title: Arylcyanoguanidines as activators of Kir6.2/SUR1K ATP channels and inhibitors of insulin release.
abstract: Phenylcyanoguanidines substituted with lipophilic electron-withdrawing functional groups, e.g. N-cyano-N'-[3,5-bis-(trifluoromethyl)phenyl]-N' '-(cyclopentyl)guanidine (10) and N-cyano-N'-(3,5-dichlorophenyl)-N' '-(3-methylbutyl)guanidine (12) were synthesized and investigated for their ability to inhibit insulin release from beta cells, to repolarize beta cell membrane potential, and to relax precontracted rat aorta rings. Structural modifications gave compounds, which selectively inhibit insulin release from betaTC6 cells (e.g. compound 10: IC(50) = 5.45 +/- 1.9 microM) and which repolarize betaTC3 beta cells (10: IC(50) = 4.7 +/- 0.5 microM) without relaxation of precontracted aorta rings (10: IC(50) > 300 microM). Inhibition of insulin release from rat islets was observed in the same concentration level as for betaTC6 cells (10: IC(50) = 1.24 +/- 0.1 microM, 12: IC(50) = 3.8 +/- 0.4 microM). Compound 10 (10 microM) inhibits calcium outflow and insulin release from perifused rat pancreatic islets. The mechanisms of action of 10 and 12 were further investigated. The compounds depolarize mitochondrial membrane from smooth muscle cells and beta cell and stimulate glucose utilization and mitochondrial respiration in isolated liver cells. Furthermore, 10 was studied in a patch clamp experiment and was found to activate Kir6.2/SUR1 and inhibit Kir6.2/SUR2B type of K(ATP) channels. These studies indicate that the observed effects of the compounds on beta cells result from activation of K(ATP) channels of the cell membrane in combination with a depolarization of mitochondrial membranes. It also highlights that small structural changes can dramatically shift the efficacy of the cyanoguanidine type of selective activators of Kir6.2/SUR2 potassium channels.
authors.affiliation: Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK 2760 Måløv, Denmark.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Tagmose
authors.forename: Søren C
authors.initials: SC
authors.lastname: Schou
authors.forename: John P
authors.initials: JP
authors.lastname: Mogensen
authors.forename: Flemming E
authors.initials: FE
authors.lastname: Nielsen
authors.forename: Per O G
authors.initials: PO
authors.lastname: Arkhammar
authors.forename: Philip
authors.initials: P
authors.lastname: Wahl
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Hansen
authors.forename: Anne
authors.initials: A
authors.lastname: Worsaae
authors.forename: Harrie C M
authors.initials: HC
authors.lastname: Boonen
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Antoine
authors.forename: Philippe
authors.initials: P
authors.lastname: Lebrun
authors.forename: John Bondo
authors.initials: JB
authors.lastname: Hansen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000819:agonists*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D005260:Female; D005947:Glucose / Q000378:metabolism; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007329:Insulin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010084:Oxidation-Reduction; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000819:agonists*; D013329:Structure-Activity Relationship; D064233:Sulfonylurea Receptors; D014982:Xenopus laevis
chemical_list: C577507:ABCC8 protein, human; C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; C577509:Abcc8 protein, rat; C577512:Abcc9 protein, rat; D006146:Guanidines; D007329:Insulin Antagonists; C487411:N-cyano-N'-(3,5-bis-(trifluoromethyl)phenyl)-N''-(cyclopentyl)guanidine; C487412:N-cyano-N'-(3,5-dichlorophenyl)-N''-(3-methylbutyl)guanidine; D009570:Nitriles; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D005947:Glucose