Stereochemical requirements of α 2-adrenergic receptors for α-methyl substituted phenethylamines

Abstract

The α 1- and α 2-adrenergic effects of the stereoisomers of α-methyl-dopamine were evaluated in guinea pig aorta and field-stimulated guinea pig ileum, respectively, in order to establish the stereochemical requirements of these receptors for α-methyl substituted phenethylamines. The α 1-adrenergic receptor did not distinguish between the stereoisomers of α-methyldopamine which is in marked contrast to the α 2-adrenergic receptor where a dramatic stereochemical preference for the 2S(+)-isomer was observed. In addition, 2R(−)-α-methyldopamine displayed no α-receptor subtype specificity whereas 2S(+)-α-methyldopamine was highly selective (23 fold) for the α 2-adrenergic receptor. These results indicate that the α 2-adrenergic receptor can recognize and accept methyl substituents at the α-carbon atom of phenethylamines when correctly oriented, while the α 1-adrenergic receptor cannot. Thus, the α-carbon atom is a major determinant of the α 2-adrenergic effects of phenethylamines, and plays an important role in determining α-receptor subtype specificity. It is hypothesized that the α 2-adrenergic receptor (but not α 1) has an additional recognition site which will accomodate α-substituted phenethylamines.