Searching for balanced hybrid NO-donor 1,4-dihydropyridines with basic properties

Purpose. Model compounds containing NO-donor furoxan moieties at the 3-posi tioned basic lateral chain of 1, a 1,4-dihydropyridine related to nicardipi ne, were synthesized in order to study their vasodilating activity as well as their basic and lipophilic behaviour. Methods. All the compounds were obtained by a modified Hantzsch approach. P otentiometry was used to determine pK(a) and lipophilicity descriptors. The furoxan 4-aryl-1,4-dihydropyridines were assessed for their ability to rel ease nitrite, in the presence of a large excess of cysteine, by the Griess reaction. Vasodilating activity of the products in the absence and in the p resence of ODQ, a well-known guanylate cyclase inhibitor, was evaluated on rat thoracic aorta. Results, The compounds display low basicity values and for this reason thei r log Ds at physiological pH are identical to the log Ps of the neutral for ms. Products 2, 3 display vasodilating action principally dependent on thei r Ca2+-antagonist properties, whereas 4 behaves as a well-balanced hybrid w ith mixed Ca2+-channel blocker and NO-dependent vasodilator activities. Conclusions. Nitrogen containing lateral chain at the 3-position of 1 is a suitable molecular region to be modified in order to obtain well-balanced f uroxan NO-donor 1,4-DHPs. This manipulation produces a decrease in the basi city. General analysis of pK(a) and lipophilicity descriptors of these new DHPs suggest that molecular flexibility could influence both their basicity and log P-1.