Tricyclic Spirolactones as Modular TRPV1 Synthetic Agonists

Yelena Mostinski, Gilad Noy, Rakesh Kumar, Dmitry Tsvelikhovsky*, Avi Priel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


TRPV1 is a prominent signal integrator of the pain system, known to be activated by vanilloids, a family of endogenous and exogenous pain-evoking molecules, through the vanilloid-binding site (VBS). The extensive preclinical profiling of small molecule inhibitors provides intriguing evidence that TRPV1 inhibition can be a useful therapeutic approach. However, the dissimilarity of chemical species that activate TRPV1 creates a major obstacle to understanding the molecular mechanism of pain induction, which is viewed as a pivotal trait of the somatosensory system. Here, we establish the existence of a unique family of synthetic agonists that interface with TRPV1 through the VBS, containing none of the molecular domains previously believed to be required for this interaction. The overarching value obtained from our inquiry is the novel advancement of the existing TRPV1 activation model. These findings uncover new potential in the area of pain treatment, providing a novel synthetic platform.

Original languageAmerican English
Pages (from-to)1688-1696
Number of pages9
JournalACS Chemical Neuroscience
Issue number8
StatePublished - 16 Aug 2017

Bibliographical note

Funding Information:
This research project was financially supported by the Israel Science Foundation (1368/12 and 1444/16 to A.P.) and the State of Lower Saxony, Hannover Germany grants (D.T.). We also gratefully acknowledge the Marie Curie Integration Grants CIG 321746 (D.T.) and 321899 (A.P.) and the German-Israeli-Foundation Grant (G.I.F. I-2330-1145.5/2012 to D.T.) for their financial support.

Publisher Copyright:
© 2017 American Chemical Society.


  • TRPV1
  • capsaicin
  • pain
  • synthetic agonists
  • tricyclic spirolactones
  • vanilloid-binding site


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