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(2 H ,5 H )‐acridinedione (A‐184209) as a novel K ATP channel inhibitor

This study reports on the identification and 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(2 H ,5 H )‐acridinedione (A‐184209) as a novel inhibitor of ATP‐sensitive K + channels. A‐184209 inhibited membrane potential changes evoked by the prototypical cyanoguanidine ATP‐sensitive K + channel opener (KCO) P1075 in both vascular (A10) and urinary bladder smooth muscle cells with IC 50 values of 1.44 and 2.24 μ M respectively. P1075‐evoked relaxation of 25 m M K + stimulated aortic strips was inhibited by A‐184209 in an apparently competitive fashion with a pA 2 value of 6.34. The potencies of A‐184209 to inhibit P1075‐evoked decreases in membrane potential responses in cardiac myocytes (IC 50 =0.53 μ M ) and to inhibit 2‐deoxyglucose‐evoked cation efflux pancreatic RINm5F cells (IC 50 =0.52 μ M ) were comparable to the values for inhibition of smooth muscle K ATP channels. On the other hand, a structural analogue of A‐184209 that lacked the gem‐dimethyl substituent, 9‐(3,4‐dichlorophenyl)‐3,4,6,7,9,10‐hexahydro‐1,8(2 H ,5 H )‐acridinedione (A‐184208), was found to be a K ATP channel opener, evoking membrane potential responses in A10 smooth muscle cells (EC 50 =385 n M ) and relaxing aortic smooth muscle strips (IC 50 =101 n M ) in a glyburide‐sensitive manner. Radioligand binding studies demonstrated that A‐184209 displaced SUR1 binding defined by [ 3 H]glyburide binding to RINm5F cell membranes with a K i value of 0.11 μ M whereas A‐184208 was ineffective. On the other hand, both A‐184209 ( K i =1.34 μ M ) and A‐184208 ( K i =1.14 μ M ) displaced binding of the KCO radioligand, [ 125 I]A‐312110 in guinea‐pig bladder membranes with similar affinities. These studies demonstrate that A‐184209 is a novel and structurally distinct compound that inhibits K ATP channels in smooth muscle with potencies comparable to glyburide. The structural overlap between DHP openers and blockers, together with their differential interaction with ligand binding sites, support the notion that both openers and blockers bind to similar or very closely coupled sites on the sulfonylurea receptor and that subtle changes in the pharmacophore itself could switch functional properties from K ATP channel activation to inhibition. British Journal of Pharmacology (2003) 138 , 393–399. doi: 10.1038/sj.bjp.0705048