(-)-(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

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.

UR - http://www.scopus.com/inward/record.url?scp=0036785473&partnerID=8YFLogxK

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

IS - 1

ER -