title: Design and synthesis of new potassium channel activators derived from the ring opening of diazoxide: study of their vasodilatory effect, stimulation of elastin synthesis and inhibitory effect on insulin release.
abstract: Benzenesulfonylureas and benzenesulfonylthioureas, as well as benzenecarbonylureas and benzenecarbonylthioureas, were prepared and evaluated as myorelaxants on 30mMKCl-precontracted rat aortic rings. The most active compounds were further examined as stimulators of elastin synthesis by vascular smooth muscle cells and as inhibitors of insulin release from pancreaticβ-cells. The drugs were also characterized for their effects on glycaemia in rats. Benzenesulfonylureas and benzenesulfonylthioureas did not display any myorelaxant activity on precontracted rat aortic rings. Such an effect could be attributed to their ionization at physiological pH. By contrast, almost all benzenecarbonylureas and benzenecarbonylthioureas displayed a myorelaxant activity, in particular the benzenecarbonylureas with an oxybenzyl group linked to the ortho position of the phenyl ring. The vasodilatory activity of the most active compounds was reduced when measured in the presence of 80mMKCl or in the presence of 30mM KCl and 10μM glibenclamide. Such results suggested the involvement, at least in part, of KATP channels. Preservation of a vasodilatory activity in rat aortic rings without endothelium indicated that the site of action of such molecules was located on the vascular smooth muscle cells and not on the endothelial cells. Some of the most active compounds also stimulated elastin synthesis by vascular smooth muscle cells. Lastly, most of the active vasorelaxant drugs, except 15k and 15t at high concentrations, did not exhibit marked inhibitory effects on the insulin releasing process and on glycaemia, suggesting a relative tissue selectivity of some of these compounds for the vascular smooth muscle.
authors.affiliation: Laboratoire de Phytochimie et de Pharmacologie, Département de Chimie, Faculté des Sciences Exactes et informatique, Université de Jijel, B.P. 98 Ouled Aissa, 18000 Jijel, Algeria.
authors.forename: Nafila
authors.initials: N
authors.lastname: Bouider
authors.affiliation: Laboratoire 'Hypoxie: Physiopathologie Cardiovasculaire et Respiratoire' (HP2), INSERM U1042-Université Grenoble Alpes, F-38042 La Tronche, France.
authors.forename: Wassim
authors.initials: W
authors.lastname: Fhayli
authors.affiliation: Laboratoire 'Hypoxie: Physiopathologie Cardiovasculaire et Respiratoire' (HP2), INSERM U1042-Université Grenoble Alpes, F-38042 La Tronche, France.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Ghandour
authors.affiliation: Laboratoire 'Hypoxie: Physiopathologie Cardiovasculaire et Respiratoire' (HP2), INSERM U1042-Université Grenoble Alpes, F-38042 La Tronche, France.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Boyer
authors.affiliation: Laboratoire de Phytochimie et de Pharmacologie, Département de Chimie, Faculté des Sciences Exactes et informatique, Université de Jijel, B.P. 98 Ouled Aissa, 18000 Jijel, Algeria.
authors.forename: Kamel
authors.initials: K
authors.lastname: Harrouche
authors.affiliation: Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles, Faculté de Médecine, 808, Route de Lennik, B-1070 Bruxelles, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Florence
authors.affiliation: Laboratoire de Chimie Pharmaceutique, Center for Interdisciplinary Research on Medicines (CIRM), Université de Liège, 1, Avenue de l'Hôpital, B-4000 Liège, Belgium. Electronic address: b.pirotte@ulg.ac.be.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.affiliation: Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles, Faculté de Médecine, 808, Route de Lennik, B-1070 Bruxelles, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lebrun
authors.affiliation: Laboratoire 'Hypoxie: Physiopathologie Cardiovasculaire et Respiratoire' (HP2), INSERM U1042-Université Grenoble Alpes, F-38042 La Tronche, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Faury
authors.affiliation: Laboratoire de Phytochimie et de Pharmacologie, Département de Chimie, Faculté des Sciences Exactes et informatique, Université de Jijel, B.P. 98 Ouled Aissa, 18000 Jijel, Algeria.
authors.forename: Smail
authors.initials: S
authors.lastname: Khelili
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D003981:Diazoxide / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004549:Elastin / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007329:Insulin Antagonists / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists*; D017208:Rats, Wistar; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001555:Benzene Derivatives; D007328:Insulin; D007329:Insulin Antagonists; D015221:Potassium Channels; D014665:Vasodilator Agents; D004549:Elastin; D013890:Thiourea; D003981:Diazoxide
keywords: Benzenecarbonylthiourea; Benzenecarbonylurea; Benzenesulfonylthiourea; Benzenesulfonylurea; Diazoxide; Elastin synthesis; Glycaemia; Insulin secretion; Myorelaxant activity; Potassium channel opener