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Modulation of the Transient Receptor Potential Vanilloid Channel TRPV4 by 4α-Phorbol Esters: A Structure−Activity Study

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KU Leuven, Department of Molecular Cell Biology, Laboratory Ion Channel Research, Campus Gasthuisberg, Herestraat 49, bus 802, Leuven, Belgium, Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Via Bovio 9, 28100 Novara, Italy, Department of Biology, Section of Cell and Developmental Biology, University of Copenhagen, 13 Universitetsparken, 2100 Copenhagen Ø, Denmark
* To whom correspondence should be addressed. For B.N.: phone, +32 16 34 5937; fax, 32 16 34 5991; E-mail, [email protected]. For G.A.: phone, +39 0321375744; fax, +39 0321375621; E-mail, [email protected]
†KU Leuven, Department of Molecular Cell Biology, Laboratory Ion Channel Research.
§Department of Biology, Section of Cell and Developmental Biology, University of Copenhagen.
‡Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche.
Cite this: J. Med. Chem. 2009, 52, 9, 2933–2939
Publication Date (Web):April 10, 2009
Copyright © 2009 American Chemical Society

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    Abstract Image

    The mechanism of activation of the transient receptor potential vanilloid 4 (TRPV4) channel by 4α-phorbol esters was investigated by combining information from chemical modification of 4α-phorbol-didecanoate (4α-PDD, 2a), site-directed mutagenesis, Ca2+ imaging, and electrophysiology. Binding of 4α-phorbol esters occurs in a loop in the TM3−TM4 domain of TRPV4 that is analogous to the capsaicin binding site of TRPV1, and the ester decoration of ring C and the A,B ring junction are critical for activity. The lipophilic ester groups on ring C serve mainly as a steering element, affecting the orientation of the diterpenoid core into the ligand binding pocket, while the nature of the A,B ring junction plays an essential role in the Ca2+-dependence of the TRPV4 response. Taken together, our results show that 4α-phorbol is a useful template to investigate the molecular details of TRPV4 activation by small molecules and obtain information for the rational design of structurally simpler ligands for this ion channel.

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    2. Saner Poplata, Andreas Tröster, You-Quan Zou, and Thorsten Bach . Recent Advances in the Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition Reactions. Chemical Reviews 2016, 116 (17) , 9748-9815.
    3. Svilen P. Simeonov, João P. M. Nunes, Krassimira Guerra, Vanya B. Kurteva, and Carlos A. M. Afonso . Synthesis of Chiral Cyclopentenones. Chemical Reviews 2016, 116 (10) , 5744-5893.
    4. Hong-Bing Wang, Xiao-Yang Wang, Li-Ping Liu, Guo-Wei Qin, and Ting-Guo Kang . Tigliane Diterpenoids from the Euphorbiaceae and Thymelaeaceae Families. Chemical Reviews 2015, 115 (9) , 2975-3011.
    5. Mengmeng Shen, Yawei Tu, Guanqun Xie, Qingsheng Niu, Hui Mao, Tingting Xie, Robert A. Flowers, II, Xin Lv, and Xiaoxia Wang . Allylsamarium Bromide-Mediated Cascade Cyclization of Homoallylic Esters. Synthesis of 2-(2-Hydroxyalkyl)cyclopropanols and 2-(2-Hydroxyethyl)bicyclo[2.1.1]hexan-1-ols. The Journal of Organic Chemistry 2015, 80 (1) , 52-61.
    6. Peter Forgo, Dóra Rédei, Zsanett Hajdu, Pál Szabó, László Szabó, and Judit Hohmann . Unusual Tigliane Diterpenes from Euphorbia grandicornis. Journal of Natural Products 2011, 74 (4) , 639-643.
    7. Alberto Pagani, Carmen Navarrete, Bernd L. Fiebich, Eduardo Muñoz and Giovanni Appendino. Synthesis and Biological Evaluation of 12-Aminoacylphorboids. Journal of Natural Products 2010, 73 (3) , 447-451.
    8. Kouharu Otsuki, Wei Li. Tigliane and daphnane diterpenoids from Thymelaeaceae family: chemistry, biological activity, and potential in drug discovery. Journal of Natural Medicines 2023, 77 (4) , 625-643.
    9. Mohit Kumar, Md. Kamaruz Zaman, Sanghita Das, Danswrang Goyary, Manash Pratim Pathak, Pronobesh Chattopadhyay. Transient Receptor Potential Vanilloid (TRPV4) channel inhibition: A novel promising approach for the treatment of lung diseases. Biomedicine & Pharmacotherapy 2023, 163 , 114861.
    10. Ammar Boudaka, Makoto Tominaga. Physiological and Pathological Significance of Esophageal TRP Channels: Special Focus on TRPV4 in Esophageal Epithelial Cells. International Journal of Molecular Sciences 2022, 23 (9) , 4550.
    11. Suhasini Rajan, Christian Schremmer, Jonas Weber, Philipp Alt, Fabienne Geiger, Alexander Dietrich. Ca2+ Signaling by TRPV4 Channels in Respiratory Function and Disease. Cells 2021, 10 (4) , 822.
    12. Sebastien Chaigne, Guillaume Cardouat, Julien Louradour, Fanny Vaillant, Sabine Charron, Frederic Sacher, Thomas Ducret, Romain Guinamard, Edward Vigmond, Thomas Hof. Transient receptor potential vanilloid 4 channel participates in mouse ventricular electrical activity. American Journal of Physiology-Heart and Circulatory Physiology 2021, 320 (3) , H1156-H1169.
    13. Trine L. Toft-Bertelsen, Nanna MacAulay. TRPing to the Point of Clarity: Understanding the Function of the Complex TRPV4 Ion Channel. Cells 2021, 10 (1) , 165.
    14. Brianna D. Guarino, Sailaja Paruchuri, Charles K. Thodeti. The role of TRPV4 channels in ocular function and pathologies. Experimental Eye Research 2020, 201 , 108257.
    15. Satyanarayana Achanta, Sven‐Eric Jordt. Transient receptor potential channels in pulmonary chemical injuries and as countermeasure targets. Annals of the New York Academy of Sciences 2020, 1480 (1) , 73-103.
    16. Masakazu Atobe. Activation of Transient Receptor Potential Vanilloid (TRPV) 4 as a Therapeutic Strategy in Osteoarthritis. Current Topics in Medicinal Chemistry 2019, 19 (24) , 2254-2267.
    17. Alexander Dietrich. Modulators of Transient Receptor Potential (TRP) Channels as Therapeutic Options in Lung Disease. Pharmaceuticals 2019, 12 (1) , 23.
    18. Amanda H. Klein. The orotrigeminal system. 2019, 205-216.
    19. Brett Boonen, Yeranddy Alpizar, Victor Meseguer, Karel Talavera. TRP Channels as Sensors of Bacterial Endotoxins. Toxins 2018, 10 (8) , 326.
    20. Alexander Dietrich, Dirk Steinritz, Thomas Gudermann. Transient receptor potential (TRP) channels as molecular targets in lung toxicology and associated diseases. Cell Calcium 2017, 67 , 123-137.
    21. Megan S. Grace, Sara J. Bonvini, Maria G. Belvisi, Peter McIntyre. Modulation of the TRPV4 ion channel as a therapeutic target for disease. Pharmacology & Therapeutics 2017, 177 , 9-22.
    22. Naoki Tsuno, Akira Yukimasa, Osamu Yoshida, Shinji Suzuki, Hiromi Nakai, Tomoyuki Ogawa, Motohiro Fujiu, Kenji Takaya, Azusa Nozu, Hiroki Yamaguchi, Hidetoshi Matsuda, Satoko Funaki, Natsue Yamanada, Miki Tanimura, Daiki Nagamatsu, Toshiyuki Asaki, Narumi Horita, Miyuki Yamamoto, Mikie Hinata, Masahiko Soga, Masayuki Imai, Yasuhide Morioka, Toshiyuki Kanemasa, Gaku Sakaguchi, Yasuyoshi Iso. Pharmacological evaluation of novel (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives as TRPV4 antagonists for the treatment of pain. Bioorganic & Medicinal Chemistry 2017, 25 (7) , 2177-2190.
    23. François Seghers, Xavier Yerna, Nadège Zanou, Olivier Devuyst, Rudi Vennekens, Bernd Nilius, Philippe Gailly. TRPV4 participates in pressure‐induced inhibition of renin secretion by juxtaglomerular cells. The Journal of Physiology 2016, 594 (24) , 7327-7340.
    24. Thomas Dalsgaard, Swapnil K. Sonkusare, Cory Teuscher, Matthew E. Poynter, Mark T. Nelson. Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice. Scientific Reports 2016, 6 (1)
    25. John P. M. White, Mario Cibelli, Laszlo Urban, Bernd Nilius, J. Graham McGeown, Istvan Nagy. TRPV4: Molecular Conductor of a Diverse Orchestra. Physiological Reviews 2016, 96 (3) , 911-973.
    26. Zhi-Liang Wei, Margaret T. Nguyen, Donogh J.R. O’Mahony, Alejandra Acevedo, Sheila Zipfel, Qingling Zhang, Luna Liu, Michelle Dourado, Candace Chi, Victor Yip, Jeff DeFalco, Amy Gustafson, Daniel E. Emerling, Michael G. Kelly, John Kincaid, Fabien Vincent, Matthew A.J. Duncton. Identification of orally-bioavailable antagonists of the TRPV4 ion-channel. Bioorganic & Medicinal Chemistry Letters 2015, 25 (18) , 4011-4015.
    27. Neil M. Goldenberg, Krishnan Ravindran, Wolfgang M. Kuebler. TRPV4: physiological role and therapeutic potential in respiratory diseases. Naunyn-Schmiedeberg's Archives of Pharmacology 2015, 388 (4) , 421-436.
    28. Jie Wang, Xiao-Wei Wang, Yang Zhang, Cui-Ping Yin, Shou-Wei Yue. Ca2+ influx mediates the TRPV4–NO pathway in neuropathic hyperalgesia following chronic compression of the dorsal root ganglion. Neuroscience Letters 2015, 588 , 159-165.
    29. Matthew A.J. Duncton. Small Molecule Agonists and Antagonists of TRPV4. 2015, 205-219.
    30. Asia Fernández-Carvajal, Gregorio Fernández-Ballester, Rosario González-Muñiz, Antonio Ferrer-Montiel. Pharmacology of TRP Channels. 2015, 41-71.
    31. Bernd Nilius, Arpad Szallasi, . Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine. Pharmacological Reviews 2014, 66 (3) , 676-814.
    32. Yosuke Kaneko, Arpad Szallasi. Transient receptor potential (TRP) channels: a clinical perspective. British Journal of Pharmacology 2014, 171 (10) , 2474-2507.
    33. Anna Garcia-Elias, Sanela Mrkonjić, Carole Jung, Carlos Pardo-Pastor, Rubén Vicente, Miguel A. Valverde. The TRPV4 Channel. 2014, 293-319.
    34. Michael Schaefer. TRPs: Modulation by Drug-Like Compounds. 2014, 1077-1106.
    35. Jeremy M. Sullivan, Thomas E. Lloyd, Charlotte J. Sumner. Hereditary Channelopathies Caused by TRPV4 Mutations. 2014, 413-440.
    36. Ulrich Wissenbach. Pharmacology of TRPV Channels. 2014, 549-575.
    37. Bernd Nilius, Thomas Voets. The puzzle of TRPV4 channelopathies. EMBO reports 2013, 14 (2) , 152-163.
    38. Kevin S. Thorneloe, Mui Cheung, Weike Bao, Hasan Alsaid, Stephen Lenhard, Ming-Yuan Jian, Melissa Costell, Kristeen Maniscalco-Hauk, John A. Krawiec, Alan Olzinski, Earl Gordon, Irina Lozinskaya, Lou Elefante, Pu Qin, Daniel S. Matasic, Chris James, James Tunstead, Brian Donovan, Lorena Kallal, Anna Waszkiewicz, Kalindi Vaidya, Elizabeth A. Davenport, Jonathan Larkin, Mark Burgert, Linda N. Casillas, Robert W. Marquis, Guosen Ye, Hilary S. Eidam, Krista B. Goodman, John R. Toomey, Theresa J. Roethke, Beat M. Jucker, Christine G. Schnackenberg, Mary I. Townsley, John J. Lepore, Robert N. Willette. An Orally Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by Heart Failure. Science Translational Medicine 2012, 4 (159)
    39. Liping Ning, Chuanwei Wang, Xinli Ding, Yang Zhang, Xuping Wang, Shouwei Yue. Functional interaction of TRPV4 channel protein with annexin A2 in DRG. Neurological Research 2012, 34 (7) , 685-693.
    40. Makoto Suzuki, Astuko Mizuno. The Molecular Mechanism of Multifunctional Mechano-Gated Channel TRPV4. 2012, 103-157.
    41. Fabien Vincent, Matthew A. J. Duncton. TRPV4 and Drug Discovery. 2012, 257-270.
    42. Maarten Gees, Grzegorz Owsianik, Bernd Nilius, Thomas Voets. TRP Channels. 2012, 563-608.
    43. R. L. Baylie, J. E. Brayden. TRPV channels and vascular function. Acta Physiologica 2011, 203 (1) , 99-116.
    44. Stephen Loukin, Zhenwei Su, Ching Kung, . Increased Basal Activity Is a Key Determinant in the Severity of Human Skeletal Dysplasia Caused by TRPV4 Mutations. PLoS ONE 2011, 6 (5) , e19533.
    45. Roberta Zaninetti, Alessandra Fornarelli, Monica Ciarletta, Dmitry Lim, Antonio Caldarelli, Tracey Pirali, Anna Cariboni, Grzegorz Owsianik, Bernd Nilius, Pier Luigi Canonico, Carla Distasi, Armando A. Genazzani. Activation of TRPV4 channels reduces migration of immortalized neuroendocrine cells. Journal of Neurochemistry 2011, 116 (4) , 606-615.
    46. Irina Vetter, Richard J. Lewis. Natural Product Ligands of TRP Channels. 2011, 41-85.
    47. Bernd Nilius, Grzegorz Owsianik. The transient receptor potential family of ion channels. Genome Biology 2011, 12 (3) , 218.
    48. Emilie D'Aldebert, Nicolas Cenac, Perrine Rousset, Laurence Martin, Corinne Rolland, Kevin Chapman, Janick Selves, Laurent Alric, Jean–Pierre Vinel, Nathalie Vergnolle. Transient Receptor Potential Vanilloid 4 Activated Inflammatory Signals by Intestinal Epithelial Cells and Colitis in Mice. Gastroenterology 2011, 140 (1) , 275-285.e3.
    49. Yalda Shokoohinia, Seyed-Ebrahim Sajjadi, Behzad Zolfaghari, Giuseppina Chianese, Giovanni Appendino, Orazio Taglialatela-Scafati. Diterpenoid (poly)esters and a ring A-seco-phorboid from the aerial parts of Euphorbia macroclada Boiss. Fitoterapia 2010, 81 (7) , 884-890.
    50. Wouter Everaerts, Bernd Nilius, Grzegorz Owsianik. The vanilloid transient receptor potential channel TRPV4: From structure to disease. Progress in Biophysics and Molecular Biology 2010, 103 (1) , 2-17.
    51. Long-Jun Wu, Tara-Beth Sweet, David E. Clapham. International Union of Basic and Clinical Pharmacology. LXXVI. Current Progress in the Mammalian TRP Ion Channel Family. Pharmacological Reviews 2010, 62 (3) , 381-404.
    52. Wouter Everaerts, Joris Vriens, Grzegorz Owsianik, Giovanni Appendino, Thomas Voets, Dirk De Ridder, Bernd Nilius. Functional characterization of transient receptor potential channels in mouse urothelial cells. American Journal of Physiology-Renal Physiology 2010, 298 (3) , F692-F701.
    53. Rajagopal Bakthavatchalam, S. David Kimball. Modulators of Transient Receptor Potential Ion Channels. 2010, 37-53.

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