02001nas a2200253   4500008004100000022001400041245015400055210007000209260000900279300001600288490000700304520110100311100002401412700001801436700001701454700002001471700002301491700002001514700001901534700002301553700002101576700002201597856012801619       2025                        eng d  a0022-262300aDual agonist/antagonist modulation of α9-containing nicotinic acetylcholine receptors by 2-ammoniumethyl ethers of stilbenol and stilbenol analogues0 aDual agonistantagonist modulation of α9containing nicotinic acet  cDEC   a26099-261200 v683 a<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>
1 aGiraudo, Alessandro1 aTae, Han-Shen1 aHung, Andrew1 aRichter, Katrin1 aShivankar, Bhavana1 aArmano, Edoardo1 aGrau, Veronika1 aPallavicini, Marco1 aAdams, David, J.1 aBolchi, Cristiano  uhttps://library.ncl.res.in/content/dual-agonistantagonist-modulation-%CE%B19-containing-nicotinic-acetylcholine-receptors-2