Abstract：
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.
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.
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.
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.
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.
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.
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.
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.
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.
摘要：
神经性疼痛(NP)是与神经损伤有关的复杂症状。用于治疗慢性NP的新药的发现已经持续了几十年。虽然由于目前可用药物的疗效和副作用不令人满意，但仍需要取得更多进展。在所有批准的慢性NP药物中，电压门控钙通道（VGCC）α2δ亚基配体，也被称为gabapentinoid，是一线治疗之一，代表了一类有效和相对安全的治疗剂。然而,由于不满意的反应率，仍需要探索新的策略。
该研究的目的是通过涵盖市售和临床前/临床两种药物来回顾加巴喷丁类药物治疗慢性NP的发现和发展的最新状况。此外，它旨在分析加巴喷丁类药物的结构-活性关系（SAR），以促进针对VGCCα2δ亚基的结构新型治疗剂的未来设计。
我们搜索了PubMedCentral,Embase,科克伦图书馆,WebofScience,Scopus,和Espacenet关于糖尿病周围神经性疼痛的文献和专利，带状疱疹后遗神经痛,纤维肌痛,从初期到2021年6月10日的电压门控钙通道α2δ亚基和相关治疗剂。通过使用Schrödinger套件中的相位模块的药效基团建模来分析类加巴喷丁的SAR。
多种加巴喷丁被鉴定为VGCCα2δ配体,其曾经被开发用于治疗慢性NP。其中,四种加巴喷丁类药物上市，一个是在活跃的后期临床试验中，八个已经停产。使用Schrödinger套件中的相位模块生成药效团模型，根据药效特征预测和分析常见药效。
综述了加巴喷丁类药物治疗慢性NP的最新发现和研究进展。此外，加巴喷丁的结构-活性关系（SAR）已通过药效基团模型进行了分析，这对于将来设计靶向VGCCα2δ亚基的结构新颖的治疗剂是有价值的。
该研究的目的是通过涵盖市售和临床前/临床两种药物来回顾加巴喷丁类药物治疗慢性NP的发现和发展的最新状况。此外，它旨在分析加巴喷丁类药物的结构-活性关系（SAR），以促进针对VGCCα2δ亚基的结构新型治疗剂的未来设计。
我们搜索了PubMedCentral,Embase,科克伦图书馆,WebofScience,Scopus,和Espacenet关于糖尿病周围神经性疼痛的文献和专利，带状疱疹后遗神经痛,纤维肌痛,从初期到2021年6月10日的电压门控钙通道α2δ亚基和相关治疗剂。通过使用Schrödinger套件中的相位模块的药效基团建模来分析类加巴喷丁的SAR。
多种加巴喷丁被鉴定为VGCCα2δ配体,其曾经被开发用于治疗慢性NP。其中,四种加巴喷丁类药物上市，一个是在活跃的后期临床试验中，八个已经停产。使用Schrödinger套件中的相位模块生成药效团模型，根据药效特征预测和分析常见药效。
综述了加巴喷丁类药物治疗慢性NP的最新发现和研究进展。此外，加巴喷丁的结构-活性关系（SAR）已通过药效基团模型进行了分析，这对于将来设计靶向VGCCα2δ亚基的结构新颖的治疗剂是有价值的。
