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.