STUDIES ON AGENTS WITH MIXED NO-DEPENDENT VASODILATING AND BETA-BLOCKING ACTIVITIES

Purpose. A series of derivatives having a propranolol-like moiety link ed to NO-donor furoxan substructures were synthesized. The main object ive of this investigation was to obtain agents with mixed No-dependent vasodilating and beta-blocking activities. Methods. Most of the targe t compounds were synthesized from the appropriate furoxans bearing XCH 2CH2NH2 (X = O, S, SO2) chains at the 4 position of the ring, using AI (C2H5)(3) in methylene chloride solution and (+/-)2,3-epoxypropyl 1-na phtyl ether. Two of the final products (X = CONH) were obtained by cou pling the appropriate furoxancarboxylic acids with -[2-hydroxy-3-(1-na phthoxy)propyl]ethylenediamine. beta(1)- and beta(2)-blocking activiti es were examined on isolated guinea pig right atria and on guinea pig trachea respectively. Vasodilating properties were assessed on endothe lium denuded strips of rat aorta Result. Some derivatives behave as we ll balanced ''hybrids'' displaying NO-dependent vasodilating and beta- blocking properties in the same concentration range. Some others displ ay either prevalent beta-blocking or vasodilating activity. Generally speaking hybrid formation lowers the affinity for beta-receptors, in p articular for beta(2)-type, to give an increase in beta(1)/beta(2) sel ectivity. Conclusions. The furoxan system is a flexible tool in design ing analogues of propranolol whose NO-donating and beta-blocking prope rties are modulated over a wide range.