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<p>Transient receptor potential vanilloid type-1 (TRPV1) channel is a polymodal receptor involved in pain perception and neuronal signalling that represents a promising target for the development of analgesics and neuroprotective agents. In this study we implement a combination of computational techniques and targeted design of chemical libraries to discover benzothiophene-substituted TRPV1 agonists with high affinity and efficacy toward TRPV1. In vitro functional experiments show that prolonged or repeated exposure to these compounds induce calcium-dependent desensitization of TRPV1, making it insensitive to noxious stimuli. We solve a cryo-electron microscopy (cryo-EM) structure of human TRPV1 (hTRPV1) in complex with the most promising benzothiophene-substituted agonist MSP20. The structure reveals molecular details of MSP20 binding to the vanilloid site and a desensitized conformation of hTRPV1, characterized by the closed ion channel pore, α-helical C-terminus and distinct behaviour of annular lipids. Our in vivo experiments demonstrate that MSP20 exhibits robust and long-lasting antinociceptive activity with ex-vivo neuroprotective effects, supporting the perspective of benzothiophene-substituted vanilloids as future analgesics.</p>

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Design, synthesis and structural mechanism of action of TRPV1 agonist MSP20 with long-lasting analgesic effect

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Arthur Neuberger,
  • Isabella Romeo,
  • Francesca Aiello,
  • Alexey Alekseev,
  • Samuele Maramai,
  • Federica Pessina,
  • Chiara Vagaggini,
  • Federica Poggialini,
  • Elena Dreassi,
  • Maria Frosini,
  • Aniello Schiano Moriello,
  • Luciano De Petrocellis,
  • Andrea Maria Morace,
  • Carmela Belardo,
  • Michela Perrone,
  • Roozbe Bonsale,
  • Livio Luongo,
  • Sabatino Maione,
  • Irina A. Talyzina,
  • Stefano Alcaro,
  • Anna Artese,
  • Antonella Brizzi,
  • Alexander I. Sobolevsky

摘要

Transient receptor potential vanilloid type-1 (TRPV1) channel is a polymodal receptor involved in pain perception and neuronal signalling that represents a promising target for the development of analgesics and neuroprotective agents. In this study we implement a combination of computational techniques and targeted design of chemical libraries to discover benzothiophene-substituted TRPV1 agonists with high affinity and efficacy toward TRPV1. In vitro functional experiments show that prolonged or repeated exposure to these compounds induce calcium-dependent desensitization of TRPV1, making it insensitive to noxious stimuli. We solve a cryo-electron microscopy (cryo-EM) structure of human TRPV1 (hTRPV1) in complex with the most promising benzothiophene-substituted agonist MSP20. The structure reveals molecular details of MSP20 binding to the vanilloid site and a desensitized conformation of hTRPV1, characterized by the closed ion channel pore, α-helical C-terminus and distinct behaviour of annular lipids. Our in vivo experiments demonstrate that MSP20 exhibits robust and long-lasting antinociceptive activity with ex-vivo neuroprotective effects, supporting the perspective of benzothiophene-substituted vanilloids as future analgesics.