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Updated: Mar 24, 2026

Intracranial Pharmacotherapy and Pain Assays in Rodents
Published on: April 9, 2019
Discovery and Optimization of a Monodisulfide Conotoxin Defines a Potent and Selective α9α10 nAChR Blocker with
Zhengji Yin1,2, Xue Song1,2, Ying Zhou1,2
1Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
Abstract:
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.
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