Study on structure-activity relationship (SAR) of simplified mirogabalin derivatives as voltage-gated calcium channel α2δ ligands for the treatment of chronic neuropathic pain.
Study on structure-activity relationship (SAR) of simplified mirogabalin derivatives as voltage-gated calcium channel α2δ ligands for the treatment of chronic neuropathic pain.
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研究简化的米洛巴林衍生物作为电压门控钙通道α2α配体治疗慢性神经病理性疼痛的构效关系（SAR）。
DOI：
10.1007/s00044-022-03006-6
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发表时间：
2022
影响因子：
2.6
通讯作者：
Huihui Ti
中科院分区：
文献类型：
--
作者：
Yuanwen Zhang;Yueming Zheng;Qingqing Wu;Fuyun Tian;Chuanjun Ma;Haiyan Xu;Li Zhan;Zhaobing Gao;Guilong Zhao;Huihui Ti
慢性神经病理性疼痛的临床治疗是一个亟待解决的问题，而电压门控性钙通道（VGCC）α2δ亚基是最有希望的治疗靶点之一。为了深入研究VGCC α2δ亚基配体（gabapentinoids）中亲脂性部分的构效关系（SAR），我们以第三代VGCC α2δ亚基配体mirogabalin为基础，设计并合成了11个双环和单环衍生物。体外测定了合成化合物与人VGCC α2δ-1亚基的竞争性结合，结果表明，加巴喷丁类化合物的亲脂部分大小受到严格限制，其中构象刚性的双环[3.2.0]庚烷/庚烯顺式融合是最优选的结构。相比之下，除了4（IC 50 = 15.2 nM）之外，单环环丁烷与显著降低的结合亲和力相关，其中取代基可以模拟双环[3.2.0]庚烷/庚烯的刚性构象;亲脂部分中的杂原子对结合亲和力有害（2，IC 50> 729 nM）。本研究所获得的构效关系研究结果将为将来设计治疗慢性神经病理性疼痛的新型加巴喷丁类药物提供参考。
A clinical therapy for chronic neuropathic pain is urgently needed, and the voltage-gated calcium channel (VGCC) α2δ.subunit is among the most promising therapeutic targets. To intensively explore the structure-activity relationship (SAR) of.the lipophilic moiety in VGCC α2δ subunit ligands (gabapentinoids), we designed and synthesized 11 bicyclic and.monocyclic derivatives based on mirogabalin, a third-generation VGCC α2δ subunit ligand. The competitive binding of the.synthesized compounds to the human VGCC α2δ-1 subunit was measured in vitro, and the results demonstrated that the.lipophilic moiety size was strictly limited in gabapentinoids, in which conformationally rigid bicylo[3.2.0]heptane/heptene.with a cis-fusion was the most preferred structure. In contrast, monocyclic cyclobutane was associated with a markedly.decreased binding affinity except in 4 (IC50 = 15.2 nM), in which the substituents could mimic the rigid conformation of.bicylo[3.2.0]heptane/heptene; heteroatoms in the lipophilic moiety were detrimental to the binding affinity (2,.IC50 > 729 nM). The SAR findings obtained in the present study will be valuable for designing novel gabapentinoid.drugs to treat chronic neuropathic pain in the future.