title: 3-and 4-substituted 4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides as potassium channel openers: synthesis, pharmacological evaluation, and structure-activity relationships.
abstract: 4-N-Substituted and -unsubstituted 3-alkyl- and 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested vs diazoxide and selected 3-alykl- and 3-(alkylamino)-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides as potassium channel openers on pancreatic and vascular tissues. Several 4-N-unsubstituted 3-(alkylamino)pyridothiadiazines and some 3-(alkylamino)-7-chlorobenzothiadiazines were found to be more potent than diazoxide for the inhibition of the insulin-releasing process. Moreover, the 3-(alkylamino)pyridothiadiazines appeared to be more selective for the pancreatic than for the vascular tissue. By means of the pharmacological results obtained on pancreatic B-cells, structure--activity relationships were deduced and a pharmacophoric model for the interaction of these drugs with their receptor site associated to the pancreatic K(ATP) channel was proposed. According to their selectivity for the B-cell (endocrine tissue) vs the vascular (smooth muscle tissue) ionic channel, selected 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4,-thiadiazine 1,1-dioxides may serve as pharmacological tools in studying the K(ATP) channels ("pancreatic-like" K(ATP) channels) in other tissues.
authors.affiliation: Laboratoire de Chimie Pharmaceutique, Université de Liége, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: de Tullio
authors.forename: B
authors.initials: B
authors.lastname: Pirotte
authors.forename: P
authors.initials: P
authors.lastname: Lebrun
authors.forename: J
authors.initials: J
authors.lastname: Fontaine
authors.forename: L
authors.initials: L
authors.lastname: Dupont
authors.forename: M H
authors.initials: MH
authors.lastname: Antoine
authors.forename: R
authors.initials: R
authors.lastname: Ouedraogo
authors.forename: S
authors.initials: S
authors.lastname: Khelili
authors.forename: C
authors.initials: C
authors.lastname: Maggetto
authors.forename: B
authors.initials: B
authors.lastname: Masereel
authors.forename: O
authors.initials: O
authors.lastname: Diouf
authors.forename: T
authors.initials: T
authors.lastname: Podona
authors.forename: J
authors.initials: J
authors.lastname: Delarge
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D003981:Diazoxide / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007202:Indicators and Reagents; D007328:Insulin; D015221:Potassium Channels; D013829:Thiadiazines; D014665:Vasodilator Agents; D003981:Diazoxide