2-Aryl- and 2-amido-benzothiazoles as multifunctional vasodilators on rat artery preparations.

Abstract: The neuroprotective agent riluzole [2-amino-6-(trifluoromethoxy)benzothiazole] has been shown to antagonize neuronal high-voltage activated Ca2+ currents. In the search for novel scaffolds leading to potential antihypertensive agents, a series of 2-aryl- and 2-amido-benzothiazoles (HUP) were assessed for their vasorelaxing property on rat aorta rings and for their L-type Ba2+ currents [I Ba(L)] blocking activity on single myocytes isolated from the rat tail artery. HUP5 and HUP30, the most potent of the series, inhibited phenylephrine-induced contraction with IC50 values in the range 3–6µM. The presence of endothelium did not modify their spasmolytic activity. Both HUP5 and HUP30 increased tissue levels of cGMP and shifted to the left the concentration–response curve to sodium nitroprusside. In rings precontracted by phenylephrine, tetraethylammonium or 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) shifted to the right the concentration–relaxation curves of HUP5 and HUP30. The antispasmodic effect of HUP5 and HUP30 was more marked on rings stimulated with 25/30mM than with 60mM K+. HUP5 and HUP30 antagonized both extracellular Ca2+ influx and Ca2+ mobilization from intracellular stores in response to phenylephrine: this effect was not modified by the presence of ODQ. I Ba(L) was partly inhibited by HUP5 and blocked by HUP30 in a concentration-dependent as well as ODQ-independent manner. In conclusion, HUP5 and HUP30 are vasorelaxing agents that stimulate soluble guanylyl cyclase, activate K+ channels, and block extracellular Ca2+ influx. The present benzothiazole derivatives form a novel class of multifunctional vasodilators which may give rise to effective antihypertensive agents. [Copyright &y& Elsevier]