Biochemical, functional and behavioral evaluation of a series of novel antipsychotic-like agents.
Two ethyl phenylpiperazine substituted isochromans and a related benzoxepine were discovered to have antipsychotic-like properties in animal screening models. Further evaluation of these compounds disclosed that, like neuroleptics, they blocked dopamine-stimulated adenylate cyclase, displaced 3H-spiperone in vitro, altered dopamine synthesis, and decreased conditioned avoidance and intracranial self-stimulation behavior. In contrast to classical neuroleptics but like clozapine, these compounds did not block apomorphine or amphetamine-induced chewing stereotypy in rats, raise serum prolactin concentrations, or increase 3H-spiperone binding after chronic dosing. However, unlike clozapine, the compounds of this series did not displace 3H-spiperone in either of two in vivo paradigms nor did they alter striatal acetylcholine concentrations. Taken together these data suggest that these isochroman and benzoxepine analogs would most probably not cause neuroleptic extrapyramidal side effects or prolactin elevations clinically. However, due to their atypical nature, their antipsychotic potential can only be assessed with certainty by careful clinical studies.
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D001584:Benzoxepins / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology*; D004298:Dopamine / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D012653:Self Stimulation / Q000187:drug effects*
D000067956:Adenylyl Cyclase Inhibitors; D014150:Antipsychotic Agents; D001578:Benzopyrans; D001584:Benzoxepins; D002839:Chromans; D004298:Dopamine