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

Abstract

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 [(3)H](+)-isradipine and [(3)H]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.

ATP-Sensitive Potassium Channel Openers and 2,3-Dimethyl-2-Butylamine Derivatives

“…Micromolar amounts of (61) also inhibit 3H-(+)-isradipine and [ 3 H]P1075 binding to rat cardiac membranes and block L-type calcium channels expressed in a mammalian cell line. Compound (61) combines the effects of dihydropyridine and pinacidil within the same concentration range, indicating that it may represent a lead structure for a novel class of pharmacological hybrid compounds [90]. …”

“…In contrast, the compound (94) with a methyl group decreases the potassium currents, whereas the compounds with benzyl or 2-hydroxy-5-chlorobenzyl groups have no effects on the potassium currents. Analysis of (84), (90), and (98) indicates that for the carbonyl on the branched substituent group of the 2,3 and 4-position, the order of intensity of changes in the potassium current is (90) > (84) > (98).…”

Electrophysiological Analysis of ATP‐Sensitive Potassium Channels in Mammalian Cells and Xenopus Oocytes

“…Radioligand binding assays. Radioligand binding assays using [ 3 H]glyburide or [ 3 H]P1075 have been used to identify compounds that exhibit high affinity for K ATP channels (Yagupolskii et al, 1999;Gopalakrishnan et al, 2000). More recently, radioligands with an improved profile such as [ 125 I]A-312110 have emerged, and these could facilitate screening for K ATP channel openers and blockers in a high-throughput manner (Gopalakrishnan et al, 2002).…”

Design, Synthesis, and Computational Studies with ADMET of Novel Cardiovascular Hybrid Drugs

“…[18] Step III) AB1-AB18 Was taken and Hantzsch synthesis was carried out to obtain AC1-AC18 dihydropyridine structures. [7][8][9][10][11][12][13][14][15][16][17][18][19] Step IV) AC1-AC18 in 10 ml of glacial acetic acid in 100 ml conical flask, warmed gently on a water bath until a clear solution results, then cooled as far as possible without the formation of crystals. To this solution added (0.015 M) of liquid bromine temperature was maintained below 45°C during the addition.…”