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
(2), and its styryl-modified analogues 21 and 22, were identified as lead compounds from a series
targeting
human α9α10, α9, and α7 nicotinic acetylcholine
receptors (nAChRs). Compounds 2 and 21 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 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-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.