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NEUROPHARMACOLOGY

Pharmacological Effects of Ephedrine Alkaloids on Human ₁- and ₂-Adrenergic Receptor Subtypes

The National Center for Natural Products Research (G.M., R.N., B.T.S., I.A.K., D.R.F.), Department of Pharmacology (S.A.B., Y.M.D., S.G.L., D.R.F.), and Department of Pharmacognosy (I.A.K.), School of Pharmacy, University of Mississippi, University, Mississippi

Ephedra species of plants have both beneficial and adverse effects primarily associated with the presence of ephedrine alkaloids. Few reports have appeared that examine the direct actions of ephedrine alkaloids on human subtypes of adrenergic receptors (ARs). In the present study, ephedrine alkaloids were evaluated for their binding affinities on human _1A-, _1B-, _1D-, _2A-, _2B-, and _2C-AR subtypes expressed in HEK and Chinese hamster ovary cells. Cell-based reporter gene assays were used to establish functional activity of ephedrine alkaloids at _1A-, _2A-, and _2C-ARs. The data showed that ephedrine alkaloids did not activate ₁- and ₂-ARs and that they antagonized the agonist-mediated effects of phenylephrine and medetomidine on ₁- and ₂-ARs, respectively. As in the binding studies, 1R,2R- and 1R,2S-ephedrine showed greater functional antagonist activity than the 1S,2R- and 1S,2S-isomers. The rank order of affinity for the isomers was 1R,2R > 1R,2S > 1S,2R > 1S,2S. The rank order of potencies of alkaloids containing a 1R,2S-configuration was norephedrine ephedrine >> N-methylephedrine. These studies have demonstrated that orientation of the -hydroxyl group on the ethylamino side chain and the state of N-methyl substitution are important for -AR binding and functional activity of the ephedrine alkaloids. In conclusion, the ephedrine isomers and analogs studied did not exhibit any direct agonist activity and were found to possess moderate antagonist activities on cloned human -ARs. The blockade of presynaptic _2A- and _2C-ARs may have a pharmacological role in the direct actions of Ephedra alkaloids.

Address correspondence to: Dr. Dennis R. Feller, Department of Pharmacology, School of Pharmacy, The University of Mississippi, University, MS 38677. E-mail: dfeller{at}olemiss.edu