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.

Pharmacological characterization of a 1,4‐dihydropyridine analogue, 9‐(3,4‐dichlorophenyl)‐3,3,6,6‐tetramethyl‐3,4,6,7,9,10‐hexahydro‐1,8(2H,5H)‐acridinedione (A‐184209) as a novel KATP channel inhibitor

“…The observation that A‐184209 inhibited smooth muscle, cardiac and pancreatic K ATP channels with similar potencies prompted us to examine the nature of K ATP channel interactions. K ATP channel inhibition could, in principle, be at the level of the sulfonylurea receptor (SUR) itself as in the case of sulfonylurea analogues or via direct blockade of the pore‐forming Kir6.2 subunit as suggested for certain imidazoline antagonists (Bell et al ., 2000). Since Kir6.2 is a constituent of various K ATP channels, it may be possible that the lack of tissue selectivity might potentially be due to its interaction with the inward rectifier alone.…”

“…Besides sulfonylureas, other earlier known blockers such as phentolamine, tetraethylammonium (quaternary ammonium salt), 5‐hydroxydecanoate, guanethidine and bretylium, albeit weak and nonselective, have served as pharmacophores for further structural optimization. Imidazoline‐based K ATP channel blockers including IMID‐1M, IMID‐26F and IMID‐4F that functionally antagonized responses to cromakalim in vascular smooth muscle tissues have been described although these compounds do not displace [ 3 H]‐P1075 or [ 3 H]‐glyburide binding (Bell et al ., 2000). The morpholinoguanidine, U‐37783A, reportedly a vascular selective K ATP channel blocker, has been shown to inhibit arterial smooth muscle channels more effectively than those from cardiac/skeletal muscle and to possess diuretic and natriuretic activity in animal models (Wellman et al ., 1999).…”