title: Synthesis and characterization of a quinolinonic compound activating ATP-sensitive K(+) channels in endocrine and smooth muscle tissues.
abstract: Original quinolinone derivatives structurally related to diazoxide were synthesized and their effects on insulin secretion from rat pancreatic islets and the contractile activity of rat aortic rings determined. A concentration-dependent decrease of insulin release was induced by 6-chloro-2-methylquinolin-4(1H)-one (HEI 713). The average IC(50) values were 16.9+/-0.8 microM for HEI 713 and 18.4+/-2.2 microM for diazoxide. HEI 713 increased the rate of (86)Rb outflow from perifused pancreatic islets. This effect persisted in the absence of external Ca(2+) but was inhibited by glibenclamide, a K(ATP) channel blocker. Inside-out patch-clamp experiments revealed that HEI 713 increased K(ATP) channel openings. HEI 713 decreased (45)Ca outflow, insulin output and cytosolic free Ca(2+) concentration in pancreatic islets and islet cells incubated in the presence of 16.7 or 20 mM glucose and extracellular Ca(2+). The drug did not affect the K(+)(50 mM)-induced increase in (45)Ca outflow. In aortic rings, the vasorelaxant effects of HEI 713, less potent than diazoxide, were sensitive to glibenclamide and to the extracellular K(+) concentration. The drug elicited a glibenclamide-sensitive increase in (86)Rb outflow from perifused rat aortic rings. Our data describe an original compound which inhibits insulin release with a similar potency to diazoxide but which has fewer vasorelaxant effects. Our results suggest that, in both aortic rings and islet tissue, the biological effects of HEI 713 mainly result from activation of K(ATP) channels ultimately leading to a decrease in Ca(2+) inflow.
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine (CP 617), Université Libre de Bruxelles, Route de Lennik 808, B-1070 Brussels, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Becker
authors.forename: M H
authors.initials: MH
authors.lastname: Antoine
authors.forename: Q A
authors.initials: QA
authors.lastname: Nguyen
authors.forename: B
authors.initials: B
authors.lastname: Rigo
authors.forename: K E
authors.initials: KE
authors.lastname: Cosgrove
authors.forename: P D
authors.initials: PD
authors.lastname: Barnes
authors.forename: M J
authors.initials: MJ
authors.lastname: Dunne
authors.forename: B
authors.initials: B
authors.lastname: Pirotte
authors.forename: P
authors.initials: P
authors.lastname: Lebrun
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002132:Calcium Radioisotopes / Q000378:metabolism; D003981:Diazoxide / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012414:Rubidium Radioisotopes / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D002132:Calcium Radioisotopes; C439306:HEI 712; C439305:HEI 713; D007328:Insulin; D008055:Lipids; D015221:Potassium Channels; D015363:Quinolones; D012414:Rubidium Radioisotopes; D000255:Adenosine Triphosphate; D005947:Glucose; D003981:Diazoxide; D005905:Glyburide; D002118:Calcium