title: N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I.
abstract: The transient receptor potential (TRP) vanilloid 4 (TRPV4) member of the TRP superfamily has recently been implicated in numerous physiological processes. In this study, we describe a small molecule TRPV4 channel activator, (N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), which we have used as a valuable tool in investigating the role of TRPV4 in the urinary bladder. GSK1016790A elicited Ca2+ influx in mouse and human TRPV4-expressing human embryonic kidney (HEK) cells (EC50 values of 18 and 2.1 nM, respectively), and it evoked a dose-dependent activation of TRPV4 whole-cell currents at concentrations above 1 nM. In contrast, the TRPV4 activator 4alpha-phorbol 12,13-didecanoate (4alpha-PDD) was 300-fold less potent than GSK1016790A in activating TRPV4 currents. TRPV4 mRNA was detected in urinary bladder smooth muscle (UBSM) and urothelium of TRPV4+/+ mouse bladders. Western blotting and immunohistochemistry demonstrated protein expression in both the UBSM and urothelium that was absent in TRPV4-/- bladders. TRPV4 activation with GSK1016790A contracted TRPV4+/+ mouse bladders in vitro, both in the presence and absence of the urothelium, an effect that was undetected in TRPV4-/- bladders. Consistent with the effects on TRPV4 HEK whole-cell currents, 4alpha-PDD demonstrated a weak ability to contract bladder strips compared with GSK1016790A. In vivo, urodynamics in TRPV4+/+ and TRPV4-/- mice revealed an enhanced bladder capacity in the TRPV4-/- mice. Infusion of GSK1016790A into the bladders of TRPV4+/+ mice induced bladder overactivity with no effect in TRPV4-/- mice. Overall TRPV4 plays an important role in urinary bladder function that includes an ability to contract the bladder as a result of the expression of TRPV4 in the UBSM.
authors.affiliation: Cardiovascular and Urogenital Centre of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA. Kevin.S.Thorneloe@gsk.com
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Thorneloe
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Sulpizio
authors.forename: Zuojun
authors.initials: Z
authors.lastname: Lin
authors.forename: David J
authors.initials: DJ
authors.lastname: Figueroa
authors.forename: Angela K
authors.initials: AK
authors.lastname: Clouse
authors.forename: Gerald P
authors.initials: GP
authors.lastname: McCafferty
authors.forename: Tim P
authors.initials: TP
authors.lastname: Chendrimada
authors.forename: Erin S R
authors.initials: ES
authors.lastname: Lashinger
authors.forename: Earl
authors.initials: E
authors.lastname: Gordon
authors.forename: Louise
authors.initials: L
authors.lastname: Evans
authors.forename: Blake A
authors.initials: BA
authors.lastname: Misajet
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Demarini
authors.forename: Josephine H
authors.initials: JH
authors.lastname: Nation
authors.forename: Linda N
authors.initials: LN
authors.lastname: Casillas
authors.forename: Robert W
authors.initials: RW
authors.lastname: Marquis
authors.forename: Bartholomew J
authors.initials: BJ
authors.lastname: Votta
authors.forename: Steven A
authors.initials: SA
authors.lastname: Sheardown
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xu
authors.forename: David P
authors.initials: DP
authors.lastname: Brooks
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Laping
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Westfall
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005260:Female; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010704:Phorbols / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D014563:Urodynamics / Q000187:drug effects*; D019459:Urothelium / Q000187:drug effects* / Q000378:metabolism
chemical_list: C517592:4alpha-phorbol 12,13-didecanone; C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D010704:Phorbols; D013449:Sulfonamides; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D007930:Leucine