# The Impact of a Quinone Scaffold on Thermo-TRPs Modulation by Dimethylheptyl Phytocannabinoids

## TL;DR

This study explores how adding a quinone group to phytocannabinoids affects their interaction with thermo-TRP channels, potentially offering new treatments for inflammatory skin diseases.

## Contribution

The integration of a quinone group into the resorcinol scaffold of DMH-pCBs increases TRPV3 potency while retaining TRPA1 activity.

## Key findings

- Quinone derivatives retain TRPA1 activity but show increased potency on TRPV3 modulation.
- Docking studies explain the binding modes of active compounds to TRPV3.
- The compounds exhibit desensitizing activity on TRPA1 and TRPV3, relevant for treating inflammatory skin diseases.

## Abstract

Phytocannabinoids (pCBs) from Cannabis sativa represent an important class of bioactive molecules, potentially useful for the treatment of a wide range of diseases. Their efficacy is due to their ability to interact with multiple targets of the endocannabinoid system, including the thermosensitive transient receptor potential (Thermo-TRPs), namely TRPV1-4, TRPA1, and TRPM8 channels. Previously, we demonstrated a shift in selectivity toward TRPA1 in the activity profile of the main pCBs, that is, CBD, ∆8-THC, CBG, CBC, and CBN, by swapping the pentyl chain with the α,α-dimethylheptyl (DMH) one. Using these derivatives as a starting point, here we investigate the effects on the thermo-TRPs activity profile of the integration of a quinone group into the resorcinol scaffold. We found that, while the activity on TRPA1 is substantially retained, an increase in potency/efficacy on the TRPV3 modulation is observed. Docking studies were used to elucidate the binding modes of the most active compounds toward this receptor, providing a rationale for this biological activity. In summary, we show that the quinone derivatives of DMH-pCBs are endowed with a TRPA1/TRPV3 desensitizing activity, potentially useful for the treatment of skin diseases sustained by inflammatory conditions.