title: 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 Ca(2+) 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 Ba(2+) 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 3-6 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 Ca(2+) influx and Ca(2+) 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 Ca(2+) influx. The present benzothiazole derivatives form a novel class of multifunctional vasodilators which may give rise to effective antihypertensive agents.
authors.affiliation: Dipartimento di Scienze della Vita, Università di Siena, via A. Moro 2, 53100 Siena, Italy. fabio.fusi@unisi.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Fusi
authors.forename: Miriam
authors.initials: M
authors.lastname: Durante
authors.forename: Giampietro
authors.initials: G
authors.lastname: Sgaragli
authors.forename: Nguyen Manh
authors.initials: NM
authors.lastname: Cuong
authors.forename: Phan Thi Phuong
authors.initials: PT
authors.lastname: Dung
authors.forename: Nguyen Hai
authors.initials: NH
authors.lastname: Nam
mesh_terms: D000818:Animals; D001158:Arteries / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D052160:Benzothiazoles / Q000737:chemistry* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032342:Muscle Cells / Q000187:drug effects; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019789:Tetraethylammonium / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; D011810:Quinoxalines; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D019789:Tetraethylammonium; D006152:Cyclic GMP; D002118:Calcium
keywords: Benzothiazoles; L-type Ca(2+) channel; Rat aorta; Soluble guanylyl cyclase; cGMP