Discovery of a Remarkable Methyl Shift Effect in the Vanilloid Activity of Triterpene Amides.

Rosa Maria Vitale,Pietro Amodeo,Aniello Schiano Moriello,Cristina Avonto,Danilo Del Prete,Luciano De Petrocellis,Giovanni Appendino

doi:10.1021/acs.jnatprod.0c00639

Abstract

As part of a study on triterpenoid conjugates, the dietary pentacyclic triterpenoids oleanolic (2a) and ursolic acids (3a) were coupled with vanillamine, and the resulting amides (2b and 3b, respectively) were assayed for activity on the vanilloid receptor TRPV1. Despite a structural difference limited to the location of a methyl group in their conformationally rigid pentacyclic core, oleanoloyl vanillamide dramatically outperformed ursoloyl vanillamide in terms of potency (EC50 = 35 ± 2 nM for 2b and 5.4 ± 2.3 μM for 3b). Using molecular docking and dynamics, this difference was translated into distinct accommodation modes at the TRPV1 vanillyl ligand pocket, suggesting a critical role of a C–H πphenyl interaction between the triterpenoid C-29 methyl and Phe591 of TRPV1. Because the molecular mechanisms underlying the activation process of transient receptor channels (TRPs) remain to be fully elucidated, the observation of spatially restricted structure–activity information is of significant relevance to identify the molecular detail of TRPV1 ligand gating.

Highlights

(3a) were coupled with vanillamine, and the resulting amides (2b and 3b, respectively) were assayed for activity on the vanilloid receptor TRPV1
Structure−activity studies have identified the critical structural determinants for TRPV1 activation by capsaicinoids,[2] and cryo-EM studies of this ion channel bound to a set of ligands have provided insights into protein− ligand interactions in the TRPV1 vanillyl pocket.[3−5] given the complexity and multimodal action of this class of receptors, the molecular details of the ligand−channel interactions have largely remained elusive, in particular, and paradoxically, for the archetypal ligand capsaicin (1).[6]
We report the discovery of a “magic” methyl shift effect[7,8] in the activity of the vanillamides of oleanolic (2a) and ursolic acid (3a) and its rationalization in terms of docking and molecular dynamics (MD) experiments in the TRPV1 ligand pocket

Summary

Introduction

(3a) were coupled with vanillamine, and the resulting amides (2b and 3b, respectively) were assayed for activity on the vanilloid receptor TRPV1. We report the discovery of a “magic” methyl shift effect[7,8] in the activity of the vanillamides of oleanolic (2a) and ursolic acid (3a) and its rationalization in terms of docking and molecular dynamics (MD) experiments in the TRPV1 ligand pocket.

Results

Conclusion