Novel TRPV1 Modulators with Reduced Pungency Induce Analgesic Effects in Mice

Anny Treat, Vianie Henri, Junke Liu, Joyce Shen, Mauricio Gil-Silva, Alejandro Morales, Avaneesh Rade, Kevin Joseph Tidgewell, Benedict Kolber, Young Shen

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Capsaicin, the compound in hot chili peppers responsible for their pungency and an agonist of the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), has long been known to promote the desensitization of nociceptors at high concentrations. This has led to the utilization and implementation of topical capsaicin cream as an analgesic to treat acute and chronic pain. Critically, the application of capsaicin cream is limited due to capsaicin’s high pungency, which is experienced prior to analgesia. To combat this issue, novel capsaicin analogues were developed to provide analgesia with reduced pungency. Analogues reported in this paper add to and show some differences from previous structure–activity relationship (SAR) studies of capsaicin-like molecules against TRPV1, including the necessity of phenol in the aromatic “A-region”, the secondary amide in the “B-region”, and modifications in the hydrophobic “C-region”. This provided a new framework for de novo small-molecule design using capsaicin as the starting point. In this study, we describe the synthesis of capsaicin analogues, their in vitro activity in Ca2+ assays, and initial in vivo pungency and feasibility studies of capsaicin analogues YB-11 and YB-16 as analgesics. Our results demonstrate that male and female mice treated with YB capsaicin analogues showed diminished pain-associated behavior in the spontaneous formalin assay as well as reduced thermal sensitivity in the hotplate assay.

Original languageEnglish
Pages (from-to)2929-2946
Number of pages18
JournalACS Omega
Issue number3
StatePublished - Jan 25 2022

Bibliographical note

Publisher Copyright:
© 2022 The Authors. Published by American Chemical Society

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering


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