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

Q2 Medicine
Santiago Loya-López , Erick J. Rodríguez-Palma , Aida Calderón-Rivera , Kimberly Gomez , Samantha Perez-Miller , Rajesh Khanna
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引用次数: 0

摘要

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。
R and S enantiomers of CBD3063, a CaV2.2 N-type calcium channel modulator, alleviate capsaicin-induced inflammatory pain
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.
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来源期刊
Neurobiology of Pain
Neurobiology of Pain Medicine-Anesthesiology and Pain Medicine
CiteScore
4.40
自引率
0.00%
发文量
29
审稿时长
54 days
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