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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Cardiovascular and Urogenital Centre of Excellence in Drug Discovery (K.S.T., A.C.S., Z.L., D.J.F., A.K.C., G.P.M., T.P.C., E.S.R.L., E.G., L.E., B.A.M., X.X., D.P.B., N.J.L., T.D.W.), GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania; Oncology Centre of Excellence in Drug Discovery (D.J.D., L.N.C., R.W.M., B.J.V.), GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania; and Transgenics, Genotyping and Viral Vectors (J.H.N., S.A.S.), GlaxoSmithKline Pharmaceuticals, Harlow, United Kingdom

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 4-phorbol 12,13-didecanoate (4-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, 4-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.

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