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

ABSTRACT: 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

SUBMITTER: Giraudo A 

PROVIDER: S-EPMC12751000 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature