Effects of N-aralkyl substitution of beta-agonists on alpha- and beta-adrenoceptor subtypes: pharmacological studies and binding assays.

The pharmacological and binding properties of four beta-adrenomimetic drugs with N-alkyl substitutions (isoprenaline, terbutaline, salbutamol and soterenol) were compared with those of four corresponding drugs with N-aralkyl substitutions (protokylol, ME 506, salmefamol and zinterol). BD-40 A, a very powerful beta 2-agonist with a related chemical structure, was also included in this study. The beta 1- and beta 2-activities of these drugs were determined on guinea-pig atria and trachea, their alpha-adrenolytic activity was measured on rat aorta and their affinities (Ki) for alpha 1- and alpha 2-adrenoceptors on rat cortical membranes were assessed using [3H]prazosin and [3H]yohimbine. In this group of beta-agonists, substitution of the N-alkyl by an N-aralkyl group had a variable effect on the beta 2-selectivity whereas alpha-adrenolytic properties were always enhanced. An increase of the affinities (Ki) for both alpha 1- and alpha 2-adrenoceptors was found but the effect was much more pronounced for alpha 1-adrenoceptors. These results indicated that the alpha-adrenolytic activity observed with the N-aralkyl beta-agonists was selective for alpha 1-adrenoceptors.