title: 1,4,2-Benzo/pyridodithiazine 1,1-dioxides structurally related to the ATP-sensitive potassium channel openers 1,2,4-Benzo/pyridothiadiazine 1,1-dioxides exert a myorelaxant activity linked to a distinct mechanism of action.
abstract: The synthesis of diversely substituted 3-alkyl/aralkyl/arylamino-1,4,2-benzodithiazine 1,1-dioxides and 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides is described. Their biological activities on pancreatic β-cells and on smooth muscle cells were compared to those of the reference ATP-sensitive potassium channel (KATP channel) openers diazoxide and 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide. The aim was to assess the impact on biological activities of the replacement of the 1,2,4-thiadiazine ring by an isosteric 1,4,2-dithiazine ring. Most of the dithiazine analogues were found to be inactive on the pancreatic tissue, although some compounds bearing a 1-phenylethylamino side chain at the 3-position exerted a marked myorelaxant activity. Such an effect did not appear to be related to the opening of KATP channels but rather reflected a mechanism of action similar to that of calcium channel blockers. Tightly related 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides were also found to exert a pronounced myorelaxant activity, resulting from both a KATP channel activation and a calcium channel blocker mechanism. The present work highlights the critical importance of an intracyclic NH group at the 4-position, as well as an exocyclic NH group linked to the 3-position of the benzo- and pyridothiadiazine dioxides, for activity on KATP channels.
authors.affiliation: Laboratoire de Chimie Pharmaceutique, Centre Interfacultaire de Recherche du Médicament (Drug Research Center), Université de Liège, CHU, 1 Avenue de l'Hôpital, B-4000 Liège, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: Pascal
authors.initials: P
authors.lastname: de Tullio
authors.forename: Xavier
authors.initials: X
authors.lastname: Florence
authors.forename: Eric
authors.initials: E
authors.lastname: Goffin
authors.forename: Fabian
authors.initials: F
authors.lastname: Somers
authors.forename: Stéphane
authors.initials: S
authors.lastname: Boverie
authors.forename: Philippe
authors.initials: P
authors.lastname: Lebrun
mesh_terms: D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis / Q000494:pharmacology; D003981:Diazoxide / Q000031:analogs & derivatives / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D054086:KATP Channels / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010276:Parasympatholytics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C416528:7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide; D001581:Benzothiadiazines; D054086:KATP Channels; D010276:Parasympatholytics; D013829:Thiadiazines; D003981:Diazoxide