The Novel Potent Multidrug Resistance Inhibitors N,N-bis(cyclohexanol)amine Aryl Esters Are Devoid of Vascular Effects

Abstract

The aim of this study was to investigate the effects of the four isomers (3a, 3b, 3c and 3d) of a novel multidrug resistance-reverting agent – 3,4,5-trimethoxybenzoic acid 4-(methyl-{4-[3-(3,4,5-trimethoxyphenyl)acryloyloxy]cyclohexyl}amino)cyclohexyl ester – on vascular functions in vitro. A comparison of their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, was performed. In rat aorta rings, 3a–d antagonized both 60 mmol/l K⁺- and phenylephrine-induced contraction in a concentration-dependent manner, with maximal relaxation values averaging 50% of controls, 3d being the most effective of the series. The vasorelaxing effect was similar either in presence or absence of intact endothelium. In rat tail artery myocytes, out of the four isomers, only 3a consistently inhibited Ba²⁺ current through Ca_v1.2 channels. Our results provide functional evidence that 3a–d are weak vasorelaxing agents, although at concentrations much higher than those effective for multidrug resistance reversion in cancer cells.