Neuropathic pain (NP) is a complex symptom related to the nerve damage. The discovery of new drugs for treating chronic NP has been continuing for several decades, while more progress is still needed to be made 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.
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. To analyze the structure-activity relationship (SAR) of gabapentinoids to facilitate the future design of structurally novel therapeutic agents targeting VGCC α2δ subunit.
We searched PubMed Central, Embase, Cochrane Library, Web of Science, Scopus and Espacenet for the literature and patents of 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 were analyzed by pharmacophore modeling using Phase module in Schrödinger suite.
A variety of gabapentinoids were identified as VGCC α2δ ligands that have ever been under development for the treatment of chronic NP. Among them, four gabapentinoids are marketed, one is at the active late clinical trials, and eight have been discontinued. Pharmacophore models were generated by using Phase module in Schrödinger suite, and common pharmacophores were predicted based on pharmacophoric features and analyzed.
The latest progress of the discovery and development of gabapentinoids for the treatment of chronic NP was reviewed. Moreover, the structure-activity relationship (SAR) of gabapentinoids is analyzed by pharmacophore modeling, which will be valuable for the future design of structurally novel therapeutic agents targeting VGCC α2δ subunit.

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