SAR of Bupropion and Its Analogs

Bupropion (15), also known as amfebuta-

(15) Bupropion

ethyl)amino]-l-propane. It is a trimethylated monocyclic phenylaminoketone and is structurally unrelated to the tricyclic antidepres-sants or MAO inhibitors. Commercially available bupropion is a racemic mixture. The two enantiomers were synthesized and assayed for their potencies as inhibitors of biogenic amine uptake into nerve endings obtained from mouse brain (212). No significant difference was found. However, the relative pharmacological activities and pharmacokinetics of the two enantiomers have not been studied. Bupropion has a novel chemical structure among antidepressants. The absence of polycyclic rings and presence of more common functional groups usually found on tranquilizers contribute to the lack of marked side effects usually seen with polycyclic antidepressants (213). Bupropion was a designed antidepressant. Aseries of compounds that included aminoketones and aminoalcohols was designed and screened for antidepressant activity by Glaxo chemists. Structure-activity relationships of a series of bupropion analogs were investigated (213). The strong electron withdrawing effect of the chloro substituent on the aromatic ring in bupropion is believed to be responsible for the lack of CNS stimulant effect. The a-ketone moiety contributes to the metabolic fate of the drug. It prevents the formation of a chloro-monoarylalkylamine metabolite, which would possibly be a CNS stimulant. The use of a tertiary butyl substituent as the alkyl group on the nitrogen atom was designed to diminish the N-dealkylation and hence prevent the formation of metabolites with sympathomimetic side effects. The meta-orientation of the two substituents on the aromatic ring was also a designed feature. The position could have high steric hindrance, and the para position would result in facile displacement and para-hydroxylation, which in turn would result in rapid elimination of the drug.

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