(-)-(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

Research output: Contribution to journalArticleResearchpeer-review

29 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

Fingerprint

9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno(3,2-b)quinolin-8(4H)-one 1,1-dioxide
KATP Channels
Urinary Bladder
Glyburide
Overactive Urinary Bladder
Smooth Muscle
Pharmacology
L-Type Calcium Channels
Neurotransmitter Receptor
In Vitro Techniques
Carbachol
Ion Channels
Membrane Potentials
Inhibitory Concentration 50
Smooth Muscle Myocytes

Cite this

Gopalakrishnan, Murali ; Buckner, Steven A. ; Whiteaker, Kristi L. ; Shieh, Char Chang ; Molinari, Eduardo J. ; Milicic, Ivan ; Daza, Anthony V. ; Davis-Taber, Rachel ; Scott, Victoria E. ; Sellers, Donna ; Chess-Williams, Russ ; Chapple, Christopher R. ; Liu, Yi ; Liu, Dong ; Brioni, Jorge D. ; Sullivan, James P. ; Williams, Michael ; Carroll, William A. ; Coghlan, Michael J. / (-)-(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. In: Journal of Pharmacology and Experimental Therapeutics. 2002 ; Vol. 303, No. 1. pp. 379-386.
@article{043fbd9312c1430c8aed64fa0301a8bb,
title = "(-)-(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+ (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.",
author = "Murali Gopalakrishnan and Buckner, {Steven A.} and Whiteaker, {Kristi L.} and Shieh, {Char Chang} and Molinari, {Eduardo J.} and Ivan Milicic and Daza, {Anthony V.} and Rachel Davis-Taber and Scott, {Victoria E.} and Donna Sellers and Russ Chess-Williams and Chapple, {Christopher R.} and Yi Liu and Dong Liu and Brioni, {Jorge D.} and Sullivan, {James P.} and Michael Williams and Carroll, {William A.} and Coghlan, {Michael J.}",
year = "2002",
month = "10",
doi = "10.1124/jpet.102.034538",
language = "English",
volume = "303",
pages = "379--386",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS",
number = "1",

}

Gopalakrishnan, M, Buckner, SA, Whiteaker, KL, Shieh, CC, Molinari, EJ, Milicic, I, Daza, AV, Davis-Taber, R, Scott, VE, Sellers, D, Chess-Williams, R, Chapple, CR, Liu, Y, Liu, D, Brioni, JD, Sullivan, JP, Williams, M, Carroll, WA & Coghlan, MJ 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, vol. 303, no. 1, pp. 379-386. https://doi.org/10.1124/jpet.102.034538

(-)-(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. / Gopalakrishnan, Murali; Buckner, Steven A.; Whiteaker, Kristi L.; Shieh, Char Chang; Molinari, Eduardo J.; Milicic, Ivan; Daza, Anthony V.; Davis-Taber, Rachel; Scott, Victoria E.; Sellers, Donna; Chess-Williams, Russ; Chapple, Christopher R.; Liu, Yi; Liu, Dong; Brioni, Jorge D.; Sullivan, James P.; Williams, Michael; Carroll, William A.; Coghlan, Michael J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 303, No. 1, 10.2002, p. 379-386.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - (-)-(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)

T2 - A novel ATP-sensitive potassium channel opener efficacious in suppressing urinary bladder contractions. I. In vitro characterization

AU - Gopalakrishnan, Murali

AU - Buckner, Steven A.

AU - Whiteaker, Kristi L.

AU - Shieh, Char Chang

AU - Molinari, Eduardo J.

AU - Milicic, Ivan

AU - Daza, Anthony V.

AU - Davis-Taber, Rachel

AU - Scott, Victoria E.

AU - Sellers, Donna

AU - Chess-Williams, Russ

AU - Chapple, Christopher R.

AU - Liu, Yi

AU - Liu, Dong

AU - Brioni, Jorge D.

AU - Sullivan, James P.

AU - Williams, Michael

AU - Carroll, William A.

AU - Coghlan, Michael J.

PY - 2002/10

Y1 - 2002/10

N2 - 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.

AB - 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.

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U2 - 10.1124/jpet.102.034538

DO - 10.1124/jpet.102.034538

M3 - Article

VL - 303

SP - 379

EP - 386

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

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