Synthesis of modified 4H-1,2,4-benzothiadiazine-1,1-dioxides and determination of their affinity and selectivity for different types of K(ATP) channels.
4H-1,2,4-Benzothiadiazine-1,1-dioxides with various substituents in positions 3, 5, and 7 were synthesized and tested as K(ATP) channel agonists in artificial cell systems (CHO cells transfected with SUR1/Kir6.2, and HEK 293 transfected with SUR2B/Kir6.1) as model systems for insulin-secreting pancreatic beta-cells and for smooth muscle cells, respectively. The effects of agonists were tested in intact cells using DiBAC4(3) [bis-(1,3-dibarbituric acid)trimethine oxanol] as a membrane potential dye, and the results compared with their binding affinity for the SUR2B-type K(ATP) channels using the radioligand [(3)H]P1075. Compounds with cycloalkyl and (cycloalkyl)methyl side chains in position 3 had higher affinities towards the SUR2B/Kir6.1 receptor compared with the parent compound diazoxide (1 a). Compounds with bulky, nonpolar residues in position 3 exhibited remarkable selectivity for SUR2B-type K(ATP) channels. The compound substituted with a bulky (1-adamantyl)methyl residue exhibited micromolar affinity and activity on SUR2B-type K(ATP) channels without being able to activate the SUR1-type K(ATP) channels.
Institute of Organic & Macromolecular Chemistry, University of Düsseldorf, Germany.
Stefan
S
Lachenicht
Andreas
A
Fischer
Claas
C
Schmidt
Marcus
M
Winkler
Achim
A
Rood
Horst
H
Lemoine
Manfred
M
Braun
D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003981:Diazoxide / Q000737:chemistry*; D006801:Humans; D054086:KATP Channels / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D014162:Transfection; D000099161:Kcnj11 Channel
D001581:Benzothiadiazines; D003981:Diazoxide; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel; C092520:uK-ATP-1 potassium channel