Discovery and Optimization of a Monodisulfide Conotoxin Defines a Potent and Selective α9α10 nAChR Blocker with Analgesic Efficacy

The α9α10 nicotinic acetylcholine receptor (nAChR) is a promising therapeutic target for neuropathic pain. In this work, we report the discovery of a monodisulfide-bridged conotoxin from a transcriptome database that acts as a potent pore blocker of the α9α10 nAChR. Structure-activity relationship studies yielded a peptide analogue with ∼2-fold increase in inhibitory potency (IC₅₀ ≈ 17 nM vs 32 nM for wild-type Qc-037) and dramatically improved subtype selectivity: both [M16R] and [F19R] exhibited ∼100-fold selectivity for α9α10 over α7 nAChR and ∼50- to 100-fold selectivity over α4β2 nAChR. In a rat model of oxaliplatin-induced cold allodynia, the optimized analogues M16R and F19R exhibited pronounced in vivo analgesic efficacy. This study not only identifies a novel mechanistic class of α9α10 nAChR inhibitor but also provides promising lead compounds for treating chemotherapy-induced neuropathic pain.