PNU 96415E

PNU-96415E, a potential antipsychotic agent with clozapine-like pharmacological properties.[Pubmed:9103528]

J Pharmacol Exp Ther. 1997 Apr;281(1):440-7.

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-HT2A receptors. In comparison to clozapine, PNU-96415E is weaker in binding to D1, D2, alpha1 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.

Discriminative stimulus properties of the atypical neuroleptic clozapine in rats: tests with subtype selective receptor ligands.[Pubmed:9890260]

Behav Pharmacol. 1998 Dec;9(8):699-710.

The interoceptive stimulus induced by clozapine (5 mg/kg, i.p.) has been characterized in an operant drug discrimination procedure in the rat using a wide range of receptor subtype-selective agonists and antagonists. Only the muscarinic receptor antagonist scopolamine generalized fully to clozapine (>80%). Partial generalization (defined here as 40% maximal generalization) was seen with the D1 receptor antagonist SCH 23390 (43% maximal generalization), the alpha1-adrenoceptor antagonist prazosin (67%) and the alpha2-adrenoceptor antagonist methoxyidazoxan (42%). All other specific agents tested induced <25% maximal generalization, including the alpha2-adrenoceptor antagonist yohimbine (24%), the histamine H1 receptor antagonist mepyramine (21%), the D2 antagonist typical neuroleptic haloperidol (23%), the D4 receptor antagonist L-745,870 (14%), the 5-hydroxytryptamine-1A (5-HT1A) receptor agonist S-14506 (8%), the 5-HT2A receptor antagonists ketanserin (0%) and M100907 (12%), the 5-HT2B/2C receptor antagonists SB 200646A (8%) and SDZ SER 082 (6%), and the 5-HT3 receptor antagonist ondansetron (0%). The clozapine discriminative stimulus was not blocked by the dopamine D1 receptor antagonist SCH 23390, or by the 5-HT1A receptor antagonist WAY 100635, when given concomitantly with clozapine. Although the results suggest that muscarinic antagonism plays a major role in the clozapine cue, the results have to be considered in the light of the full generalization to clozapine seen with various antipsychotic agents which have very low affinity for muscarinic receptors, including zotepine, quetiapine, JL13 and PNU 96415 (a finding replicated in rats from the same breeding colony as those which generalized to scopolamine). Thus, generalization to clozapine for antipsychotics with multiple affinities but with low muscarinic affinity is probably mediated by additive or perhaps supra-additive actions at other receptors, although extensive studies with various combinations of drug mixtures are required to validate this hypothesis.