Studies of the KATP Channel Opening Activity of the New Dihydropyridine Compound 9-(3-Cyanophenyl)-3,4,6,7,9,10-Hexahydro-1,8-(2H, 5H)-Acridinedione in Bladder Detrusor In Vitro

Jh, Li; Gd, Yasay; St, Kau; Cj, Ohnmacht; Da, Trainor; Ad, Bonev; Tj, Heppner; Mt, Nelson

doi:10.1097/00005392-199806000-00212

Cited by 3 publications

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“…9) is ZM-244085 18 [60,61]. The effects on low and high KCl induced contractions, 86 Rb efflux, and [ 3 H]P1075 binding in guinea-pig bladder strips were used to characterize the in vitro KCO properties of ZM-244085 versus first-generation KCOs [60].…”

Section: Bladder-selective Dhp-related Structuresmentioning

confidence: 99%

Second-Generation KATP Channel Openers

Mannhold¹,

Leclerc²

2005

MRMC

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Section: Bladder-selective Dhp-related Structuresmentioning

confidence: 99%

Second-Generation KATP Channel Openers

Mannhold¹,

Leclerc²

2005

MRMC

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Electrophysiological properties of the bladder

Fry

Sui

1998

Int Urogynecol J

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The electrophysiological properties of detrusor smooth muscle are described, in particular with regard to their influence on the contractile properties of the tissue. The Ca2+ and K+ channel activities are most important in generating action potentials, but the role of several other ionic currents is described, including Cl-, Ca2+-activated, stretch-activated and ligand-gated channels. The variable appearance and functions of different ionic currents in disease states is discussed, as well as the question of whether electrical activity can transmit between adjacent smooth muscle cells. In addition, the precise role that electrophysiological phenomena play in the regulation of the contractile state of the smooth muscle cells, as well as the generation of bladder electromyograms, is discussed.

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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 K_ATP channel inhibitor

Gopalakrishnan

Miller

Buckner

et al. 2003

British J Pharmacology

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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(2H,5H)‐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 IC50 values of 1.44 and 2.24 μM respectively. P1075‐evoked relaxation of 25 mM K+ stimulated aortic strips was inhibited by A‐184209 in an apparently competitive fashion with a pA2 value of 6.34. The potencies of A‐184209 to inhibit P1075‐evoked decreases in membrane potential responses in cardiac myocytes (IC50=0.53 μM) and to inhibit 2‐deoxyglucose‐evoked cation efflux pancreatic RINm5F cells (IC50=0.52 μM) were comparable to the values for inhibition of smooth muscle KATP 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(2H,5H)‐acridinedione (A‐184208), was found to be a KATP channel opener, evoking membrane potential responses in A10 smooth muscle cells (EC50=385 nM) and relaxing aortic smooth muscle strips (IC50=101 nM) in a glyburide‐sensitive manner. Radioligand binding studies demonstrated that A‐184209 displaced SUR1 binding defined by [3H]glyburide binding to RINm5F cell membranes with a Ki value of 0.11 μM whereas A‐184208 was ineffective. On the other hand, both A‐184209 (Ki=1.34 μM) and A‐184208 (Ki=1.14 μM) displaced binding of the KCO radioligand, [125I]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 KATP 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 KATP channel activation to inhibition. British Journal of Pharmacology (2003) 138, 393–399. doi:

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Studies of the KATP Channel Opening Activity of the New Dihydropyridine Compound 9-(3-Cyanophenyl)-3,4,6,7,9,10-Hexahydro-1,8-(2H, 5H)-Acridinedione in Bladder Detrusor In Vitro

Cited by 3 publications

References 0 publications

Second-Generation KATP Channel Openers

Second-Generation KATP Channel Openers

Electrophysiological properties of the bladder

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 K_ATP channel inhibitor

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Studies of the KATP Channel Opening Activity of the New Dihydropyridine Compound 9-(3-Cyanophenyl)-3,4,6,7,9,10-Hexahydro-1,8-(2H, 5H)-Acridinedione in Bladder Detrusor In Vitro

Cited by 3 publications

References 0 publications

Second-Generation KATP Channel Openers

Second-Generation KATP Channel Openers

Electrophysiological properties of the bladder

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

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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 K_ATP channel inhibitor