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

Q2 Medicine

Neurobiology of Pain Pub Date : 2025-05-16 DOI:10.1016/j.ynpai.2025.100185

Santiago Loya-López , Erick J. Rodríguez-Palma , Aida Calderón-Rivera , Kimberly Gomez , Samantha Perez-Miller , Rajesh Khanna

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Abstract

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.

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CaV2.2 n型钙通道调节剂CBD3063的R和S对映体可减轻辣椒素引起的炎症性疼痛

n型电压门控钙通道（CaV2.2）在疼痛信号传导中起着关键作用，使其成为疼痛治疗的有希望的靶点。然而，由于副作用和血脑屏障穿透不足，CaV2.2的直接阻滞剂的疗效有限。在之前的工作中，我们开发了CBD3063，一种小分子拟肽，破坏CaV2.2- crmp2（塌陷反应介质蛋白2）的相互作用，导致CaV2.2电流减少和疼痛缓解，没有副作用。在这项研究中，我们研究了CBD3063的(R)和(S)对映体对其药理作用的单独贡献。来自小鼠背根神经节（DRG）感觉神经元的全细胞膜片钳记录显示(S)和(R)对映体降低了CaV2.2电流。此外，外消旋CBD3063和(S)对映体在辣椒素诱导的炎症性疼痛模型中表现出抗伤害性作用。这些发现表明(S)和(R)对映体有助于CBD3063的治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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