clozapine and sonepiprazole

The present study describes the pharmacological profile of the putative antipsychotic drug Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole). The in vitro receptor profile of Lu 35-138 revealed high affinity (K(i)=5 nM) and competitive antagonism (K(b)=8 nM) at dopamine D(4) receptors combined with potent 5-HT uptake inhibition (IC(50)=3.2 nM) and moderate alpha(1)-adrenoceptor affinity (K(i)=45 nM). In vivo, Lu 35-138 selectively counteracted hyperlocomotion induced by d-amphetamine (0.5 mg/kg; ED(50)=4.0 mg/kg, s.c.) in rats and phencyclidine (PCP; 2.5 mg/kg; ED(50)=13 mg/kg, s.c.) in mice. Lu 35-138 was unable to affect hyperlocomotion induced by a high dose of d-amphetamine (2.0 mg/kg), which indicates a preferential action on limbic versus striatal structures. A similar limbic selectivity of Lu 35-138 was indicated in voltammetric measure of dopamine output in the core and shell subdivisions of the nucleus accumbens in rats. Furthermore, a relatively large dose of Lu 35-138 (18 mg/kg, s.c.) counteracted d-amphetamine-induced disruption of pre-pulse inhibition in rats and repeated administration of Lu 35-138 (0.31 or 1.25 mg/kg, p.o. once daily for 3 weeks) reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, underlining its antipsychotic-like profile. Lu 35-138 failed to induce catalepsy in rats or dystonia in Cebus apella monkeys and did not deteriorate spatial memory in rats as assessed by water maze performance. Collectively, these results suggest that Lu 35-138 possesses antipsychotic activity combined with a low extrapyramidal and cognitive side effect liability.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Animals, Outbred Strains; Benzodiazepines; Cebus; Citalopram; Clozapine; Cognition; Dihydropyridines; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Haloperidol; Haplorhini; Humans; Indoles; Male; Mice; Molecular Structure; Motor Activity; Olanzapine; Piperazines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Dopamine D4; Risperidone; Selective Serotonin Reuptake Inhibitors; Sulfonamides

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.

Topics: Animals; Antipsychotic Agents; CHO Cells; Cloning, Molecular; Cricetinae; Dopamine D2 Receptor Antagonists; Humans; Kinetics; Levodopa; Models, Chemical; Piperazines; Pyridines; Pyridones; Pyrroles; Rats; Receptors, Dopamine D2; Receptors, Dopamine D4; Structure-Activity Relationship; Sulfonamides

Topics: Animals; Antipsychotic Agents; Biological Availability; CHO Cells; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Ergolines; Humans; Molecular Structure; Piperazines; Protein Binding; Quinpirole; Receptors, Adrenergic; Receptors, Dopamine D4; Receptors, Serotonin; Schizophrenia; Sulfonamides