Studies on agents with mixed NO-dependent and calcium channel antagonisticvasodilating activities

Purpose. To obtain new cardiovascular agents with mixed Ca2+-channel antago nistic and NO-donor properties, a series of "hybrid" 1,4-dihydropyridines ( 1,4-DHPs), bearing NO-donating furoxan moieties on the 3-positioned lateral ester chain were synthesized and pharmacologically characterized. Furazan analogues were also prepared and investigated for control purposes, because they are unable to release NO.(4) Methods. Synthesis of the models was achieved by a modified Hantzsch approa ch. All of the final furoxan 1,4-DHPs were assessed for their ability to pr oduce nitrite in the presence of a large excess of cysteine by the Griess r eaction. Vasodilating activity was evaluated on rat aorta and expressed as EC50 and EC50MB values, obtained in the absence and in the presence of meth ylene blue (MB) respectively, a well-known guanylate cyclase inhibitor. Aff inities to 1,4-DHP receptor on Ca2+-channels, expressed as IC50 values, wer e determined through displacement experiments of [H-3]-nitrendipine on rat cortex homogenates. Results. Some hybrid compounds (derivatives 15a, 15b, 16a, and 16b) display ed vasodilating activity depending predominantly on their Ca2+-channel bloc ker properties. By contrast, some others (derivatives 17a, 17b, and 21) beh aved as well-balanced hybrids with mixed Ca2+-channel blocking and NO-depen dent vasodilating activities. Conclusion. This work demonstrates the possibility of obtaining well-balanc ed hybrids endowed with mixed NO-donor and Ca2+-channel blocker properties using appropriate 1,4-DHP and furoxan moieties. A procedure for the individ ual evaluation of the NO-dependent vasodilator component and that due to Ca 2+-channel blocking is proposed.