INFLUENCE OF SUBSTITUTED PHENETHYLAMINES ON LIPOLYSIS, IN VITRO. III. STEREOSELECTIVITY

¹ The Ohio State University College of Pharmacy, Divisions of Pharmacology and Medicinal Chemistry, Columbus, Ohio

Investigations were undertaken to establish the steric interaction of phenethylamines on the release of glycerol from rat adipose tissue, in vitro. Primary emphasis was placed upon stereoselectivity at the asymmetric -and/or -carbon of the ethylamino side chain. Both stereoisomers of norepinephrine, -methyldopamine, nordefrin, metaraminol and soterenol were found to increase glycerol release, whereas the isomers of ephedrine, norephedrine, amphetamine, methamphetamine and p-hydroxyamphetamine were inactive and able to inhibit norepinephrine-induced lipolysis. It was found that (1) the R-isomers of norepinephrine and soterenol, the S-isomer of -methyldopamine and the 1R ,2S-isomers of nordefrin and metaraminol were more active than their corresponding enantiomers, respectively, (2) the inhibitory actions of the 1R, 2S-isomers of ephedrine and norephedrine were observed to be nearly identical and were 20 to 30 times greater than the remaining stereoisomers, i.e., the 1S,2R-, 1R,2R-. or 1S,2S-isomers, (3) the 1R,2S-isomer of ephedrine [D(-)-ephedrine] was found to be a competitive antagonist, whereas the 1S,2R-isomer of ephedrine [L(+)-ephedrine] was a noncompetitive antagonist and (4) no stereoselective or potency differences in biological activity were noted with isomers of amphetamine, methamphetamine, p-hydroxyamphetamine or less active isomers of ephedrine and norephedrine. These data indicate that the orientation of the -hydroxyl group in the R-configuration was important for the stimulatory or inhibitory actions of these compounds and the absolute stereoechemistry of the -hydroxyl group and, to a lesser degree, the -methyl group plays a role in the interaction of phenethylamine with the adrenergic adipose tissue receptor system.

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