Loya-López Santiago, Rodríguez-Palma Erick J, Calderón-Rivera Aida, Gomez Kimberly, Perez-Miller Samantha, Khanna Rajesh
Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, USA.
Center for Advanced Pain Therapeutics and Research (CAPTOR), College of Medicine, University of Florida, Gainesville, FL, USA.
Neurobiol Pain. 2025 May 16;18:100185. doi: 10.1016/j.ynpai.2025.100185. eCollection 2025 Jul-Dec.
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.
N型电压门控钙通道（Ca2.2）在疼痛信号传导中起关键作用，使其成为有前景的疼痛治疗靶点。然而，由于副作用和血脑屏障穿透不足，Ca2.2的直接阻滞剂疗效有限。在先前的工作中，我们开发了CBD3063，一种小分子肽模拟物，它破坏Ca2.2与CRMP2（塌陷反应介导蛋白2）的相互作用，从而减少Ca2.2电流并缓解疼痛且无副作用。在本研究中，我们研究了CBD3063的（R）和（S）对映体对其药理作用的各自贡献。从小鼠背根神经节（DRG）感觉神经元进行的全细胞膜片钳记录表明，（S）和（R）对映体均降低了Ca2.2电流。此外，外消旋CBD3063和（S）对映体在辣椒素诱导的炎性疼痛模型中表现出抗伤害感受作用。这些发现表明，（S）和（R）对映体均对CBD
