Protokylol Hydrochloride

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.

The rat jugular vein provides a model system for the determination of both dissociation constants and relative agonist efficacies for compounds interacting with β-1 and β-2 adrenergic receptors.Dissociation constants for β-1 and β-2 adrenergic receptor antagonists were calculated by determining the inhibition of concentration-response curves to norepinephrine and isoproterenol, resp.Data obtained in the jugular vein for propranolol, practolol, metoprolol and dichloroisoproterenol closely agreed with dissociation constants reported for these compounds based on data generated in both atria and trachea as well as data obtained from binding studies and adenylate cyclase inhibition.However, use of the jugular vein compared to use of multiple tissues ensures constant conditions of uniform innervation, receptor population, and drug disposition parameters for determination of β-1 and β-2 dissociation constantsFurthermore, agonist activity can also be evaluated and compared, providing an advantage relative to receptor binding studies.With this technique, the β-adrenergic receptor antagonists penbutolol and carazolol showed greater affinity for β-1 and β-2 adrenergic receptors (12- and 16-fold, resp.) than propranolol, and carazolol selectively interacted with β-2 adrenergic receptors.For the selective β-2 receptor agonists isoproterenol, salbutamol, metaproterenol, and protokylol, 50% relaxation occurred with 1-3% receptor occupation, whereas for the selective β-1 adrenergic agonists norepinephrine, nylidrin, and prenalterol, 40-100% receptor occupation was necessary for 50% relaxation.Thus, a clear separation of β-adrenergic receptor agonists occurred in the jugular vein, with selective β-2 receptor agonists having higher relative efficacies than selective β-1 adrenergic receptor agonists in this system.The use of this tissue may provide a rapid and efficient method for assigning β-adrenergic subtype specificity for agonists and antagonists and permits quant. determination of antagonist dissociation constants for β-1 and β-2 receptors.