Dual Agonist/Antagonist Modulation of α9-Containing Nicotinic Acetylcholine Receptors by 2-Ammoniumethyl Ethers of Stilbenol and Stilbenol Analogues

2-(Cyclohexyldimethylammoniumethyl)ether of 4-stilbenol (<b>2</b>), and its styryl-modified analogues <b>21</b> and <b>22</b>, were identified as lead compounds from a series targeting human α9α10, α9, and α7 nicotinic acetylcholine receptors (nAChRs). Compounds <b>2</b> and <b>21</b> exhibited potent, and subtype-selective modulation of α9-containing receptors, with low nanomolar IC₅₀ values and dual agonist/antagonist activity in a concentration-dependent manner. In contrast, compound <b>22</b> acted as a selective, pure antagonist. Molecular dynamics (MD) simulations of compound <b>21</b> 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-1β release at nanomolar concentrations. These findings identify α9α10-selective ligands as promising scaffolds for the development of nonopioid analgesics and immunomodulators, with favorable selectivity over α7 nAChRs to minimize CNS-related side effects.