Structure-activity relationship study on alpha1 adrenergic receptor antagonists from beer.

Hordatine A and aperidine have been previously isolated from beer as active ingredients, which bind to muscarinic M3 receptor. In addition, these compounds have exhibited antagonist activity against the alpha1A adrenoceptor. Although the relative structures of these two molecules have previously been determined, the absolute stereochemistry was unclear. Hence, to elucidate the absolute stereochemistry of natural hordatine A, we synthesized each enantiomer of hordatine A and aperidine from optically pure dehydrodi-p-coumaric acid. Several additional related compounds were also synthesized for structure-activity relationship studies. Chiral column HPLC analysis demonstrated that the absolute stereochemistry of natural hordatine A is (2S,3S), while based on the isomerization mechanism, the stereochemistry of aperidine is (2R,3S). The alpha1A adrenoceptor binding activity of (2R,3R)-hordatine A is the most potent among the enantiomeric pairs of hordatines and aperidines. Furthermore, the related, synthetic compound, (2R,3R)-methyl benzofurancarboxylate exhibits antagonist activity against the alpha1A adrenoceptor at a lower concentration than that of hordatine A.