Rimcazole (BW 234U), a novel antipsychotic agent whose mechanism of action cannot be explained by a direct blockade of postsynaptic dopaminergic receptors in brain

Rimcazole is a novel antipsychotic agent free of extrapyramidal side effects as judged by its profile in animal behavioral models and by results of early clinical trials in acute schizophrenic patients. The present study shows that rimcazole is different biochemically from the typical and atypical neuroleptics. Concentrations of 10−5 to 10−4 M are necessary to achieve even weak effects on dopamine-stimulated adenylate cyclase activity (D1 receptors), [3H]dopamine binding in mesolimbic and striatal areas of rat brain. Rimcazole's extremely weak potency as a D2 receptor blocker in brain was readily apparent when compared to several other neuroleptics: It was 160 times weaker than sulpiride, the least potent striatal D2 receptor blocker studied, and 10,000 times weaker than haloperidol, the most potent. Rimcazole had no effect on many of the enzymes involved in catecholamine synthesis and metabolism in vitro, did not effect the synthesis of [3H]dopamine from [3H]tyrosine in vivo, and did not alter the effects of a dopaminergic agonist and a dopaminergic antagonist on [3H]dopamine synthesis in vivo. It was moderately potent as an inhibitor of serotonin (5-HT2) receptors but had only weak effects on muscarinic cholinergic, α1–, α2 –, β –adrenergic, benzodiazepine, GABA, adenosine (A1 and A2), glycine, serotonin (5-HT1), imipramine, neurotensin, and phencyclidine receptors and calcium channels in binding assays. It was a moderately potent, competitive inhibitor of dopamine uptake in vitro and had no pharmacologically relevant effects on the spontaneous release of biogenic amines from isolated nerve endings. These data suggest that if rimcazole is shown to be a clinically effective antipsychotic agent, it will be the first antipsychotic whose mechanism of action cannot be explained by a direct blockade of postsynaptic dopaminergic (D2) receptors in brain.