(-)-(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.
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.
Gopalakrishnan
Murali
M
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Illinois 60064, USA. murali.gopalakrishnan@abbott.com
Buckner
Steven A
SA
Whiteaker
Kristi L
KL
Shieh
Char-Chang
CC
Molinari
Eduardo J
EJ
Milicic
Ivan
I
Daza
Anthony V
AV
Davis-Taber
Rachel
R
Scott
Victoria E
VE
Sellers
Donna
D
Chess-Williams
Russ
R
Chapple
Christopher R
CR
Liu
Yi
Y
Liu
Dong
D
Brioni
Jorge D
JD
Sullivan
James P
JP
Williams
Michael
M
Carroll
William A
WA
Coghlan
Michael J
MJ
D018528:ATP-Binding Cassette Transporters; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D001577:Benzophenones / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D003503:Cyclobutanes / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D054086:KATP Channels; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology*
C466801:9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno(3,2-b)quinolin-8(4H)-one 1,1-dioxide; D018528:ATP-Binding Cassette Transporters; D000577:Amides; D001577:Benzophenones; D003499:Cyclic S-Oxides; D003503:Cyclobutanes; D054086:KATP Channels; D009570:Nitriles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D015363:Quinolones; C119323:WAY 133537; C095007:Zeneca ZD 6169; C092520:uK-ATP-1 potassium channel