clozapine and tiospirone

The effect of acute treatment with seven atypical antipsychotic drugs and four typical antipsychotic drugs on serotonin2 (5-HT2) receptor binding sites in rat cerebral cortex was studied. Among the atypical antipsychotic drugs examined, clozapine, fluperlapine, RMI-81582 and setoperone decreased the density of 5-HT2 receptors, but ticspirone, amperozide and melperone did not. None of the drugs affected the Kd value. Among the typical antipsychotic drugs, loxapine decreased Bmax and increased the Kd of 5-HT2 receptor binding sites, whereas chlorpromazine and cis-flupenthixol had no effect. Clothiapine, a typical antipsychotic drug of the same chemical class as clozapine, decreased Bmax without increasing Kd. The downregulation of 5-HT2 receptor binding sites following a single injection of clozapine, 20 mg/kg, remained almost unchanged during the first 72 hrs and was still significantly decreased for up to 120 hrs. There was no relationship between the affinity for the downregulation of rat cortical 5-HT2 receptor binding site and 5-HT2 receptor density. Coadministration of the D1 dopamine agonist, SKF-38393, did not affect the clozapine-induced downregulation. It is suggested that rapid and prolonged downregulation of 5-HT2 receptor sites is characteristic of some but not all atypical antipsychotic drugs and is not specific to atypical antipsychotic drugs. Dibenzo-epines (clozapine, loxapine, amoxapine, chlothiapine) consistently downregulate 5-HT2 receptors in frontal cortex after acute treatment.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antipsychotic Agents; Butyrophenones; Cerebral Cortex; Chlorpromazine; Clozapine; Dibenzazepines; Dibenzothiazepines; Down-Regulation; Flupenthixol; Kinetics; Loxapine; Male; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Serotonin; Spiro Compounds; Time Factors

Members of the series of title compounds were tested for potential antipsychotic activity in relevant receptor binding assays and behavioral screens. Structure-activity relationships within the series are discussed. Compound 24 (BMY 13859-1), a (1,2-benzisothiazol-3-yl)piperazine derivative, was selected for further study because of its potent and selective profile in primary CNS tests. It was active in the Sidman avoidance paradigm and blocked amphetamine-induced stereotyped behavior in dogs for up to 7 h. The compound's lack of typical neuroleptic-like effects in the rat catalepsy test and its failure to produce dopamine receptor supersensitivity following chronic administration indicate that it should not cause the movement disorders commonly associated with antipsychotic therapy. Although 24 has potent affinity for dopaminergic binding sites, its even greater affinity for serotonin receptors suggests that a serotonergic component may be relevant to its atypical profile. Compound 24 is currently undergoing clinical evaluation in schizophrenic patients.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Binding, Competitive; Catalepsy; Cerebral Cortex; Corpus Striatum; Isoxazoles; Male; Models, Molecular; Norepinephrine; Oxazoles; Physostigmine; Piperazines; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Serotonin; Sleep; Spiro Compounds; Stereotyped Behavior; Structure-Activity Relationship; Thiazoles

Two adult female cebus apella monkeys with persistent tardive dyskinesia (TD) were given acute i.m. injections of reference neuroleptics (chlorpromazine, haloperidol, thioridazine, and clozapine) or of potential new antipsychotic agents (MJ 13859-1 and MJ 13980-1). The drugs were assessed for their ability to modify TD symptoms or to produce acute neurologic reactions. Effects of three doses of MJ 13859-1 administered orally were also examined. At the doses used, thioridazine and clozapine had little or no effect. Chlorpromazine, haloperidol, MJ 13859-1 and MJ 13980-1 reduced or abolished TD and concomitantly produced hypokinesia, akinesia, mask expression, trembling, and reduced response to stimuli. Haloperidol also produced a mildly abnormal posture. In addition to the above effects, MJ 13859-1 also produced "slow motion" movement, sustained bizarre postures, sudden falls, and episodes of severe rigidity with trembling.

Topics: Animals; Antipsychotic Agents; Cebus; Chlorpromazine; Clozapine; Dyskinesia, Drug-Induced; Female; Haloperidol; Motor Activity; Posture; Spiro Compounds; Thioridazine