3H]spiperone to membranes prepared from human DA D4.2 CHO K1 cells was saturable with a Kd of 93 +/- 0.51 pM and a Bmax of 768 +/- 22 fmol per mg protein. 3. Clozapine, apomorphine, and S(+)-NPA were more selective for D4.2 than for D2L receptors, with D2L/D4.2 ratios of 5.7, 7.1, and 19.6, respectively. 4. Functional studies indicated that DA D4.2 receptors expressed in CHO K1 cells inhibited forskolin stimulated cAMP levels showing coupling to G-proteins. 5. Two reciprocal human D2L and D4.2 chimeric receptors (D2L/D4.2 and D4.2/D2L) were constructed by exchanging the amino-terminal end to the third transmembrane (TM) of one receptor with the counter part of the other receptor and expressing them transiently into COS-7 cells. The chimeric D2L/D4.2 receptor displayed non-detectable specific binding of [3H] spiperone and other ligands. The chimeric D4.2/D2L receptor binding affinities of DA agonists were more affected than that of antagonists, suggesting that binding affinities of agonists are more sensitive to changes in receptor conformation than that of antagonists. 6. This study characterized the pharmacology of a novel synthesized DA D4.2 receptor that provides a useful model for screening of potential D4.2 receptor agonist and antagonist.

3-[[(4-Aryl-1-piperazinyl)alkyl]cyclohexyl]-1H-indoles as dopamine D2 partial agonists and autoreceptor agonists.

A series of arylpiperazines and tetrahydropyridines joined to indoles by semirigid cycloalkyl spacers were prepared. Target compounds were studied for their ability to bind to the DA D2 receptor in vitro and to inhibit dopamine synthesis and spontaneous locomotor activity in rats. Effects of tether length and relative stereochemistry were assessed for a series of 2-pyridylpiperazines. The cyclohexylethyl spacer was found to be the most active in the series. Further studies explored effects of changes in the arylpiperazine and indole portions of the molecule. From these studies trans-2-[[4-(1H-3-indolyl)cyclohexyl]ethyl]-4- (2-pyridinyl)piperazine (30a) was selected for further evaluation. It was characterized as a partial agonist of DA D2 receptors in vitro and caused decreases in dopamine synthesis and release as well as dopamine neuronal firing. Compound 30a was shown to be devoid of behavioral effects associated with postsynaptic DA D2 receptor activation. Furthermore, compound 30a was shown both to decrease DA synthesis and to inhibit Sidman avoidance responding in squirrel monkeys. These findings suggest that DA D2 partial agonists with the appropriate level of intrinsic activity can act to decrease dopamine synthesis and release and may have potential utility as antipsychotic agents.

The pharmacology of the novel and selective sigma ligand, PD 144418.

The pharmacology of PD 144418 (1-propyl-5-(3-p-tolyl-isoxazol-5-yl)-1,2,3,6-tetrahydropyridine) was characterized using neurochemical, biochemical and behavioral techniques. For sigma (sigma 1 and sigma 2 respectively) sites, PD 144418 affinities were determined using whole guinea pig brain membranes with [3H](+)-pentazocine and neuroblastoma x glioma cell membranes using [3H]1,3,di-O-tolylguanidine (DTG) in the presence of 200 nM (+)-pentazocine. PD 144418 exhibited an affinity for sigma 1 of 0.08 nM (Ki) versus a K1 of 1377 nM for sigma 2 site. Additional receptor binding studies indicated that PD 144418 lacked affinity for dopaminergic, adrenergic, muscarinic and a variety of other receptors. In vitro studies indicated that PD 144418 reversed the N-methyl-D-aspartate (NMDA)-induced increase in cyclic GMP (cGMP) in rat cerebellar slices without affecting the basal levels, suggesting that sigma 1 sites may be important in the regulation of glutamine-induced actions. PD 144418 potentiated the decrease in 5-hydroxytryptophan caused by haloperidol in the mesolimbic region, but by itself had no effect in 5-hydroxytrypamine (5-HT) and dopamine (DA) synthesis. Behaviorally, similar to other sigma ligands, PD 144418 antagonized mescaline-induced scratching at doses that did not alter spontaneous motor activity. This action is suggestive of potential antipsychotic property. It exhibited no anxiolytic and antidepressant properties in the models used. These results show that PD 144418 is a very selective sigma 1 agent, devoid of any significant affinity for other receptors and that sigma 1 site may modulate actions in the CNS.