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2000
Volume 31, Issue 37
  • ISSN: 1381-6128
  • E-ISSN: 1873-4286
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Abstract

Aims

We aimed to synthesize small-molecule compounds by modifying the chemical structure of GSK101 and screening for novel TRPV4 agonists with high specificity and selective sensory response.

Background

GSK1016790A (GSK101) effectively activates Transient Receptor Potential Vanilloid 4 (TRPV4) and simultaneously induces mechanical allodynia and acute itch. However, as a commonly used tool compound for studying sensory function, its dual effects of pain and itch can interfere with each other.

Objective

To design and synthesize a series of small-molecule compounds targeting TRPV4, evaluate their properties to identify the most specific tool compounds targeting TRPV4, and determine the correlation between TRPV4 activation and sensory response.

Methods

In this study, live-cell Ca2+ imaging in a heterogeneous expression system was employed to evaluate the activity of synthetic compounds, molecular docking was performed to predict binding interactions and behavioral tests for itch and pain were combined with pharmacological and genetic strategies to assess physiological responses.

Results

We synthesized nine GSK101 analogues and identified six small-molecule agonists that exhibited TRPV4-targeting excitability, preserved TRPV4-mediated mechanical pain perception, and attenuated the acute itch response.

Conclusion

Our study provides new insight into the role of TRPV4 in pain and itch sensation and introduces LM0038, the most potent agonist, as a novel alternative to GSK101. With enhanced biological activity, it may serve as a valuable tool for studying TRPV4 function.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2025-10-28

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References

  1. LiedtkeW. TRPV4 plays an evolutionary conserved role in the transduction of osmotic and mechanical stimuli in live animals.J. Physiol.20055671535810.1113/jphysiol.2005.08896315961428
     [Google Scholar]
  2. GülerA.D. LeeH. IidaT. ShimizuI. TominagaM. CaterinaM. Heat-evoked activation of the ion channel, TRPV4.J. Neurosci.200222156408641410.1523/JNEUROSCI.22‑15‑06408.200212151520
     [Google Scholar]
  3. ShibasakiK. TRPV4 activation by thermal and mechanical stimuli in disease progression.Lab. Invest.2020100221822310.1038/s41374‑019‑0362‑231896814
     [Google Scholar]
  4. GevaertT. VriensJ. SegalA. EveraertsW. RoskamsT. TalaveraK. OwsianikG. LiedtkeW. DaelemansD. DewachterI. Van LeuvenF. VoetsT. De RidderD. NiliusB. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding.J. Clin. Invest.2007117113453346210.1172/JCI3176617948126
     [Google Scholar]
  5. DuttaB. AryaR.K. GoswamiR. AlharbiM.O. SharmaS. RahamanS.O. Role of macrophage TRPV4 in inflammation.Lab. Invest.2020100217818510.1038/s41374‑019‑0334‑631645630
     [Google Scholar]
  6. LanZ. ChenL. FengJ. XieZ. LiuZ. WangF. LiuP. YueX. DuL. ZhaoY. YangP. LuoJ. ZhuZ. HuX. CaoL. LuP. SahR. LavineK. KimB. HuH. Mechanosensitive TRPV4 is required for crystal-induced inflammation.Ann. Rheum. Dis.202180121604161410.1136/annrheumdis‑2021‑22029534663597
     [Google Scholar]
  7. GolevaE. BerdyshevE. LeungD.Y.M. Epithelial barrier repair and prevention of allergy.J. Clin. Invest.201912941463147410.1172/JCI12460830776025
     [Google Scholar]
  8. MooreC. GuptaR. JordtS.E. ChenY. LiedtkeW.B. Regulation of pain and itch by TRP channels.Neurosci. Bull.201834112014210.1007/s12264‑017‑0200‑829282613
     [Google Scholar]
  9. GraceM.S. BaxterM. DubuisE. BirrellM.A. BelvisiM.G. Transient receptor potential ( TRP ) channels in the airway: Role in airway disease.Br. J. Pharmacol.2014171102593260710.1111/bph.1253824286227
     [Google Scholar]
  10. RajanS. SchremmerC. WeberJ. AltP. GeigerF. DietrichA. Ca2+ signaling by TRPV4 channels in respiratory function and disease.Cells202110482210.3390/cells1004082233917551
     [Google Scholar]
  11. PerkinsM.E. VizzardM.A. Transient receptor potential vanilloid type 4 (TRPV4) in urinary bladder structure and function.Curr. Top. Membr.2022899513810.1016/bs.ctm.2022.06.00236210154
     [Google Scholar]
  12. McNultyA.L. LeddyH.A. LiedtkeW. GuilakF. TRPV4 as a therapeutic target for joint diseases.Naunyn Schmiedebergs Arch. Pharmacol.2015388443745010.1007/s00210‑014‑1078‑x25519495
     [Google Scholar]
  13. YanJ. YeF. JuY. WangD. ChenJ. ZhangX. YinZ. WangC. YangY. ZhuC. ZhouY. CaoP. XuY. YuG. TangZ. Cimifugin relieves pruritus in psoriasis by inhibiting TRPV4.Cell Calcium20219710242910.1016/j.ceca.2021.10242934087722
     [Google Scholar]
  14. RodriguesP. RuviaroN.A. TrevisanG. TRPV4 role in neuropathic pain mechanisms in rodents.Antioxidants20221212410.3390/antiox1201002436670886
     [Google Scholar]
  15. GraceM.S. BonviniS.J. BelvisiM.G. McIntyreP. Modulation of the TRPV4 ion channel as a therapeutic target for disease.Pharmacol. Ther.201717792210.1016/j.pharmthera.2017.02.01928202366
     [Google Scholar]
  16. DarbyW.G. GraceM.S. BaratchiS. McIntyreP. Modulation of TRPV4 by diverse mechanisms.Int. J. Biochem. Cell Biol.20167821722810.1016/j.biocel.2016.07.01227425399
     [Google Scholar]
  17. ThorneloeK.S. SulpizioA.C. LinZ. FigueroaD.J. ClouseA.K. McCaffertyG.P. 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.J. Pharmacol. Exp. Ther.2008326243244210.1124/jpet.108.13929518499743
     [Google Scholar]
  18. KlausenT.K. PaganiA. MinassiA. Ech-ChahadA. PrenenJ. OwsianikG. HoffmannE.K. PedersenS.F. AppendinoG. NiliusB. Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: A structure-activity study.J. Med. Chem.20095292933293910.1021/jm900100719361196
     [Google Scholar]
  19. VincentF. AcevedoA. NguyenM.T. DouradoM. DeFalcoJ. GustafsonA. SpiroP. EmerlingD.E. KellyM.G. DunctonM.A.J. Identification and characterization of novel TRPV4 modulators.Biochem. Biophys. Res. Commun.2009389349049410.1016/j.bbrc.2009.09.00719737537
     [Google Scholar]
  20. EveraertsW. ZhenX. GhoshD. VriensJ. GevaertT. GilbertJ.P. HaywardN.J. McNamaraC.R. XueF. MoranM.M. StrassmaierT. UykalE. OwsianikG. VennekensR. De RidderD. NiliusB. FangerC.M. VoetsT. Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis.Proc. Natl. Acad. Sci. USA201010744190841908910.1073/pnas.100533310720956320
     [Google Scholar]
  21. ThorneloeK.S. CheungM. BaoW. AlsaidH. LenhardS. JianM.Y. CostellM. Maniscalco-HaukK. KrawiecJ.A. OlzinskiA. GordonE. LozinskayaI. ElefanteL. QinP. MatasicD.S. JamesC. TunsteadJ. DonovanB. KallalL. WaszkiewiczA. VaidyaK. DavenportE.A. LarkinJ. BurgertM. CasillasL.N. MarquisR.W. YeG. EidamH.S. GoodmanK.B. ToomeyJ.R. RoethkeT.J. JuckerB.M. SchnackenbergC.G. TownsleyM.I. LeporeJ.J. WilletteR.N. An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure.Sci. Transl. Med.20124159159ra14810.1126/scitranslmed.300427623136043
     [Google Scholar]
  22. GoyalN. SkrdlaP. SchroyerR. KumarS. FernandoD. OughtonA. NortonN. SprecherD.L. CheriyanJ. Clinical pharmacokinetics, safety, and tolerability of a novel, first-in-class TRPV4 ion channel inhibitor, GSK2798745, in healthy and heart failure subjects.Am. J. Cardiovasc. Drugs201919333534210.1007/s40256‑018‑00320‑630637626
     [Google Scholar]
  23. StewartG.M. JohnsonB.D. SprecherD.L. ReddyY.N.V. ObokataM. GoldsmithS. BartB. OughtonA. FillmoreC. BehmD.J. BorlaugB.A. Targeting pulmonary capillary permeability to reduce lung congestion in heart failure: A randomized, controlled pilot trial.Eur. J. Heart Fail.20202291641164510.1002/ejhf.180932227554
     [Google Scholar]
  24. VincentF. DunctonM.A. TRPV4 agonists and antagonists.Curr. Top. Med. Chem.201111172216222610.2174/15680261179690486121671873
     [Google Scholar]
  25. FuS. MengH. InamdarS. DasB. GuptaH. WangW. ThompsonC.L. KnightM.M. Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1β mediated articular cartilage matrix destruction.Osteoarthritis Cartilage2021291899910.1016/j.joca.2020.08.00233395574
     [Google Scholar]
  26. ZhangS. LuK. YangS. WuY. LiaoJ. LuY. WuQ. ZhaoN. DongQ. ChenL. DuY. Activation of transient receptor potential vanilloid 4 exacerbates myocardial ischemia-reperfusion injury via JNK-CaMKII phosphorylation pathway in isolated mice hearts.Cell Calcium202110010248310.1016/j.ceca.2021.10248334628110
     [Google Scholar]
  27. WangY. HaoY. JinJ. YiZ. LiuY. ZhouH. ZhaoG. WenL. DongH. ZhangY. ZhangM. JiaY. HanL. XuH. WangT. FengJ. TRPV4 is not the molecular sensor for bacterial lipopolysaccharides-induced calcium signaling.Cell. Immunol.202338310465110.1016/j.cellimm.2022.10465136493524
     [Google Scholar]
  28. Pineda-TorraI. GageM. de JuanA. PelloO.M. Isolation, culture, and polarization of murine bone marrow-derived and peritoneal macrophages.Methods Mol. Biol.2015133910110910.1007/978‑1‑4939‑2929‑0_626445783
     [Google Scholar]
  29. ChaplanS.R. BachF.W. PogrelJ.W. ChungJ.M. YakshT.L. Quantitative assessment of tactile allodynia in the rat paw.J. Neurosci. Methods1994531556310.1016/0165‑0270(94)90144‑97990513
     [Google Scholar]
  30. HaoY. WuL. WangY. ShanD. LiuY. FengJ. ChangY. WangT. LPS exacerbates TRPV4-mediated itch through the intracellular TLR4-PI3K signalling.J. Cell. Mol. Med.20242813e1850910.1111/jcmm.1850938957035
     [Google Scholar]
  31. JiR.R. ChamessianA. ZhangY.Q. Pain regulation by non-neuronal cells and inflammation.Science2016354631257257710.1126/science.aaf892427811267
     [Google Scholar]
  32. MooreC. CevikbasF. PasolliH.A. ChenY. KongW. KempkesC. ParekhP. LeeS.H. KontchouN.A. YehI. JokerstN.M. FuchsE. SteinhoffM. LiedtkeW.B. UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling.Proc. Natl. Acad. Sci. USA201311034E3225E323410.1073/pnas.131293311023929777
     [Google Scholar]
  33. CalvoM. DawesJ.M. BennettD.L.H. The role of the immune system in the generation of neuropathic pain.Lancet Neurol.201211762964210.1016/S1474‑4422(12)70134‑522710756
     [Google Scholar]
  34. OhsakiA. TanumaS. TsukimotoM. TRPV4 channel-regulated ATP release contributes to γ-irradiation-induced production of IL-6 and IL-8 in epidermal keratinocytes.Biol. Pharm. Bull.201841101620162610.1248/bpb.b18‑0036130022772
     [Google Scholar]
  35. Marek-JozefowiczL. NedoszytkoB. GrochockaM. ŻmijewskiM.A. CzajkowskiR. CubałaW.J. SlominskiA.T. Molecular mechanisms of neurogenic inflammation of the skin.Int. J. Mol. Sci.2023245500110.3390/ijms2405500136902434
     [Google Scholar]
  36. ZelenkaM. SchäfersM. SommerC. Intraneural injection of interleukin-1β and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain.Pain2005116325726310.1016/j.pain.2005.04.01815964142
     [Google Scholar]
  37. KunerR. KunerT. Cellular circuits in the brain and their modulation in acute and chronic pain.Physiol. Rev.2021101121325810.1152/physrev.00040.201932525759
     [Google Scholar]
  38. YosipovitchG. KimB. LugerT. LernerE. MetzM. AdiriR. CanosaJ.M. ChaA. StänderS. Similarities and differences in peripheral itch and pain pathways in atopic dermatitis.J. Allergy Clin. Immunol.2024153490491210.1016/j.jaci.2023.10.03438103700
     [Google Scholar]
  39. YanL WangJ CaiX LiouYC ShenHM HaoJ Macrophage plasticity: Signaling pathways, tissue repair, and regeneration.MedComm202458e65810.1002/mco2.658
     [Google Scholar]
  40. MenonN. KishenA. Nociceptor–macrophage interactions in apical periodontitis: How biomolecules link inflammation with pain.Biomolecules2023138119310.3390/biom1308119337627258
     [Google Scholar]
  41. FioreN.T. DebsS.R. HayesJ.P. DuffyS.S. Moalem-TaylorG. Pain-resolving immune mechanisms in neuropathic pain.Nat. Rev. Neurol.202319419922010.1038/s41582‑023‑00777‑336859719
     [Google Scholar]
  42. SuttleA. WangP. DiasF.C. ZhangQ. LuoY. SimmonsL. BortsovA. TchivilevaI.E. NackleyA.G. ChenY. Sensory neuron-TRPV4 modulates temporomandibular disorder pain via CGRP in mice.J. Pain202324578279510.1016/j.jpain.2022.12.00136509176
     [Google Scholar]
  43. SunS. DongX. Trp channels and itch.Semin. Immunopathol.201638329330710.1007/s00281‑015‑0530‑426385480
     [Google Scholar]
  44. PanQ. GuoS.S. ChenM. SuX.Y. GaoZ.L. WangQ. XuT.L. LiuM.G. HuJ. Representation and control of pain and itch by distinct prefrontal neural ensembles.Neuron20231111524142431.e710.1016/j.neuron.2023.04.03237224813
     [Google Scholar]
  45. KanjuP. ChenY. LeeW. YeoM. LeeS.H. RomacJ. ShahidR. FanP. GoodenD.M. SimonS.A. SpasojevicI. MookR.A. LiddleR.A. GuilakF. LiedtkeW.B. Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.Sci. Rep.2016612689410.1038/srep2689427247148
     [Google Scholar]
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Identification of Novel Selective Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists
Curr. Pharm. Des. 31, 3017 (2025); https://doi.org/10.2174/0113816128381222250428094819
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  • Article Type:     Research Article
Keyword(s): acute itch; GSK101; LM0038; mechanical pain; sensory response; TRPV4

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