(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637): a novel ATP-sensitive potassium channel opener efficacious in suppressing urinary bladder contractions. I. In vitro characterization.

Abstract

Alterations in the myogenic activity of the bladder smooth muscle are thought to serve as a basis for the involuntary detrusor contractions associated with the overactive bladder. Activation of ATP-sensitive K(+) (K(ATP)) channels has been recognized as a potentially viable mechanism to modulate membrane excitability in bladder smooth muscle. In this study, we describe the preclinical pharmacology of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a novel 1,4-dihydropyridine K(ATP) channel opener (KCO) that demonstrates enhanced bladder selectivity for the suppression of unstable bladder contractions in vivo relative to other reference KCOs. A-278637 activated K(ATP) channels in bladder smooth muscle cells in a glyburide (glibenclamide)-sensitive manner as assessed by fluorescence membrane potential assays using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (EC(50) = 102 nM) and by whole cell patch clamp. Spontaneous (myogenic) phasic activity of pig bladder strips was suppressed (IC(50) = 23 nM) in a glyburide-sensitive manner by A-278637. A-278637 also inhibited carbachol- and electrical field-stimulated contractions of bladder strips, although the respective potencies were 8- and 13-fold lower compared with inhibition of spontaneous phasic activity. As shown in the accompanying article [Brune ME, Fey TA, Brioni JD, Sullivan JP, Williams M, Carroll WA, Coghlan MJ, and Gopalakrishnan M (2002) J Pharmacol Exp Ther 303:387-394], A-278637 suppressed myogenic contractions in vivo in a model of bladder instability with superior selectivity compared with other KCOs, WAY-133537 [(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)cyclobut-1-enylamino]-3-ethyl-benzonitrile] and ZD6169 [(S)-N-(4-benzoylphenyl)3,3,3-trifluro-2hydroxy-2-methyl-priopionamide]. A-278637 did not interact with other ion channels, including L-type calcium channels or other neurotransmitter receptor systems. The pharmacological profile of A-278637 represents an attractive basis for further investigations of selective K(ATP) channel openers for the treatment of overactive bladder via myogenic etiology.

• Authors: Murali Gopalakrishnan, Steven A Buckner, Kristi L Whiteaker, Char-Chang Shieh, Eduardo J Molinari, Ivan Milicic, Anthony V Daza, Rachel Davis-Taber, Victoria E Scott, Donna Sellers, Russ Chess-Williams, Christopher R Chapple, Yi Liu, Dong Liu, Jorge D Brioni, James P Sullivan, Michael Williams, William A Carroll, Michael J Coghlan
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 303 Issue 1 Pg. 379-86 (Oct 2002) ISSN: 0022-3565 [Print] United States
• PMID: 12235274 (Publication Type: Journal Article)

Chemical References

• 9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno(3,2-b)quinolin-8(4H)-one 1,1-dioxide
• ATP-Binding Cassette Transporters
• Amides
• Benzophenones
• Cyclic S-Oxides
• Cyclobutanes
• KATP Channels
• Nitriles
• Potassium Channel Blockers
• Potassium Channels
• Potassium Channels, Inwardly Rectifying
• Quinolones
• WAY 133537
• Zeneca ZD 6169
• uK-ATP-1 potassium channel

Topics

• ATP-Binding Cassette Transporters
• Amides (pharmacology)
• Animals
• Aorta, Thoracic (drug effects, physiology)
• Benzophenones (pharmacology)
• Cyclic S-Oxides (pharmacology)
• Cyclobutanes (pharmacology)
• Guinea Pigs
• Humans
• In Vitro Techniques
• Ion Channel Gating (drug effects, physiology)
• KATP Channels
• Kinetics
• Male
• Membrane Potentials (drug effects, physiology)
• Muscle Contraction (drug effects)
• Muscle Relaxation (drug effects, physiology)
• Muscle, Smooth (drug effects, physiology)
• Muscle, Smooth, Vascular (drug effects, physiology)
• Nitriles (pharmacology)
• Patch-Clamp Techniques
• Portal Vein (drug effects, physiology)
• Potassium Channel Blockers
• Potassium Channels (drug effects, physiology)
• Potassium Channels, Inwardly Rectifying
• Quinolones (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Urinary Bladder (drug effects, physiology)