Abstract

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 α_1A-, α_1B-, α_1D-, α_2A-, α_2B-, and α_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 α_1A-, α_2A-, and α_2C-ARs. The data showed that ephedrine alkaloids did not activate α₁- and α₂-ARs and that they antagonized the agonist-mediated effects of phenylephrine and medetomidine on α₁- and α₂-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 β-hydroxyl group on the ethylamino side chain and the state of N-methyl substitution are important for α-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 α-ARs. The blockade of presynaptic α_2A- and α_2C-ARs may have a pharmacological role in the direct actions of Ephedra alkaloids.