Pregabalin enhances nonrapid eye movement sleep.

Pregabalin, an analog of gamma-aminobutyric acid (GABA) that does not interact with GABA receptors, is in development as an analgesic, an anticonvulsant, and an anxiolytic. We evaluated the potential somnogenic actions of pregabalin in rats and compared it to those of triazolam, a widely used hypnotic. Pregabalin increased the duration of nonrapid eye movement sleep (NREMS) and decreased rapid eye movement sleep (REMS) after either dark onset or light onset administration. Triazolam increased duration of NREMS and had no effect on duration of REMS. Pregabalin markedly increased the duration of NREMS episodes and decreased the number of NREMS episodes. Power spectrum analysis revealed pregabalin-induced dose-dependent increases in relative delta power after administration. In contrast, triazolam decreased electroencephalographic power density in low frequency bands. Results suggest that pregabalin is a potential sleep modulating agent.

Mouse strains differ under a simple schedule of operant learning.

Recent advances in understanding the composition of the human and mouse genomes have paved the way to a more detailed understanding of the influence of genes on behavior, particularly learning and memory. One problem with many learning paradigms is the great length of training time required to generate a stable baseline. Our goal for the current studies was to develop a method of rapidly assessing learning and to use it to compare various strains of mice. The acquisition of a simple nose-poke was determined in operant chambers with two nose-poke holes illuminated: a single nose poke in one hole resulted in the presentation of 0.01 ml evaporated milk; responses in the other hole did not result in dipper presentation. All mice of the B6JxImJ F1, C57BL/6J, 129X1/SvJ and C3H/HeJ mice emitted 50 or more correct operant responses, whereas fewer than 50% of 129X1/SvJ and 75-90% of mice of Balb/cByJ, DBA/2J and the outbred CD-1 mice emitted 50 or more correct operant responses. On average, C57BL/6J emitted 50 operative responses in less than 30 min, whereas DBA/2J mice required nearly 1 h to complete 50 operative responses. Other strains performed at intermediate levels. There was no apparent relationship between operant activity and locomotor activity that may have influenced response acquisition. These findings are consistent with those reported using other learning paradigms and provide a rapid method of learning assessment.

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.

Subtype-selective N-methyl-D-aspartate receptor antagonists: synthesis and biological evaluation of 1-(heteroarylalkynyl)-4-benzylpiperidines.

4-[4-(4-Benzylpiperidin-1-yl)but-1-ynyl]phenol (8) and 4-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]phenol (9) are potent NR1A/2B receptor antagonists (IC(50) values 0.17 and 0.10 microM, respectively). Administered intraperitoneally, they both potentiated the activity of L-DOPA in the unilaterally 6-hydroxydopamine-lesioned (6-OHDA) rat, a model of Parkinson's disease. However, compound 9 was not active orally, likely due to rapid first-pass metabolism of the phenol moiety. The phenol was replaced by several bicyclic heterocyclic systems containing an NH group to function as a H-bond donor in the hope that these would be less likely to undergo rapid metabolism. In general, indoles, indazoles, benzotriazoles, indolones, and isatins gave analogues with weaker NR1A/2B activity than the parent phenols, while benzimidazolones and benzimidazolinones gave equipotent or more potent analogues. The preference for a para arrangement between the H-bond donor and the linking acetylene moiety was confirmed, and a propyne link was preferred over a butyne link. Substitution on the benzyl group or a 4-hydroxyl group on the piperidine had little effect on NR1A/2B potency; however, 4-hydroxypiperidines demonstrated slightly improved selectivity for NR1A/2B receptors versus alpha-1 adrenergic and dopamine D2 receptor affinity. From this study, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1, 3-dihydrobenzoimidazol-2-one (46b) was identified as a very potent, selective NR1A/2B receptor antagonist (IC(50) value 0.0053 microM). After oral administration at 10 and 30 mg/kg, 46b potentiated the effects of L-DOPA in the 6-OHDA-lesioned rat and seemed to have improved oral bioavailability but lower brain penetration compared to phenol 9.

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.

Subtype-selective N-methyl-D-aspartate receptor antagonists: benzimidazalone and hydantoin as phenol replacements.

Previous work in our laboratories investigating compounds with structural similarity to ifenprodil (5) and 6 (CP101,606) resulted in compound 7 as a potent and selective antagonist of the NR1/2B subtype of the NMDA receptors. Replacement of the phenol group of 7 with a benzimidazalone group tethered by a three-carbon chain to 4-benzylpiperidine resulted in a slightly less active, but selective, compound. Lengthening the carbon tether resulted in a decrease in NR1/2B potency. Replacement of the phenol ring with a hydantoin resulted in weak antagonists. Compound 11a was one of the most potent NR1/2B antagonists from this study. Compound 11a also potentiated the effects of L-DOPA in a rat model of Parkinson's disease (the 6-hydroxydopamine-lesioned rat), dosed at 30 mg/kg orally.

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.

Parallel synthesis of a series of subtype-selective NMDA receptor antagonists.

A series of 1-(heteroarylthioalkyl)-4-benzylpiperidines was rapidly synthesized through the use of parallel synthesis to investigate the binding affinity for the NR1A/2B receptor subtype.

Discovery of subtype-selective NMDA receptor ligands: 4-benzyl-1-piperidinylalkynylpyrroles, pyrazoles and imidazoles as NR1A/2B antagonists.

4-Benzyl-1-[4-(1H-imidazol-4-yl)but-3-ynyl]piperidine (8) has been identified as a potent antagonist of the NR1A/2B subtype of the NMDA receptor. When dosed orally, this compound potentiates the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease.

Subtype-selective N-methyl-D-aspartate receptor antagonists: synthesis and biological evaluation of 1-(arylalkynyl)-4-benzylpiperidines.

A search of our compound library for compounds with structural similarity to ifenprodil (5) and haloperidol (7) followed by in vitro screening revealed that 4-benzyl-1-(4-phenyl-3-butynyl)piperidine (8) was a moderately potent and selective antagonist of the NR1A/2B subtype of NMDA receptors. Substitution on the benzyl group of 8 did not significantly affect NR1A/2B potency, while addition of hydrogen bond donors in the para position of the phenyl group enhanced NR1A/2B potency. Addition of a hydroxyl moiety to the 4-position of the piperidine group slightly reduced NR1A/2B potency while reducing alpha-1 adrenergic and dopamine D2 receptor binding affinities substantially, resulting in improved overall selectivity for NR1A/2B receptors. Finally, the butynyl linker was replaced with propynyl or pentynyl. When the phenyl was para substituted with amine or acetamide groups, the NR1A/2B potency order was butynyl > pentynyl >> propynyl. For the para methanesulfonamide or hydroxyl groups, the order was butynyl approximately propynyl > pentynyl. The hydroxyl propyne (48) and butyne (23) were among the most potent NR1A/2B antagonists from this study. They both potentiated the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease, dosed at 10 mg/kg ip, but 48 was not active at 30 mg/kg po.

Reversal of haloperidol-induced extrapyramidal side effects in cebus monkeys by 8-hydroxy-2-(di-n-propylamino)tetralin and its enantiomers.

(+/-)-8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), (+)-8-OH-DPAT, and (-)-8-OH-DPAT produced dose-related reversals of haloperidol-induced extrapyramidal side effects (EPS) in cebus monkeys, with all compounds producing similar almost complete reversals at 0.1 mg/kg i.m. These compounds were more potent than apomorphine, which reversed haloperidol-induced EPS at 0.3, but not 0.1, mg/kg i.m. The data indicate that the reversal of haloperidol-induced EPS by (+/-)-8-OH-DPAT and its enantiomers is mediated via effects at 5-HT1A receptors, not dopamine D2 receptors. Thus, inclusion of 5-HT1A agonist activity in novel antipsychotics may reduce EPS liability.

Modulation of dopamine neuronal activity by glutamate receptor subtypes.

In vitro and in vivo electrophysiological studies have been used to assess the effects of glutamate, as well as specific agonists and antagonists for ionotropic, N-methyl-D-aspartate (NMDA), (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate, and metabotropic subtypes of the glutamate receptor, on the neuronal firing activity of midbrain, substantia nigra zona compacta (A9) and ventral tegmental area (A10), dopamine neurons. In in vitro experiments, agonists for all glutamate receptor subtypes depolarize the membrane and increase firing rate. In in vivo experiments, iontophoretic application of these agonists increases the firing rate and induces burst-firing. Studies with subtype selective antagonists suggest that a tonic glutamate tone, acting via NMDA receptors, may modulate the firing activity of some dopamine neurons. Glutamatergic afferents from the subthalamus, pedunculopontine nucleus and frontal cortex can modulate the firing activity of dopamine neurons. The role(s) of the different glutamate receptor subtypes and pathways in mediating the physiological and pathological effects on dopamine systems is an area for further investigation.

Metabotropic glutamate receptor-mediated inhibition and excitation of substantia nigra dopamine neurons.

Microiontophoretic drug application and extracellular recording techniques were used to evaluate the effects of the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate(1S,3R-ACPD) on dopamine (DA) neurons in the substantia nigra zona compacta (SNZC) of chloral hydrate-anesthetized rats. 1S,3R-ACPD had a biphasic effect on the firing rate of DA cells, initially decreasing, then increasing the firing rate. 1S,3R-ACPD also increased the burst-firing activity of DA neurons. Application of the ionotropic receptor (iGluR) agonists (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA) increased the firing rates of neurons which had responded to 1S,3R-ACPD, indicating that mGluRs and iGluRs reside on the same neurons. The initial inhibitory period was not antagonized by systemic haloperidol or iontophoretic bicuculline, indicating a lack of DA or gamma-amino-n-butyric acid (GABA) involvement in this effect. Combined application of the AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), and the NMDA antagonist, (I)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphoric acid (CPP), at currents which antagonized AMPA and NMDA, did not antagonize either the inhibitory or excitatory effects of 1S,3R-ACPD. Application of the metabotropic antagonist (S)-4-carboxy-phenylglycine antagonized both the inhibitory and excitatory effects of 1S,3R-ACPD. These results indicate that mGluRs may play a role in the modulation of dopaminergic activity in the SNZC.

Pharmacokinetics and pharmacodynamics of an investigational antipsychotic agent, CI-1007, in rats and monkeys.

PURPOSE: To study the pharmacokinetics (PK) and pharmacodynamics (PD) of an investigational antipsychotic agent, CI-1007, in rats and monkeys. METHODS: CI-1007 and a pharmacologically active metabolite, PD 147693 (M1), were evaluated in animal antipsychotic tests (inhibition of dopamine neuron firing and spontaneous locomotor activity in rats, and inhibition of continuous avoidance in monkeys). Plasma concentrations of CI-1007 and M1 were determined using validated HPLC assays. Log-linear and link models were used for PK/PD analysis. RESULTS: CI-1007 and M1 have shown similar effects on dopamine neuron firing (2.5 mg/kg i.p.), and produced dose-related effects on spontaneous locomotor activity in rats (0.3-30 mg/kg p.o.) and on continuous avoidance in monkeys (0.6-1.2 mg/kg p.o.). After pharmacologically active CI-1007 doses, mean plasma CI-1007 Cmax increased from 19 to 200 ng/ml in Sprague-Dawley rats at doses of 3-30 mg/ kg, and from 8.1 to 34 ng/ml in squirrel monkeys at doses of 0.6-1.2 mg/kg, but corresponding plasma M1 Cmax values were near or below the limit of quantitation (5 ng/ml). CI-1007 EC50 was 31.1 ng/ml in rats, calculated from a long-linear regression. In monkeys, CI-1007 ECe50, gamma, and Keo at 0.6 and 1.2 mg/kg were 4.8 and 4.5 ng/ml, 1.9 and 2.0, and 0.47 and 0.48 hr-1, respectively, calculated by the link model. CONCLUSIONS: CI-1007 has shown dose-related pharmacokinetics and pharmacodynamics in rats and monkeys. Although M1 produces antipsychotic-like effects similar to CI-1007, the contribution of M1 to the activity of the parent drug may not be significant in rats and monkeys as based on plasma levels. CI-1007 plasma concentration correlates log-linearly with inhibition effect from the rat locomotor study. The counter-clockwise hysteresis relationship of CI-1007 plasma concentration and inhibition effect from the monkey avoidance test was described by a link model, and the resulting Ce (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve.

Aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines as potential antipsychotic agents: synthesis and structure-activity relationships.

A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with dopaminergic activity is described. The structure-activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and inhibition of locomotor activity (LMA) in rodents. The basic amine, alkyne chain length, and aryl groups were varied. Compounds having a 4-phenyl-1,2,3,6-tetrahydropyridine and an aryl group with hydrogen-bonding substituents separated by a butynyl chain were found to have the most potent dopaminergic activity. Several compounds that were found to have exceptional in vivo activity in LMA inhibition in rodents were evaluated for additional pharmacological activity including binding affinities for other DA receptor subtypes as well as effects on brain DA synthesis, DA neuronal firing, and conditioned avoidance responding in squirrel monkeys.

Identification, characterization and pharmacological profile of three metabolites of (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenylcyclohexen-1- yl)methyl]pyridine (CI-1007), a dopamine autoreceptor agonist and potential antipsychotic agent.

Liquid chromatographic-mass spectrometric (LC-MS) analysis of plasma taken from cynomolgus monkeys dosed orally with (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenylcyclohexen-1- yl)methyl]pyridine (1), a dopamine (DA) autoreceptor agonist and potential antipsychotic agent, revealed several metabolites. The molecular masses of three major metabolites suggested that they were mono- and dihydroxylated derivatives of 1. We synthesized compounds 2 and 3, the two possible mono-p-hydroxyphenyl derivatives of 1, along with the bis-p-hydroxyphenyl derivative 4. These compounds coeluted by HPLC with the three hydroxylated metabolites of 1. Compounds 2-4 all had high affinities for DA D2 and D3 receptors and moderate affinities for D4 receptors. Like 1, compound 2 decreased DA synthesis and neuronal firing in rat brain, indicative of DA autoreceptor activation. Compound 2 inhibited exploratory locomotor activity in rodents and was active in the Sidman avoidance test in squirrel monkeys, predictive of antipsychotic activity in humans. Compounds 3 and 4 showed weak activity in all these tests. After squirrel monkeys were dosed with 1 orally at the ED100 dose of the Sidman avoidance test, the plasma concentration of 2 was below the limit of quantitation. Therefore, these metabolites are unlikely to contribute greatly to the potent activity seen with 1 in the Sidman avoidance test.

CI-1007, a dopamine partial agonist and potential antipsychotic agent. II. Neurophysiological and behavioral effects.

CI-1007 has been described in receptor binding and biochemical tests as a dopamine (DA) partial agonist that exhibits DA autoreceptor agonist effects. The present studies describe the profile of CI-1007 in electrophysiological and behavioral tests. CI-1007 inhibited the firing of substantia nigra DA neurons with intrinsic DA agonist activity that was less than that of the full agonists apomorphine and talipexole but greater than that of the weak partial agonist SDZ 208-912. CI-1007 was more potent after intracerebroventricular versus intraperitoneal injection in inhibiting spontaneous locomotor activity in mice, indicating a central site of action. In rats, CI-1007 inhibited locomotor activity after i.v. and p.o. injection, but did not produce locomotor stimulation or induce stereotypy, indicating a lack of postsynaptic DA agonist activity. The relative potencies of CI-1007 for inhibiting apomorphine-stimulated behaviors versus spontaneous locomotor activity in rodents indicated weak postsynaptic DA antagonist actions, consistent with a partial agonist profile. Similar to known antipsychotics, CI-1007 potently inhibited Sidman avoidance responding in squirrel monkeys, but, in contrast to most available antipsychotics, CI-1007 caused only mild extrapyramidal dysfunction in squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. These data indicate that CI-1007 is a DA partial agonist of moderate intrinsic activity that activates brain DA autoreceptors, produces behavioral effects predictive of antipsychotic efficacy and has a low liability for induction of extrapyramidal side effects.

Evidence for N-methyl-D-aspartate and AMPA subtypes of the glutamate receptor on substantia nigra dopamine neurons: possible preferential role for N-methyl-D-aspartate receptors.

The present studies utilized extracellular single-unit recordings in chloral hydrate-anesthetized rats to evaluate the contribution of N-methyl-D-aspartate (NMDA) and (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) subtypes of glutamate receptors to the excitatory effects of glutamate on substantia nigra dopamine neurons. Iontophoretic administration of NMDA, AMPA and glutamate increased the firing rate and amount of burst-firing of dopamine neurons. Iontophoretic application of the NMDA antagonist (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP) inhibited the excitatory effect of NMDA and glutamate, but not that of AMPA. Iontophoretic application of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)-quinoxaline (NBQX), inhibited the excitatory effect of AMPA and glutamate, but not that of NMDA. CPP produced a greater antagonism of the glutamate excitation than did NBQX. In addition, CPP, but not NBQX, reduced the firing rate and burst-firing of a subpopulation of DA neurons. These data indicate that both NMDA and AMPA receptors are present on substantia nigra dopamine neurons and suggest that NMDA receptors may be more sensitive than AMPA receptors to endogenous glutamate and that a tonic glutamate tone, acting via NMDA receptor stimulation, may modulate the firing rate and burst-firing activity of some dopamine neurons.

The discovery and structure-activity relationships of 1,2,3,6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents.

A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine (14), was identified. The structure-activity relationships surrounding this compound were studied by synthesis of analogues and evaluation of their dopaminergic activity. The cyclohexene substitution pattern was varied along with the length of the chain connecting the 1,2,3,6-tetrahydro-4-phenylpyridine to the cyclohexene. Compound 14, having the 1,3-substitution pattern and a single methylene chain, was the most potent. The 1,2,3,6-tetrahydro-4-phenylpyridine could be replaced by other aryl-cyclic amines with a slight loss in activity. The phenyl group on the cyclohexene ring could be para substituted; electron-donating groups were better tolerated than electron-withdrawing groups. Finally, the enantiomers of 14 were resolved via the 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate salts. Although both isomers were partial DA agonists, the (+)-enantiomer had higher intrinsic activity than the (-)-enantiomer. Syntheses were developed that allowed rapid preparation of analogues. An X-ray crystal structure determination of an intermediate identified the (+)-isomer of 14 as having R configuration. This compound, designated CI-1007 (PD 143188), was found to have antipsychotic-like activity in behavioral tests; in particular, it was orally active in the conditioned avoidance test in squirrel monkeys with an ED50 of 0.6 mg/kg. The overall profile suggests that (R)-(+)-14 may be a clinically useful antipsychotic agent.