PNU-96415E, a potential antipsychotic agent with clozapine-like pharmacological properties.
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.
Tang
A H
AH
Central Nervous System Research, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
Franklin
S R
SR
Himes
C S
CS
Smith
M W
MW
Tenbrink
R E
RE
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism
D014150:Antipsychotic Agents; C105376:PNU 96415E; D010879:Piperazines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D003024:Clozapine; D003913:Dextroamphetamine