R and S enantiomers of CBD3063, a Ca2.2 N-type calcium channel modulator, alleviate capsaicin-induced inflammatory pain.

N-type voltage-gated calcium channels (Ca2.2) play a pivotal role in pain signaling, rendering them promising targets for pain treatment. However, direct blockers of Ca2.2 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 Ca2.2-CRMP2 (collapsin response mediator protein 2) interaction, resulting in a reduction of Ca2.2 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 Ca2.2 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.