title: KATP channel openers: tissue selectivity of original 3-alkylaminopyrido- and 3-alkylaminobenzothiadiazine 1,1-dioxides.
abstract: The present study was designed to further evaluate the biological effects and tissue selectivity of new 3-alkylaminobenzo- and 3-alkylaminopyridothiadiazine 1,1-dioxides bearing identical branched alkylamino chains at the 3-position. These original compounds were compared with their parent molecules; namely the K(ATP) channel openers diazoxide and pinacidil. All tested 3-alkylamino-substituted derivatives provoked a marked, concentration-dependent inhibition of the glucose-induced insulin secretion from rat pancreatic islets. The 3-alkylaminopyridothiadiazine 1,1-dioxides evoked a weak vasorelaxant activity whilst their 7-halo-substituted benzothiadiazine counterparts elicited pronounced, concentration-dependent, relaxations of rat aortic rings. The myorelaxant effect of the different drugs was tightly correlated with their capacity to increase (86)Rb outflow ((42)K substitute) from prelabelled and perifused rat aortic rings. EC(50)/IC(50) ratios (vascular/pancreatic) revealed a pronounced selectivity of the 3-alkylaminopyridothiadiazine 1,1-dioxides towards the pancreatic endocrine tissue. Structure-activity relationships suggest that, besides the requirement of an electronegative pole at the 7-position of the heterocycle, a minimal steric hindrance confers an optimal insulin-secreting cell selectivity. Lastly, radioisotopic, electrophysiological and pharmacological investigations indicate that the marked vasorelaxant properties of the 3-alkylaminobenzothiadiazine 1,1-dioxides are related to the activation of smooth muscle K(ATP) channels.
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine (CP617), Université Libre de Bruxelles, Route de Lennik 808, B-1070 Brussels, Belgium. plebrun@ulb.ac.be
authors.forename: Philippe
authors.initials: P
authors.lastname: Lebrun
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Becker
authors.forename: Nicole
authors.initials: N
authors.lastname: Morel
authors.forename: Philippe
authors.initials: P
authors.lastname: Ghisdal
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Antoine
authors.forename: Pascal
authors.initials: P
authors.lastname: de Tullio
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D054086:KATP Channels / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D007328:Insulin; D054086:KATP Channels; D013829:Thiadiazines; D005905:Glyburide