Novel TRPV1 Channel Agonists With Faster and More Potent Analgesic Properties Than Capsaicin.

Yorley Duarte,Fernando González-Nilo,Pedro Olivares,Ignacio Díaz-Franulic,Jimmy Stehberg,Javier Cáceres,Diego Arriagada,Romina V Sepúlveda

doi:10.3389/fphar.2020.01040

Abstract

The transient receptor potential vanilloid 1 (TRPV1) ion channel is a member of the family of Transient Receptor Potential (TRP) channels that acts as a molecular detector of noxious signals in primary sensory neurons. Activated by capsaicin, heat, voltage and protons, it is also well known for its desensitization, which led to the medical use of topically applied TRPV1 agonist capsaicin for its long-lasting analgesic effects. Here we report three novel small molecules, which were identified using a Structure-Based Virtual Screening for TRPV1 from the ZINC database. The three compounds were tested using electrophysiological assays, which confirmed their capsaicin-like agonist activity. von Frey filaments were used to measure the analgesic effects of the compounds applied topically on tactile allodynia induced by intra-plantar carrageenan. All compounds had anti-nociceptive activity, but two of them showed faster and longer lasting analgesic effects than capsaicin. The present results suggest that TRPV1 agonists different from capsaicin could be used to develop topical analgesics with faster onset and more potent effects.

Highlights

Transient receptor potential (TRP) ion channel superfamily involves 30 members, organized in seven subfamilies, from which it is possible to distinguish ten thermosensitive TRP (ThermoTRP) channels (Latorre et al, 2009; Diaz-Franulic et al, 2016)
We applied the structure-based virtual screening method using as a target the vanilloid pocket binding of transient receptor potential vanilloid 1 (TRPV1), through the National Cancer Institute (NCI) Diversity 3 library of compounds to identify novel TRPV1 agonists
Three of these compounds were experimentally tested in electrophysiological assays; all acted as TRPV1 agonists, exhibiting an EC50 4–9-fold lower than capsaicin

Summary

Introduction

Transient receptor potential (TRP) ion channel superfamily involves 30 members, organized in seven subfamilies, from which it is possible to distinguish ten thermosensitive TRP (ThermoTRP) channels (Latorre et al, 2009; Diaz-Franulic et al, 2016). Novel TRPV1 Agonists capsaicin has analgesic effects, resulting from the functional desensitization of primary nociceptors (Jancso et al, 1967; Szolcsanyi, 2004). The available TRPV1 channel structure allows the search for small molecules with potentially high affinity for the capsaicin binding site by performing a virtual screening (VS) over large libraries containing millions of compounds. Such strategy avoids the expensive and time-consuming high throughput screening of thousands of molecules using in vitro assays. This study opens the possibility of developing novel and more effective pain relief compounds targeting the TRPV1 channel

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Discussion

Conclusion