Alkylating .beta.-blockers: activity of isomeric bromoacetyl alprenolol menthanes

Abstract

An affinity label for .beta.-adrenoceptors, N-(bromoacetyl)-N''-[3-(o-allylphenoxy)-2-hydroxypropyl]-1,8-diamino-p-menthane, has been extensively used in the form of a mixture of four isomers. In the present study, all four isomers were isolated, their structures elucidated, and their interactions with .beta.-adrenoceptors characterized. The isomer with the aromatic (pharmacophore) group on carbon 1 of p-menthane and with the Z configuration (Z-1) predominates in the mixture and has the highest affinity for .beta.-adrenoceptors of rat heart (KD = 3 .times. 10-8 M) and lungs (KD = 2 .times. 10-8 M). This isomer acts as a ligand that binds irreversibly at the drug binding site of the receptor (i.e., after treatment and extensive washing of the membrane preparation, the concentration of the receptors is decreased in a dose-dependent manner), while binding characteristics of the remaining receptors are not changed. The corresponding E diastereomer (E-1) also binds irreversibly to the drug binding site of the receptor. The isomer with the aromatic group on carbon 8 and the Z configuration (Z-8) modifies the receptor noticeably only at higher concentrations and then on a site apparently different from the drug-binding site, i.e., affinity of receptors after the treatment and washing is changed. The corresponding E diastereomer (E-8) modified both the drug-binding and alternative binding site. The results suggest that there is some flexibility in the conformation of the .beta.-adrenoceptor that enables pairs of ligands, differing by axial or equatorial positions of critical groups, to alkylate the receptor in an analogous manner.