IN VITRO INTERACTIONS OF THE NEW ANOREXIC AGENT WY-5244 WITH CARDIAC AND VASCULAR TISSUE AND WITH ADRENERGIC MECHANISMS

¹ Pharmacological Evaluation Section, Wyeth Laboratories, Inc., Radnor, Pennsylvania

Wy-5244, 1-(p-chlorophenyl)-1,2,3,4,5,6-hexahydro-2,5-benzodiazocine diHCl, has been previously shown to be an effective anorexic agent and to possess cardiovascular effects differing markedly from those of d-amphetamine and similar antiappetite drugs, i.e., the rapid i.v. injection of Wy-5244 to anesthetized dogs resulted in a primary depression of cardiovascular function followed by slight stimulation. The present experiments attempted to evaluate the sympathomimetic actions of the compound in isolated preparations not subject to homeostatic mechanisms and to examine in greater detail the interaction of Wy-5244 with adrenergic substances. Wy-5244 caused a slight increase in contractile force in isolated cat atria but depressed contractility at higher concentrations. d-Amphetamine, on the other hand, increased contractile force markedly. Both d-amphetamine and Wy-5244 contracted rabbit aortic strips. The response to the former was equivalent to approximately 50% of the maximum attained with norepinephrine whereas the response to Wy-5244 was about 10% of this amount. These experiments indicate that Wy-5244 had only weak sympathomimetic activity. However, the compound profoundly influenced the actions of other substances on adrenergic mechanisms indicating that it did, indeed, affect these systems. Inotropic responses to norepinephrine and d-amphetamine were potentiated and inhibited, respectively, by Wy-5244 in isolated cat atria. Further, Wy-5244, as well as d-amphetamine and imipramine, antagonized guanethidine-induced inhibition of sympathetically mediated contraction of the guinea-pig vas deferens. In "receptor protection" experiments pretreatment of rabbit aortic strips with Wy-5244 or d-amphetamine antagonized the adrenergic blocking activity of subsequently administered phenoxybenzamine.