@article {49964,
	title = {Dual agonist/antagonist modulation of α9-containing nicotinic acetylcholine receptors by 2-ammoniumethyl ethers of stilbenol and stilbenol analogues},
	journal = {Journal of Medicinal Chemistry},
	volume = {68},
	year = {2025},
	month = {DEC },
	pages = {26099-26120},
	type = {Article},
	abstract = {<p>
	2-(Cyclohexyldimethylammoniumethyl)ether of 4-stilbenol (2), and its styryl-modified analogues 21 and 22, were identified as lead compounds from a series targeting human alpha 9 alpha 10, alpha 9, and alpha 7 nicotinic acetylcholine receptors (nAChRs). Compounds 2 and 21 exhibited potent, and subtype-selective modulation of alpha 9-containing receptors, with low nanomolar IC50 values and dual agonist/antagonist activity in a concentration-dependent manner. In contrast, compound 22 acted as a selective, pure antagonist. Molecular dynamics (MD) simulations of compound 21 supported a concentration-dependent allosteric mechanism, with orthosteric binding at low concentrations and vestibular site interaction at higher levels. In a human monocytic cell line, all three compounds inhibited ATP-induced IL-1 beta release at nanomolar concentrations. These findings identify alpha 9 alpha 10-selective ligands as promising scaffolds for the development of nonopioid analgesics and immunomodulators, with favorable selectivity over alpha 7 nAChRs to minimize CNS-related side effects.</p>
},
	issn = {0022-2623},
	doi = {10.1021/acs.jmedchem.5c02173},
	author = {Giraudo, Alessandro and Tae, Han-Shen and Hung, Andrew and Richter, Katrin and Shivankar, Bhavana and Armano, Edoardo and Grau, Veronika and Pallavicini, Marco and Adams, David J. and Bolchi, Cristiano}
}
