# R and S enantiomers of CBD3063, a CaV2.2 N-type calcium channel modulator, alleviate capsaicin-induced inflammatory pain

## TL;DR

This study shows that both forms of CBD3063 reduce pain by targeting calcium channels, with one form also shifting channel behavior.

## Contribution

The study reveals the distinct pharmacological roles of CBD3063 enantiomers in pain relief.

## Key findings

- Both (S) and (R) CBD3063 reduce N-type calcium currents in sensory neurons.
- The (S) enantiomer shifts calcium channel inactivation leftward.
- Racemic CBD3063 and the (S) enantiomer show antinociceptive effects in inflammatory pain models.

## Abstract

•Both (S) CBD3063 and (R) CBD3063 similarly reduce N-type Ca2 + currents.•The (S) enantiomer shifts Ca2 + channel inactivation leftward.•Racemic CBD3063 shows antinociceptive effects in vivo.•Both (S) CBD3063 and (R) CBD3063 contribute to CBD3063′s antinociceptive properties.

Both (S) CBD3063 and (R) CBD3063 similarly reduce N-type Ca2 + currents.

The (S) enantiomer shifts Ca2 + channel inactivation leftward.

Racemic CBD3063 shows antinociceptive effects in vivo.

Both (S) CBD3063 and (R) CBD3063 contribute to CBD3063′s antinociceptive properties.

N-type voltage-gated calcium channels (CaV2.2) play a pivotal role in pain signaling, rendering them promising targets for pain treatment. However, direct blockers of CaV2.2 have demonstrated limited efficacy due to adverse side effects and inadequate blood–brain barrier penetration. In previous work, we developed CBD3063, a small molecule peptidomimetic that disrupts the CaV2.2-CRMP2 (collapsin response mediator protein 2) interaction, resulting in a reduction of CaV2.2 currents and pain relief without side effects. In this study, we investigated the individual contributions of the (R) and (S) enantiomers of CBD3063 to its pharmacological effects. Whole-cell patch-clamp recordings from mouse dorsal root ganglion (DRG) sensory neurons indicated that the (S) and (R) enantiomers reduced CaV2.2 currents. Furthermore, racemic CBD3063 and the (S) enantiomer exhibited antinociceptive effects in the capsaicin-induced model of inflammatory pain. These findings suggest that the (S) and (R) enantiomers contribute to the therapeutic effects of CBD3063.