In vitro pharmacologic activity of congener derivatives and model conjugates of propranolol and practolol

Previous studies in our laboratory suggested that synthetized derivatives of isoproterenol and histamine could create agonists more potent and receptor and/or tissue selective than the parent compound. In the present study we have evaluated the hypothesis that our results with isoproterenol and histamine derivatives could be extended to include beta-adrenergic antagonists. With this purpose in mind, fourteen derivatives of propranolol and practolol were synthesized and tested in four in vitro systems. The congeners and conjugates were tested using biologic assays (blocking of cAMP accumulation) and/or radioligand binding assays in S-49 lymphoma cells and in rat adipocytes, heart and lung which contain beta 1 and/or beta 2 receptors. Our results indicate that structural modifications distant from the pharmacophore alter the pharmacologic profile of the parent compound. The relative potencies of the derivatives were dependent upon several key factors including the length of the methylene spacer chain and the nature of the substituents on the aromatic ring. The presence of a spacer group with four methylenes resulted in the most active compound in each series when tested on S-49 cells. The derivatives with a paramethyl toluidide group were more potent than the derivatives with a trifluoromethyl toluidide group. The dipeptide derivatives were more potent on adipocyte than S-49 cells, suggesting a preference for beta 1 receptors. Some of the same modifications that led to altered potency and which resulted in an increased receptor and/or tissue selectivity using the progenitors isoproterenol or histamine did extrapolate to the beta blockers. Our data suggest that alterations in receptor and/or tissue selectivity must be imparted by the carrier moiety of the drug and may be related to the biochemical microenvironment of the receptors.