6-(alkylamino)-9-alkylpurines. A new class of potential antipsychotic agents

James L. Kelley, R. Morris Bullock, Mark P. Krochmal, Ed W. McLean, James A. Linn, Micheal J. Durcan, Barrett R. Cooper

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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.

Original languageEnglish
Pages (from-to)3207-3216
Number of pages10
JournalJournal of Medicinal Chemistry
Volume40
Issue number20
DOIs
Publication statusPublished - Oct 9 1997

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Kelley, J. L., Morris Bullock, R., Krochmal, M. P., McLean, E. W., Linn, J. A., Durcan, M. J., & Cooper, B. R. (1997). 6-(alkylamino)-9-alkylpurines. A new class of potential antipsychotic agents. Journal of Medicinal Chemistry, 40(20), 3207-3216. https://doi.org/10.1021/jm960662s