R and S enantiomers of CBD3063, a Ca_V2.2 N-type calcium channel modulator, alleviate capsaicin-induced inflammatory pain

N-type voltage-gated calcium channels (Ca_V2.2) play a pivotal role in pain signaling, rendering them promising targets for pain treatment. However, direct blockers of Ca_V2.2 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 Ca_V2.2-CRMP2 (collapsin response mediator protein 2) interaction, resulting in a reduction of Ca_V2.2 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 Ca_V2.2 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.