Interaction of a novel dihydropyridine K+ channel opener, A‐312110, with recombinant sulphonylurea receptors and KATP channels: comparison with the cyanoguanidine P1075

• Published in: British journal of pharmacology 2004-04, Vol.141 (7), p.1098-1105
• Main Authors: Felsch, Holger, Lange, Ulf, Hambrock, Annette, Löffler‐Walz, Cornelia, Russ, Ulrich, Carroll, William A, Gopalakrishnan, Murali, Quast, Ulrich
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; ATP-Binding Cassette Transporters - drug effects; ATP-Binding Cassette Transporters - genetics; binding to SUR and to Kir6.2/SUR; Biological and medical sciences; Cell Line; cyanoguanidine P1075; dihydropyridine A‐312110; Dihydropyridines - chemistry; Dihydropyridines - pharmacology; Drug Interactions - physiology; Guanidines - chemistry; Guanidines - pharmacology; Humans; Ion Channel Gating; KATP channel openers; Kidney - cytology; Kidney - embryology; Magnesium - chemistry; Magnesium - metabolism; Medical sciences; Membrane Proteins - chemistry; Membrane Proteins - drug effects; Membrane Proteins - genetics; MgATP shift; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; opener affinity; opener binding and MgATP; opener efficacy; opener potency; Patch-Clamp Techniques - methods; Pharmacology. Drug treatments; Potassium Channels - drug effects; Potassium Channels - genetics; Potassium Channels - physiology; Potassium Channels, Inwardly Rectifying - drug effects; Potassium Channels, Inwardly Rectifying - genetics; Pyridines - chemistry; Pyridines - pharmacology; Receptors, Drug - drug effects; Receptors, Drug - genetics; Recombinant Proteins - drug effects; Recombinant Proteins - genetics; Sulfonylurea Receptors; Thiophenes - chemistry; Thiophenes - pharmacology; Tritium
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705718

ATP‐sensitive K+ channels (KATP channels) are composed of pore‐forming subunits (Kir6.x) and of regulatory subunits, the sulphonylurea receptors (SURx). Synthetic openers of KATP 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. 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 Ki 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 β‐cell), both openers showed little binding up to 100 μM. In the presence of MgATP, both openers inhibited [3H]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. In inside‐out patches, the two openers activated the Kir6.2/SUR2A and Kir6.2/SUR2B channels with similar potency (∼50 nM). Both were almost 2 × more efficacious in opening the Kir6.2/SUR2B than the Kir6.2/SUR2A channel. The results show that the novel dihydropyridine A‐312110 is a potent KATP channel opener with binding and channel‐opening properties similar to those of P1075. British Journal of Pharmacology (2004) 141, 1098–1105. doi:10.1038/sj.bjp.0705718