Vol. 281, Issue 1, 440-447, 1997

PNU-96415E, a Potential Antipsychotic Agent with Clozapine-Like Pharmacological Properties

A. H. Tang, S. R. Franklin, C. S. Himes, M. W. Smith and R. E. Tenbrink

Central Nervous System Research (A.H.T., S.R.F., C.S.H.), Chemical & Biological Screening (M.W.S.), and Structural, Analytical & Medicinal Chemistry (R.E.T.), Pharmacia & Upjohn, Inc., Kalamazoo, Michigan

The atypical antipsychotic drug clozapine interacts with multiple transmitter systems, among them the D₄ subtype of dopamine receptors. PNU-96415E is chemically unrelated to clozapine and has its highest binding affinity for the D₄ and 5-HT_2A receptors. In comparison to clozapine, PNU-96415E is weaker in binding to D₁, D₂, ₁ and muscarinic receptors. PNU-96415E inhibited exploratory locomotor activity in mice and rats, and antagonized d-amphetamine-induced locomotor stimulation in rats. It antagonized apomorphine-induced cage climbing, and blocked head and body twitch produced by 5-HTP in mice. Like clozapine, but unlike haloperidol, PNU-96415E did not antagonize stereotypic behaviors produced by a high dose of d-amphetamine or methylphenidate in rats and mice. PNU-96415E blocked conditioned avoidance in rats but produced no catalepsy, a pattern similar to clozapine but different from haloperidol. In rats trained to discriminate clozapine from saline injections, the stimulus effect generalized completely with PNU-96415E, but not haloperidol. This profile of pharmacological activities is consistent with that of an atypical antipsychotic and, as in the case with clozapine, the behavioral effects of PNU-96415E cannot be ascribed to a single receptor mechanism.