6-(ALKYLAMINO)-9-ALKYLPURINES - A NEW CLASS OF POTENTIAL ANTIPSYCHOTIC AGENTS

A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluate d for the property of antagonizing the behavioral effects in animals o f the dopamine agonist apomorphine. This model for identifying potenti al antipsychotic agents is based on the hypothesis that agents that an tagonize apomorphine-induced aggressive behavior in rats and apomorphi ne-induced climbing in mice, but that do not block stereotyped behavio r, could have an antipsychotic effect in humans without producing extr apyramidal side effects. The antiaggressive-behavior activity of lead compound 1 hylamino)-9-(3-phenylalaninamidobenzyl)-9H-purine) was impr oved 48-fold with -(cyclopropylmethyl)-2-(trifluoromethyl)-9H-purine ( 80) (po ED50 of 2 mg/kg), which was obtained through an iterative sequ ence of structure-activity relationship studies that encompassed evalu ation of the effects of structure variations at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the dur ation 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 furthe r due to undesirable effects on the stomach.