title: The identification of a potent imidazoline-based vascular K(ATP) channel antagonist.
abstract: In this study the activity of a number of novel imidazoline-based compounds (IMID series) was assessed by functional and binding studies to determine their actions at K(ATP) channels. The novel compounds, which we synthesised, were methoxy-, methyl-, butyl- and fluorophenyl derivatives of clonidine. In functional studies we determined the potency (by calculating a pK(B) value) of the IMID compounds to antagonise levcromakalim responses in segments of isolated pig coronary artery. The most potent compounds identified (laboratory codes: IMID-1M, IMID-26F and IMID-4F) had apparent pK(B) values of approximately 7 which is similar to that for the sulphonylurea, glibenclamide and the lipophilic quaternary ion, tetraphenylphosphonium. This inhibitory action was specific for levcromakalim since the imidazoline antagonist IMID-1M failed to effect vasorelaxation response-curves to the non-KATP channel opener, sodium nitroprusside. In the spontaneously beating rat right atrium preparation the majority of the compounds were able to cause slowing of heart rate, but with low EC50 values (approximately 10-30 microM). In binding studies, the compounds were unable to displace binding of [3H]P1075 to bovine aortic smooth muscle preparations nor [3H]glibenclamide binding to rat cerebral cortex membranes. These studies show that some imidazoline-based compounds are potent antagonists of levcromakalim-mediated vasorelaxation responses in the pig coronary artery. The compounds displayed only minimal bradycardic activity. The site of action of the imidazoline compounds does not appear to be the same as that used by K(ATP) channel openers or sulphonylurea-based antagonists. It is likely that these compounds interact with the K(ATP) channel pore itself.
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Bell
authors.forename: J
authors.initials: J
authors.lastname: Favaloro
authors.forename: V
authors.initials: V
authors.lastname: Khalil
authors.forename: M M
authors.initials: MM
authors.lastname: Iskander
authors.forename: G A
authors.initials: GA
authors.lastname: McPherson
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002417:Cattle; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D019806:Cromakalim / Q000494:pharmacology; D005905:Glyburide / Q000378:metabolism / Q000494:pharmacology; D006146:Guanidines / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D054086:KATP Channels; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011725:Pyridines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D007004:Hypoglycemic Agents; D007093:Imidazoles; D054086:KATP Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011725:Pyridines; D014665:Vasodilator Agents; C092520:uK-ATP-1 potassium channel; D019806:Cromakalim; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; C022192:alinidine; D003000:Clonidine; D005905:Glyburide