clozapine and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol

A series of 1-(pyrimidin-2-yl)piperazine derivatives were prepared and evaluated in receptor binding assays and in in vivo behavioral paradigms as potential atypical antipsychotic agents. Compound 16 (BMS 181100 (formerly BMY 14802)) emerged as the lead compound from within the series on the basis of its good activity and duration of action in the inhibition of both conditioned avoidance responding and apomorphine-induced stereotopy in the rat. Compound 16 not only failed to induce catalepsy in the rat but was quite effective in reversing the cataleptic effect of neuroleptic agents, thus indicating a low propensity for causing extrapyramidal side effects. In comparison to reference antipsychotic agents, 16 appeared to be less sedating and was relatively weaker in causing muscle incoordination. The compound was essentially inactive in binding to dopamine D2 receptors and its chronic administration to rats did not result in dopamine receptor supersensitivity. It exhibited modest to weak affinity for 5-HT1A and alpha 1 receptors but was found to be a fairly potent ligand for sigma binding sites (IC50 vs (+)-[3H]-3-PPP = 112 nM). Although the resolved enantiomers of racemic 16 did not show dramatic differences from racemate or from each other in most tests, the R(+) enantiomer was up to 11-fold more potent than its antipode in binding to sigma sites. Several studies have indicated that 16 may be a limbic-selective agent which may modulate dopaminergic activity by an indirect mechanism. The compound has been selected for clinical evaluation in the treatment of psychosis.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Catalepsy; Molecular Structure; Piperazines; Pyrimidines; Rats; Receptors, Dopamine D2; Stereoisomerism; Stereotyped Behavior

An atypical antipsychotic drug clozapine and a selective sigma antagonist BMY 14802 were significantly less effective in the behavioural experiments (against apomorphine, d-amphetamine and MK-801), as well in the radioligand binding studies against 3H-spiperone (dopamine2-receptors) and 3H-haloperidol (sigma receptors) in the rat brain, as compared to a typical antipsychotic compound haloperidol. Contrary to haloperidol and BMY 14802, clozapine was a relatively selective antagonist of MK-801-induced motor excitation in the mouse. A nearly 3-fold lower dose of clozapine was needed to block the effect of MK-801 (6.4 mumol/kg) as compared to the action of amphetamine (17 mumol/kg). Haloperidol and clozapine, but not BMY 14802, antagonized apomorphine-induced aggressiveness in the rat. After long-term treatment (for 15 days) with BMY 14802 (10 mg/kg daily), haloperidol (0.5 mg/kg daily) and clozapine (10 mg/kg daily) the motor depressant effect of apomorphine (0.15 mg/kg) was reversed. Chronic haloperidol treatment, but not administration of BMY 14802 and clozapine, increased the number of dopamine2-receptors in the rat brain. BMY 14802 caused upregulation of sigma receptors in frontal cortex, whereas haloperidol induced the opposite change in cerebellum. Repeated treatment with clozapine significantly augmented the motor stimulating effect of MK-801 in rats. Simultaneously with a behavioural change the density of 3H-TCP binding sites in the rat forebrain was elevated after long-term treatment with clozapine, probably indicating the involvement of PCP binding sites at NMDA channel in the action of clozapine.

Topics: Animals; Brain; Clozapine; Ligands; Male; Mice; Motor Activity; Phencyclidine; Psychotropic Drugs; Pyrimidines; Rats; Receptors, Dopamine; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma

Rats trained on a lever-release version of the conditioned avoidance response (CAR) task were used to test the behavioral effects of established and putative antipsychotic drugs. Baseline CAR latencies decreased as the conditioned-unconditioned stimulus interval was shortened from 500 to 250 ms. Haloperidol, clozapine, and BMY-14802 decreased successful avoidance responses and increased avoidance latencies in a dose-dependent manner without affecting the latency of escape responses. In contrast, sulpiride failed to affect either successful avoidance response rates or avoidance latency. Sulpiride, however, significantly attenuated d-amphetamine-induced locomotion and rearing compared to vehicle-treated controls. Similar effects of these antipsychotics have been reported on shuttlebox avoidance, and these results now are confirmed in a CAR paradigm that achieves greater control over behavior. Because this paradigm elicits a discrete forelimb response without activating numerous muscle groups, it is potentially useful as a tool for examining neuronal mechanisms underlying the behavioral effects of antipsychotic drugs.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Clozapine; Dextroamphetamine; Dose-Response Relationship, Drug; Haloperidol; Male; Psychotropic Drugs; Pyrimidines; Rats; Rats, Inbred Strains; Stereotyped Behavior; Sulpiride

In preclinical studies, BMY-14802 [alpha-(fluorophenyl)-4-(5-fluoro-2-pyramidinyl)-l-piperazine-buta nol], a potent sigma ligand, exhibited a profile similar to clozapine, an atypical antipsychotic agent. Several atypical antipsychotics have previously been demonstrated to increase dopamine (DA) metabolism without altering DA release in vivo, suggesting a potential mechanism for their lack of extrapyramidal side effects. BMY-14802 increased DA metabolism and release while clozapine increased DA metabolism but decreased DA release in the mouse. This is the first demonstration of a sigma ligand mediated DA release in vivo. The lack of extrapyramidal side effects, despite the enhanced DA release in vivo after BMY-14802 suggests that the atypical profile of clozapine can not be explained by its depressant actions on DA release alone.

Topics: 3,4-Dihydroxyphenylacetic Acid; alpha-Methyltyrosine; Animals; Anti-Anxiety Agents; Brain Chemistry; Clozapine; Corpus Striatum; Dibenzazepines; Dopamine; Homovanillic Acid; Male; Methyltyrosines; Mice; Olfactory Bulb; Pyrimidines

The present experiments compared the ability of a new potential antipsychotic drug, BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine- butanol), to alter the electrophysiological activity of midbrain dopamine (DA) neurons in the rat substantia nigra (A9) and ventral tegmental area (A10). Intravenous administration of BMY 14802 reversed the rate-suppressant effects of the DA agonist apomorphine on both A9 and A10 DA neurons; however, this reversal occurred at significantly lower doses in A10 than in A9. These effects of BMY 14802 appeared not to be mediated by DA receptors because, unlike the established antipsychotic drugs haloperidol and clozapine, BMY 14802 pretreatment failed to block apomorphine-induced suppression of A10 DA cells. Repeated s.c. administration (28 days) of BMY 14802 (2.5-10.0 mg/kg) reduced the number of spontaneously active A10 DA cells recorded per electrode track without affecting the number of A9 DA cells. This inactivation of A10 DA neurons was only partially reversed by the administration of apomorphine. Thus, it is uncertain as to whether this effect was produced by depolarization block as occurs during repeated administration of known antipsychotic drugs. These findings indicate that BMY 14802 influences DA neurotransmission by a nondopaminergic (perhaps sigma opioid) mechanism. The more potent effect of BMY 14802 on A10 DA neurons suggests that this novel compound may exert antipsychotic effects without producing significant extrapyramidal side effects.

Topics: Animals; Antipsychotic Agents; Apomorphine; Brain; Clozapine; Dopamine; Electrophysiology; Haloperidol; Male; Neurons; Pyrimidines; Rats; Rats, Inbred Strains