(-)-(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

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

*Corresponding author for this work

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30 Citations (Scopus)

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+ (KATP) 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 1,1dioxide (A-278637), a novel 1,4-dihydropyridine KATP 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 KATP 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 (EC50 = 102 nM) and by whole cell patch clamp. Spontaneous (myogenic) phasic activity of pig bladder strips was suppressed (IC50 = 23 nM) in a glyburide-sensitive manner by A-278637. A-278637 also inhibited carbachol- and electrical fieldstimulated 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-ethylbenzonitrile] 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 KATP channel openers for the treatment of overactive bladder via myogenic etiology.

Original languageEnglish
Pages (from-to)379-386
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume303
Issue number1
DOIs
Publication statusPublished - Oct 2002
Externally publishedYes

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    Gopalakrishnan, M., Buckner, S. A., Whiteaker, K. L., Shieh, C. C., Molinari, E. J., Milicic, I., Daza, A. V., Davis-Taber, R., Scott, V. E., Sellers, D., Chess-Williams, R., Chapple, C. R., Liu, Y., Liu, D., Brioni, J. D., Sullivan, J. P., Williams, M., Carroll, W. A., & Coghlan, M. J. (2002). (-)-(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. Journal of Pharmacology and Experimental Therapeutics, 303(1), 379-386. https://doi.org/10.1124/jpet.102.034538