Direct effects of ephedrine isomers on human β-adrenergic receptor subtypes

Ephedrine and its alkaloids are used for the treatment of asthma, nasal congestion, and obesity. Ephedrine, with two chiral centers, exists as four isomers that exhibit direct and indirect effects on both alpha- and beta-adrenergic receptors (AR). Our main goal was to study the direct effects of the ephedrine isomers on human beta(1)-, beta(2)-, and beta(3)-AR expressed in Chinese hamster ovary cells. Previous work indicated that the ephedrine isomers are inactive as agonists and that 1R,2S-ephedrine is more potent than the 1S,2R-isomer as an antagonist of catecholamine-induced lipolysis in rat adipose tissue (Lee et al., J Pharmacol Exp Ther 190: 249-259, 1974). Stimulation of adenylyl cyclase, associated with cyclic AMP accumulations, was measured by a luciferase reporter gene assay. On human beta(1)-AR, the rank order of potency (EC50 values, maximal response relative to isoproterenol = 100%) was 1R,2S-ephedrine (0.5 mu M, 68%) > 1S,2R ephedrine (72 mu M, 66%) > 1S,2S-pseudoephedrine (309 mu M, 53%) = 1R,2R-pseudoephedrine (1122 mu M, 53%). On human beta(2)-AR, the rank order of potency was 1R,2S-ephedrine (0.36 mu M, 18%) > 1R,2R-pseudoephedrine (7 mu M, 50%) greater than or equal to 1S,2S-pseudoephedrine (10 mu M, 47%) > 1S,2R-ephedrine (106 mu M, 22%). Only 1R,2S-ephedrine showed significant agonist activity on human beta(3)-AR with an EC50 = 45 mu M and a maximal response of 31%. Our studies demonstrated that (a) stereoselective and rank order differences exist among the direct effects of ephedrine isomers; (b) 1R,2S-ephedrine is the most potent of the four ephedrine isomers on all three human beta-AR; and (c) 1R,2S- ephedrine was nearly equipotent as a beta(1)-/beta(2)-AR agonist and the only isomer possessing weak partial agonist activity on beta(3)-AR. (C) 1999 Elsevier Science Inc.