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

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 (IC 50 = 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 , IC 50 > 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. Graphical abstract