Interaction of a novel dihydropyridine K+ channel opener, A-312110, with recombinant sulphonylurea receptors and KATP channels: comparison with the cyanoguanidine P1075.
1. ATP-sensitive K(+) channels (K(ATP) channels) are composed of pore-forming subunits (Kir6.x) and of regulatory subunits, the sulphonylurea receptors (SURx). Synthetic openers of K(ATP) channels form a chemically heterogeneous class of compounds that are of interest in several therapeutic areas. We have investigated the interaction of a novel dihydropyridine opener, A-312110 ((9R)-9-(4-fluoro-3-iodophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno [2,3-e]pyridin-8(7H)-one-1,1-dioxide), with SURs and Kir6/SUR channels in comparison to the cyanoguanidine opener P1075. 2. In the presence of 1 mM MgATP, A-312110 bound to SUR2A (the SUR in cardiac and skeletal muscle) and to SUR2B (smooth muscle) with K(i) values of 14 and 18 nM; the corresponding values for P1075 were 16 and 9 nM, respectively. Decreasing the MgATP concentration reduced the affinity of A312110 binding to SUR2A significantly more than that to SUR2B; for P1075, the converse was true. At SUR1 (pancreatic beta-cell), both openers showed little binding up to 100 microM. 3. In the presence of MgATP, both openers inhibited [(3)H]glibenclamide binding to the SUR2 subtypes in a biphasic manner. In the absence of MgATP, the high-affinity component of the inhibition curves was absent. 4. In inside-out patches, the two openers activated the Kir6.2/SUR2A and Kir6.2/SUR2B channels with similar potency (approximately 50 nm). Both were almost 2 x more efficacious in opening the Kir6.2/SUR2B than the Kir6.2/SUR2A channel. 5. The results show that the novel dihydropyridine A-312110 is a potent K(ATP) channel opener with binding and channel-opening properties similar to those of P1075.
Felsch
Holger
H
Department of Pharmacology and Toxicology, Medical Faculty, University of Tübingen, Wilhelmstr. 56, D-72074 Tuebingen, Germany.
Lange
Ulf
U
Hambrock
Annette
A
Löffler-Walz
Cornelia
C
Russ
Ulrich
U
Carroll
William A
WA
Gopalakrishnan
Murali
M
Quast
Ulrich
U
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000235:genetics; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology*; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating; D007668:Kidney / Q000166:cytology / Q000196:embryology; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects* / Q000235:genetics; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011955:Receptors, Drug / Q000187:drug effects* / Q000235:genetics; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics; D064233:Sulfonylurea Receptors; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D014316:Tritium
C475728:(9R)-9-(4-fluoro-3-iodophenyl)-2,3,5,9-tetrahydro-4H-pyrano(3,4-b)thieno(2,3-e)pyridin-8(7H)-one-1,1-dioxide; C577507:ABCC8 protein, human; C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; D004095:Dihydropyridines; D006146:Guanidines; D008565:Membrane Proteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011725:Pyridines; D011955:Receptors, Drug; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; D013876:Thiophenes; C117780:mitochondrial K(ATP) channel; D014316:Tritium; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D000255:Adenosine Triphosphate; D008274:Magnesium; C004711:dicyandiamido