New 1,4-dihydropyridines conjugated to furoxanyl moieties, endowed with both nitric oxide-like and calcium channel antagonist vasodilator activities

A series of 4-phenyl-1,4-dihydropyridines substituted at the ortho and meta positions of the phenyl ring with NO-donating furoxan moieties and their n on-NO-releasing furazan analogues were synthesized and pharmacologically ch aracterized. The vasodilator activities of these compounds were evaluated o n rat aorta and expressed as EC50 values or as EC50iGC values when obtained in the presence of inhibitors of guanylate cyclase methylene blue (MB) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-(ODQ). Affinities to 1,4-DHP recep tors on Ca2+ channels, expressed as IC50 values, were determined through di splacement experiments of [H-3]-nitrendipine on rat cortex homogenates. A l inear correlation between IC50 and EC50 values was found for compounds unab le to release NO. EC50calcd values for derivatives containing NO-donor moie ties, expression of the Ca2+-blocking component of their vasodilator activi ty, were interpolated on this linear regression. They showed a good corresp ondence with EC50iGC values determined in the presence of soluble guanylate cyclase inhibitors. Analysis of (EC50EC50)-E-iGC/ ratios provided a useful tool to distinguish well-balanced hybrids from derivatives biased toward C a2+-blocking or NO-dependent vasodilator activity. A detrimental effect on affinity to the 1,4-DHP receptor, due to substitution at the ortho and meta positions of the 4-phenyl ring, was observed. SAR to explain this effect i s proposed.