Open AccessDiscovery of Methylene Thioacetal-Incorporated α-RgIA Analogues as Potent and Stable Antagonists of the Human α9α10 Nicotinic Acetylcholine Receptor for the Treatment of Neuropathic Pain
Author(s) -
Nan Zheng,
Sean Christensen,
Cheryl Dowell,
Landa Purushottam,
Jack J. Skalicky,
J. Michael McIntosh,
Danny HungChieh Chou
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00802
Subject(s) - chemistry , thioacetal , nicotinic agonist , pharmacology , neuropathic pain , acetylcholine receptor , nicotinic antagonist , in vivo , receptor , stereochemistry , biochemistry , medicine , microbiology and biotechnology , acetal , biology
α9-Containing nicotinic acetylcholine receptors (nAChRs) are key targets for the treatment of neuropathic pain. α-Conotoxin RgIA4 is a peptide antagonist of human α9α10 nAChRs with high selectivity. However, structural rearrangement reveals a potential liability for clinical applications. We herein report our designer RgIA analogues stabilized by methylene thioacetal as nonopioid analgesic agents. We demonstrate that replacing disulfide loop I [Cys I -Cys III ] with methylene thioacetal in the RgIA skeleton results in activity loss, whereas substitution of loop II [Cys II -Cys IV ] can be accommodated. The lead molecule, RgIA-5524, exhibits highly selective inhibition of α9α10 nAChRs with an IC 50 of 0.9 nM and much reduced degradation in human serum. In vivo studies showed that RgIA-5524 relieves chemotherapy-induced neuropathic pain in wild type but not α9 knockout mouse models, demonstrating that α9-containing nAChRs are necessary for the therapeutic effects. This work highlights the application of methylene thioacetal as a disulfide surrogate in conotoxin-based, disulfide-rich peptide drugs.