Study on structure-activity relationship (SAR) of simplified mirogabalin derivatives as voltage-gated calcium channel α2δ ligands for the treatment of chronic neuropathic pain

摘要

A clinical therapy for chronic neuropathic pain is urgently needed, and the voltage-gated calcium channel (VGCC) alpha 2 delta subunit is among the most promising therapeutic targets. To intensively explore the structure-activity relationship (SAR) of the lipophilic moiety in VGCC alpha 2 delta subunit ligands (gabapentinoids), we designed and synthesized 11 bicyclic and monocyclic derivatives based on mirogabalin, a third-generation VGCC alpha 2 delta subunit ligand. The competitive binding of the synthesized compounds to the human VGCC alpha 2 delta-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=15.2nM), 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>729nM). The SAR findings obtained in the present study will be valuable for designing novel gabapentinoid drugs to treat chronic neuropathic pain in the future. @@@ [Graphical ]

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