Direct effects of ephedrine isomers on human beta-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 beta1-, beta2-, and beta3-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 beta1-AR, the rank order of potency (EC50 values, maximal response relative to isoproterenol = 100%) was 1R,2S-ephedrine (0.5 microM, 68%) > 1S,2R-ephedrine (72 microM, 66%) > 1S,2S-pseudoephedrine (309 microM, 53%) = 1R,2R-pseudoephedrine (1122 microM, 53%). On human beta2-AR, the rank order of potency was 1R,2S-ephedrine (0.36 microM, 78%) > 1R,2R-pseudoephedrine (7 microM, 50%) > or = 1S,2S-pseudoephedrine (10 microM, 47%) > 1S,2R-ephedrine (106 microM, 22%). Only 1R,2S-ephedrine showed significant agonist activity on human beta3-AR with an EC50 = 45 betaM 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 beta1-/beta2-AR agonist and the only isomer possessing weak partial agonist activity on beta3-AR.