Journal article
Authors list: Andleeb, Hina; Papke, Roger L.; Stokes, Clare; Richter, Katrin; Herz, Sara M.; Chiang, Ka; Kanumuri, Siva R. Raju; Sharma, Abhisheak; Damaj, M. Imad; Grau, Veronika; Horenstein, Nicole A.; Thakur, Ganesh A.
Publication year: 2024
Pages: 8642-8666
Journal: Journal of Medicinal Chemistry
Volume number: 67
Issue number: 11
ISSN: 0022-2623
eISSN: 1520-4804
Open access status: Hybrid
DOI Link: https://doi.org/10.1021/acs.jmedchem.3c02429
Publisher: American Chemical Society
Abstract:
There is an urgent need for nonopioid treatments for chronic and neuropathic pain to provide effective alternatives amid the escalating opioid crisis. This study introduces novel compounds targeting the alpha 9 nicotinic acetylcholine receptor (nAChR) subunit, which is crucial for pain regulation, inflammation, and inner ear functions. Specifically, it identifies novel substituted carbamoyl/amido/heteroaryl dialkylpiperazinium iodides as potent agonists selective for human alpha 9 and alpha 9 alpha 10 over alpha 7 nAChRs, particularly compounds 3f, 3h, and 3j. Compound 3h (GAT2711) demonstrated a 230 nM potency as a full agonist at alpha 9 nAChRs, being 340-fold selective over alpha 7. Compound 3c was 10-fold selective for alpha 9 alpha 10 over alpha 9 nAChR. Compounds 2, 3f, and 3h inhibited ATP-induced interleukin-1 beta release in THP-1 cells. The analgesic activity of 3h was fully retained in alpha 7 knockout mice, suggesting that analgesic effects were potentially mediated through alpha 9* nAChRs. Our findings provide a blueprint for developing alpha 9*-specific therapeutics for pain.
Citation Styles
Harvard Citation style: Andleeb, H., Papke, R., Stokes, C., Richter, K., Herz, S., Chiang, K., et al. (2024) Explorations of Agonist Selectivity for the α9*nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation, Journal of Medicinal Chemistry, 67(11), pp. 8642-8666. https://doi.org/10.1021/acs.jmedchem.3c02429
APA Citation style: Andleeb, H., Papke, R., Stokes, C., Richter, K., Herz, S., Chiang, K., Kanumuri, S., Sharma, A., Damaj, M., Grau, V., Horenstein, N., & Thakur, G. (2024). Explorations of Agonist Selectivity for the α9*nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation. Journal of Medicinal Chemistry. 67(11), 8642-8666. https://doi.org/10.1021/acs.jmedchem.3c02429
Keywords
ALPHA-9; CONOTOXIN; NICOTINIC ACETYLCHOLINE-RECEPTORS; RGIA
