Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 4. Central nervous system depressants.
The synthesis of 1'-[3-(4-fluorobenzyoyl)propyl]-3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] (2a) and eight halo and methoxy analogues is described. The compounds were generally more potent per os than chlorpromazine in the Sidman avoidance paradigm in rats and less potent than haloperido. 1'-[3-(4-Fluorobenzoyl)propyl]-3-(4-fluorophenyl)spiro[isobenzofuran-1(3H),4'-piperidine] (2e) approached the per os potency of haloperidol in this test and was shown to be active in inhibiting monkey avoidance also. Compound 2e was much less active than haloperidol in antagonizing apomorphine-induced emesis in dogs, apomorphine-induced stereotypy in rats, and amphetamine-induced circling in lesioned rats. This lack of nonselective, dopamine-receptor blocking effects makes 2e attrative as a potential neuroleptic.
D000661:Amphetamine / Q000037:antagonists & inhibitors; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis; D001058:Apomorphine / Q000037:antagonists & inhibitors; D001362:Avoidance Learning / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000138:chemical synthesis*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004924:Escape Reaction / Q000187:drug effects; D005260:Female; D000882:Haplorhini; D006801:Humans; D008297:Male; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects; D012453:Saimiri; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
D014150:Antipsychotic Agents; D002492:Central Nervous System Depressants; D011954:Receptors, Dopamine; D013141:Spiro Compounds; D000661:Amphetamine; D001058:Apomorphine