2-alkyl-3-Alkylamino-2H-Benzo- and pyridothiadiazine 1,1-dioxides: from K+ATP channel openers to Ca++ channel blockers?
A series of 2-alkyl-3-alkylamino-2H-benzo- and 2-alkyl-3-alkylamino-2H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides, structurally related to BPDZ 44 and BPDZ 73, two potent pancreatic B-cells K+ATP channel openers, were synthesized and tested on rat pancreatic islets (endocrine tissue) as well as on rat aorta rings (vascular smooth muscle tissue). Alkylation of the 2-position led to double bond tautomerization and formation of compounds with a 2H-conformation. In contrast to the previously described pyridothiadiazine dioxides, such as BPDZ 44, and 7-chlorobenzothiadiazine dioxides, such as BPDZ 73, the 2-alkyl-substituted analogs were found to be poorly active on the insulin releasing process although most drugs exhibited a vasorelaxant activity. As a result, the new 2-alkyl-substituted pyridinic compounds expressed a selectivity profile (vascular smooth muscle tissue vs pancreatic tissue) opposite to that of their non-alkyl-substituted counterparts, i.e. BPDZ 44. Additional investigations revealed that, in contrast to their non 2-alkyl-substituted analogs, the most interesting 2-methyl-substituted derivatives did not express the pharmacological profile of classical K+ATP channel openers. The pharmacological results rather suggest that alkylation of the 2-position of the thiadiazine ring led to drugs that could act as Ca2+ channel blockers rather than as potassium channel openers.
Ouedraogo
Raogo
R
Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles, 808 route de Lennik, B-1070 Brussels, Belgium.
Becker
Bénédicte
B
Boverie
Stéphane
S
Somers
Fabian
F
Antoine
Marie-Hélène
MH
Pirotte
Bernard
B
Lebrun
Philippe
P
de Tullio
Pascal
P
D018528:ATP-Binding Cassette Transporters; D000473:Alkanes / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology*; D003981:Diazoxide / Q000138:chemical synthesis / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D015221:Potassium Channels / Q000819:agonists*; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; D000473:Alkanes; D002121:Calcium Channel Blockers; D007202:Indicators and Reagents; D007328:Insulin; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D013829:Thiadiazines; C092520:uK-ATP-1 potassium channel; D003981:Diazoxide