K-ATP channel openers: Tissue selectivity of original 3-alkylaminopyrido- and 3-alkylaminobenzothiadiazine 1,1-dioxides
(2008) Biochemical Pharmacology — Vol. 75, n° 2, p. 468-475 (2008)
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- 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 Rb-86 outflow (K-42 substitute) from prelabelled and perifused rat aortic rings. EC50/IC50 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. (c) 2007 Elsevier Inc. All rights reserved.
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Lebrun, P., Becker, B., Morel, N., Ghisdal, P., Antoine, M.-H., de Tullio, P., & Pirotte, B. (2008). K-ATP channel openers: Tissue selectivity of original 3-alkylaminopyrido- and 3-alkylaminobenzothiadiazine 1,1-dioxides. Biochemical Pharmacology, 75(2), 468-475. https://doi.org/10.1016/j.bcp.2007.08.032 (Original work published 2008)