title: 6-(alkylamino)-9-alkylpurines. A new class of potential antipsychotic agents.
abstract: A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This model for identifying potential antipsychotic agents is based on the hypothesis that agents that antagonize apomorphine-induced aggressive behavior in rats and apomorphine-induced climbing in mice, but that do not block stereotyped behavior, could have an antipsychotic effect in humans without producing extrapyramidal side effects. The antiaggressive-behavior activity of lead compound 1 (6-(dimethylamino)-9-(3-phenylalaninamidobenzyl)-9H-purine) was improved 48-fold with 6-(cyclopropylamino)-9-(cyclopropylmethyl)-2-(trifluoromethyl)-9H- purine (80) (po ED50 of 2 mg/kg), which was obtained through an iterative sequence of structure--activity relationship studies that encompassed evaluation of the effects of structure variations at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the duration of action was improved with the 6-(cyclopropylamino) substituent, potency was further enhanced with an N-formyl prodrug, and an agent with reduced cardiovascular effect emerged with the 2-trifluoromethyl purine 80. This potential antipsychotic agent was not developed further due to undesirable effects on the stomach.
authors.affiliation: Division of Organic Chemistry, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Kelley
authors.forename: R M
authors.initials: RM
authors.lastname: Bullock
authors.forename: M P
authors.initials: MP
authors.lastname: Krochmal
authors.forename: E W
authors.initials: EW
authors.lastname: McLean
authors.forename: J A
authors.initials: JA
authors.lastname: Linn
authors.forename: M J
authors.initials: MJ
authors.lastname: Durcan
authors.forename: B R
authors.initials: BR
authors.lastname: Cooper
mesh_terms: D000374:Aggression / Q000187:drug effects; D000478:Alkylation; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004123:Dimethylamines / Q000138:chemical synthesis / Q000494:pharmacology; D005746:Gastric Emptying / Q000187:drug effects; D007928:Lethal Dose 50; D051379:Mice; D008956:Models, Chemical; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D002227:Carbazoles; D004123:Dimethylamines; D011687:Purines; C034516:dimethylamine; C034931:rimcazole; D001058:Apomorphine