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

Citations Over TimeTop 12% of 1996 papers

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.

Related Papers

• → Triphenylphosphonium salts of 1,2,4-benzothiadiazine 1,1-dioxides related to diazoxide targeting mitochondrial ATP-sensitive potassium channels(2013)15 cited
• Diazoxide increases glutamate uptake by astrocytes via activating mitochondrial ATP-sensitive potassium channels(2006)
• Pharmacological evaluation of 3-alkylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides structurally related to the KATP channel opener diazoxide(1999)
• Pharmacological characteristic of new benzothiadiazine derivatives,targeting the cardiac mitochondrial ATP-sensitive potassium channel(2009)
• Vasodilative properties of BPDZ 79, a new potassium channel opener, in isolated aorta.(1997)