Discovery 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
| Autor: | Jack J. Skalicky, Cheryl Dowell, Sean Christensen, Landa Purushottam, Danny Hung-Chieh Chou, Nan Zheng, J. Michael McIntosh |
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| Rok vydání: | 2021 |
| Předmět: |
Thioacetal
Peptide Receptors Nicotinic Pharmacology 01 natural sciences Article Structure-Activity Relationship 03 medical and health sciences Acetals In vivo Drug Discovery Humans Sulfhydryl Compounds 030304 developmental biology Acetylcholine receptor chemistry.chemical_classification 0303 health sciences Dose-Response Relationship Drug Molecular Structure Chemistry Antagonist 0104 chemical sciences 010404 medicinal & biomolecular chemistry Nicotinic acetylcholine receptor Nicotinic agonist Neuropathic pain Neuralgia Molecular Medicine Conotoxins |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00802 |
| Popis: | The 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 non-opioid 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 disulfide surrogate in conotoxin-based, disulfide-rich peptide drugs. |
| Databáze: | OpenAIRE |
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