Molecular Pharmacology, Vol 20, 377-381, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Conformational Preferences of Amphetamine Analogues for Inhibition of Phenylethanolamine N-Methyltransferase

Conformationally Defined Adrenergic Agents. 5

¹ Departments of Medicinal Chemistry and Biochemistry, University of Kansas, Lawrence, Kansas 66045

A series of conformationally defined amphetamine analogues was examined for their ability to inhibit competitively the enzyme phenylethanolamine N-methyltransferase (PNMT). Among these were compounds based on the benzobicyclo-[2.2.1]heptene and the benzobicyclo-[2.2.2]octene structures which, depending upon the point of the attachment of the amino group, closely approximate a trans antiperiplanar or a gauche conformation of amphetamine. Some more flexible conformationally restricted amphetamine analogues which had been previously evaluated as inhibitors of PNMT were included in the study for comparison. In all cases, those compounds which mimicked the gauche conformation of amphetamine failed to inhibit competitively PNMT, whereas compounds which approximated a fully extended (trans antiperiplanar) conformation showed significant inhibition. Therefore, the indication from the data is that phenylethylamines must be able to achieve a fully extended conformation of the side chain in order to bind to the PNMT active site.

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ACKNOWLEDGMENTS We gratefully acknowledge the efforts of Brian Andrews, Daniel Flynn, Stephen Jacober, Julie Matthews, Dr. Thomas Reitz, Theresa Rothauser, Dr. James Ruth, and Dr. Eric Walters in the preparation of some of the compounds used in the study.