Vasorelaxation by New Hybrid Compounds Containing Dihydropyridine and Pinacidil-Like Moieties

• Published in: Journal of medicinal chemistry 1999-12, Vol.42 (25), p.5266-5271
• Main Authors: Yagupolskii, Lev M, Antepohl, Wolfram, Artunc, Ferruh, Handrock, Renate, Klebanov, Boris M, Maletina, Irina I, Marxen, Bent, Petko, Kirill I, Quast, Ulrich, Vogt, Anna, Weiss, Carolin, Zibold, Jutta, Herzig, Stefan
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - drug effects; Calcium Channels, L-Type - physiology; Cardiovascular system; CHO Cells; Cricetinae; Dihydropyridines - chemistry; In Vitro Techniques; Magnetic Resonance Spectroscopy; Medical sciences; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiology; Pharmacology. Drug treatments; Pinacidil - chemistry; Potassium Channels - agonists; Rats; Rats, Wistar; Spectrophotometry, Infrared; Vasodilator Agents - chemical synthesis; Vasodilator Agents - chemistry; Vasodilator Agents - pharmacology; Vasodilator agents. Cerebral vasodilators
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990443h

The synthesis and pharmacological properties of a novel type of vasorelaxant hybrid compounds are described. The investigated compounds originate from fluorinated 4-aryl-1,4-dihydropyridines, which are known calcium channel blockers, and/or from fluorinated analogues of pinacidil, which is an opener of ATP-sensitive potassium channels. In particular, we studied the most potent 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 pinacidil analogue 3. In isolated rat mesenteric arteries, micromolar concentrations of 4a relaxed contractions exerted by K+-depolarization or by norepinephrine. The latter effect was sensitive to the potassium channel blocker glibenclamide. Micromolar 4a also inhibited [3H](+)-isradipine and [3H]P1075 binding to rat cardiac membranes, and it blocked L-type calcium channels expressed in a mammalian cell line. The respective parent compounds 1b and 3 were always more potent and more selective regarding calcium channel or potassium channel interaction, respectively. In contrast, 4a combined both effects within the same concentration range, indicating that it may represent a lead structure for a novel class of pharmacological hybrid compounds.