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

Abstract

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 α- and β-adrenergic receptors (AR). Our main goal was to study the direct effects of the ephedrine isomers on human β 1-, β 2-, and β 3-AR expressed in Chinese hamster ovary cells. Previous work indicated that the ephedrine isomers are inactive as agonists and that 1 R,2 S-ephedrine is more potent than the 1 S,2 R-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 β 1-AR, the rank order of potency ( ec 50 values, maximal response relative to isoproterenol = 100%) was 1 R,2 S-ephedrine (0.5 μM, 68%) > 1 S,2 R-ephedrine (72 μM, 66%) > 1 S,2 S- pseudoephedrine (309 μM, 53%) = 1 R,2 R- pseudoephedrine (1122 μM, 53%). On human β 2-AR, the rank order of potency was 1 R,2 S-ephedrine (0.36 μM, 78%) > 1 R,2 R- pseudoephedrine (7 μM, 50%) ≥ 1 S,2 S- pseudoephedrine (10 μM, 47%) > 1 S,2 R-ephedrine (106 μM, 22%). Only 1 R,2 S-ephedrine showed significant agonist activity on human β 3-AR with an ec 50 = 45 μM 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) 1 R,2 S-ephedrine is the most potent of the four ephedrine isomers on all three human β-AR; and (c) 1 R,2 S- ephedrine was nearly equipotent as a β 1-/β 2-AR agonist and the only isomer possessing weak partial agonist activity on β 3-AR.