Effects of N-aralkyl substitution of β-agonists on α- and β-adrenoceptor subtypes: pharmacological studies and binding assays

Abstract

Abstract The pharmacological and binding properties of four β-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 β2-agonist with a related chemical structure, was also included in this study. The β1- and β2-activities of these drugs were determined on guinea-pig atria and trachea, their α-adrenolytic activity was measured on rat aorta and their affinities (Ki) for α1- and α2-adrenoceptors on rat cortical membranes were assessed using [3H]prazosin and [3H]yohimbine. In this group of β-agonists, substitution of the N-alkyl by an N-aralkyl group had a variable effect on the β2-selectivity whereas α-adrenolytic properties were always enhanced. An increase of the affinities (Ki) for both α1- and α2-adrenoceptors was found but the effect was much more pronounced for α1-adrenoceptors. These results indicated that the α-adrenolytic activity observed with the N-aralkyl β-agonists was selective for α1-adrenoceptors.