Vasorelaxation by new hybrid compounds containing dihydropyridine and pinacidil-like moieties

The synthesis and pharmacological properties of a novel type of vasorelaxan t hybrid compounds are described. The investigated compounds originate from fluorinated 4-aryl-1,4-dihydropyridines, which are known calcium channel b lockers, and/or from fluorinated analogues of pinacidil, which is an opener of ATP-sensitive potassium channels. In particular, we studied the most po tent hybrid, 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-difluoromethoxy-5-N-(N "- cyano-N'-1,2,2-trimethyl-propylguanidyl)-phenyl)-1,4-dihydropyridine (4a), together with its parent compounds, the dihydropyridine 1b and the pinacidi l analogue 3. In isolated rat mesenteric arteries, micromolar concentration s of 4a relaxed contractions exerted by K+-depolarization or by norepinephr ine. The latter effect was sensitive to the potassium channel blocker glibe nclamide. Micromolar 4a also inhibited [H-3](+)-isradipine and [H-3]P1075 b inding to rat cardiac membranes, and it blocked L-type calcium. channels ex pressed in a mammalian cell line. The respective parent compounds 1b and 3 were always more potent and more selective regarding calcium channel or pot assium channel interaction, respectively. In contrast, 4a combined both eff ects within the same concentration range, indicating that it may represent a lead structure for a novel class of pharmacological hybrid compounds.