电压门控钙通道 α2δ 亚基配体治疗慢性神经性疼痛的研究进展及基于药效团模型的构效关系（SAR）研究。
Review of Voltage-gated Calcium Channel α2δ Subunit Ligands for the Treatment of Chronic Neuropathic Pain and Insight into Structure-activity Relationship (SAR) by Pharmacophore Modeling.
机构信息
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
Tianjin Institute of Pharmaceutical Research, Tianjin 300301, China.
出版信息
Curr Med Chem. 2022 Aug 15;29(30):5097-5112. doi: 10.2174/0929867329666220407093727.
BACKGROUND
Neuropathic pain (NP) is a complex symptom related to nerve damage. The discovery of new drugs for treating chronic NP has been continuing for several decades, while more progress is still needed because of the unsatisfactory efficacy and the side effects of the currently available drugs. Among all the approved drugs for chronic NP, voltage- gated calcium channel (VGCC) α2δ subunit ligands, also known as gabapentinoids, are among the first-line treatment and represent a class of efficacious and relatively safe therapeutic agents. However, new strategies are still needed to be explored due to the unsatisfied response rate.
OBJECTIVE
The aim of the study is to review the latest status of the discovery and development of gabapentinoids for the treatment of chronic NP by covering both the marketed and the preclinical/clinical ones. Moreover, it aims to analyze the structure-activity relationship (SAR) of gabapentinoids to facilitate the future design of structurally novel therapeutic agents targeting the VGCC α2δ subunit.
METHODS
We searched PubMed Central, Embase, Cochrane Library, Web of Science, Scopus, and Espacenet for the literature and patents on diabetic peripheral neuropathic pain, postherpetic neuralgia, fibromyalgia, voltage-gated calcium channel α2δ subunit and related therapeutic agents from incipient to June 10, 2021. The SAR of gabapentinoids was analyzed by pharmacophore modeling using the Phase module in the Schrödinger suite.
RESULTS
A variety of gabapentinoids were identified as VGCC α2δ ligands that have ever been under development to treat chronic NP. Among them, four gabapentinoids are marketed, one is in the active late clinical trials, and eight have been discontinued. Pharmacophore models were generated using the phase module in the Schrödinger suite, and common pharmacophores were predicted based on pharmacophoric features and analyzed.
CONCLUSION
The latest progress in the discovery and development of gabapentinoids for the treatment of chronic NP was reviewed. Moreover, the structure-activity relationship (SAR) of gabapentinoids has been analyzed by pharmacophore modeling, which will be valuable for the future design of structurally novel therapeutic agents targeting the VGCC α2δ subunit.
背景
神经病理性疼痛（NP）是一种与神经损伤相关的复杂症状。几十年来，人们一直在寻找治疗慢性 NP 的新药，尽管目前已有一些药物，但由于疗效不理想和存在副作用，仍需要更多的进展。在所有批准用于慢性 NP 的药物中，电压门控钙通道（VGCC）α2δ亚基配体，也称为加巴喷丁类药物，是一线治疗药物，是一类有效且相对安全的治疗药物。然而，由于反应率不理想，仍需要探索新的策略。
目的
本研究旨在通过涵盖已上市和临床前/临床药物，综述加巴喷丁类药物治疗慢性 NP 的最新发现和开发状况。此外，还旨在分析加巴喷丁类药物的构效关系（SAR），以促进未来针对 VGCCα2δ亚基设计结构新颖的治疗药物。
方法
我们检索了 PubMed Central、Embase、Cochrane Library、Web of Science、Scopus 和 Espacenet 中的文献和专利，检索内容涉及糖尿病周围神经病理性疼痛、带状疱疹后神经痛、纤维肌痛、电压门控钙通道α2δ亚基和相关治疗药物，检索时限为从起始到 2021 年 6 月 10 日。使用 Schrödinger 套件中的 Phase 模块对加巴喷丁类药物进行药效团建模，以分析其构效关系。
结果
确定了多种加巴喷丁类药物，它们作为 VGCCα2δ 配体，一直在被开发用于治疗慢性 NP。其中，有 4 种加巴喷丁类药物已上市，1 种处于积极的后期临床试验阶段，8 种已被终止。使用 Schrödinger 套件中的 Phase 模块生成药效团模型，根据药效团特征预测共有药效团，并进行分析。
结论
综述了加巴喷丁类药物治疗慢性 NP 的最新发现和开发进展。此外，通过药效团建模分析了加巴喷丁类药物的构效关系（SAR），这对未来设计针对 VGCCα2δ 亚基的结构新颖的治疗药物具有重要价值。
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