Effect of phenylpropanolamine and related compounds on beta-adrenoceptor-induced activation of adenylyl cyclase

While oral administration of therapeutic doses of phenylpropanolamine (PPA) does little to cardiovascular function in humans, intravenous doses administered to experimental animals are known to alter heart rate and blood pressure. Previous in vivo and in vitro studies have documented a beta-adrenoceptor agonist action for PPA and thus it was of interest to investigate whether these effects could be partially mediated by a direct interaction with beta-adrenoceptors. Phenylpropanolamine, [1R, 2R]-(-)-norephedrine, [1S, 2S]-(+)-norephedrine, [1S, 2R]-(+)-norpseudoephedrine, [S]-(+)-amphetamine, and [1R, 2S]-(-)-ephedrine, were compared with the known beta-adrenoceptor agonists [R]-(-)-epinephrine (EPI), [R]-(-)-norepinephrine (NE), and [R*, S*]-(+/-)-isoproterenol (ISO) for their ability to increase the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cAMP) in minces of rat heart. Of the compounds investigated only NE, EPI, and ISO, as well as, forskolin, which directly stimulates adenylyl cyclase, significantly (p < 0.05) increased intracellular levels of cAMP. The other phenethylamines were without effect. The results of this study demonstrate that PPA and its diastereomers do not act directly at beta-adrenoceptors to alter cardiac function and supports the hypothesis that significant agonist activity of beta-phenethylamines at the beta-adrenoceptor requires phenolic/aryl ether substitution on the phenyl-ring (typically positions 3, 4 and/or 5).