Potent and selective activation of the pancreatic beta-cell type K(ATP) channel by two novel diazoxide analogues.
OBJECTIVE
We investigated the pharmacological properties of two novel ATP sensitive potassium (K(ATP)) channel openers, 6-Chloro-3-isopropylamino-4 H-thieno[3,2- e]-1,2,4-thiadiazine 1,1-dioxide (NNC 55-0118) and 6-chloro-3-(1-methylcyclopropyl)amino-4 H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NN414), on the cloned cardiac (Kir6.2/SUR2A), smooth muscle (Kir6.2/SUR2B) and pancreatic beta cell (Kir6.2/SUR1) types of K(ATP) channel.


METHODS
We studied the effects of these compounds on whole-cell currents through cloned K(ATP) channels expressed in Xenopus oocytes or mammalian cells (HEK293). We also used inside-out macropatches excised from Xenopus oocytes.


RESULTS
In HEK 293 cells, NNC 55-0118 and NN414 activated Kir6.2/SUR1 currents with EC(50) values of 0.33 micromol/l and 0.45 micromol/l, respectively, compared with that of 31 micro mol/l for diazoxide. Neither compound activated Kir6.2/SUR2A or Kir6.2/SUR2B channels expressed in oocytes, nor did they activate Kir6.2 expressed in the absence of SUR. Current activation was dependent on the presence of intracellular MgATP, but was not supported by MgADP.


CONCLUSIONS
Both NNC 55-0118 and NN414 selectively stimulate the pancreatic beta-cell type of K(ATP) channel with a higher potency than diazoxide, by interaction with the SUR1 subunit. The high selectivity and efficacy of the compounds could prove useful for treatment of disease states where inhibition of insulin secretion is beneficial.
Dabrowski
M
M
University Laboratory of Physiology, Parks Road, Oxford, UK.
Larsen
T
T
Ashcroft
F M
FM
Bondo Hansen
J
J
Wahl
P
P
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002460:Cell Line; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D003981:Diazoxide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D009130:Muscle, Smooth / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009865:Oocytes; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists / Q000378:metabolism*; D051381:Rats; D011955:Receptors, Drug / Q000378:metabolism; D064233:Sulfonylurea Receptors; D014982:Xenopus laevis
C577507:ABCC8 protein, human; C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; C577509:Abcc8 protein, rat; C577511:Abcc9 protein, mouse; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; C475618:NN 414; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate; C411625:NNC 55-0118; D003981:Diazoxide