Cardiovascular pharmacology2-Aryl- and 2-amido-benzothiazoles as multifunctional vasodilators on rat artery preparations

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 [IBa(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 3-6 µM. 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 25/30 mM than with 60 mM 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. IBa(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.