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

  • J Med Chem. 2025 Dec 25;68(24):26099-26120. doi: 10.1021/acs.jmedchem.5c02173.
Alessandro Giraudo  1 ,  Han-Shen Tae  2 ,  Andrew Hung  3 ,  Katrin Richter  4  5 ,  Bhavana Shivankar  3  6 ,  Edoardo Armano  1 ,  Veronika Grau  4 ,  Marco Pallavicini  1 ,  David J Adams  2 ,  Cristiano Bolchi  1
Affiliations
  • 1. Department of Pharmaceutical Sciences, Università Degli Studi of Milan, Milano I-20133, Italy.
  • 2. Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia.
  • 3. School of Science, STEM College, RMIT University, Melbourne, Victoria 3001, Australia.
  • 4. Department of General and Thoracic Surgery, Laboratory of Experimental Surgery, Justus-Liebig-University, German Center for Lung Research [DZL], Cardio-Pulmonary Institute [CPI], Giessen 35385, Germany.
  • 5. Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach 53359, Germany.
  • 6. Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory, Pune 41108, India.
PMID: 41358472 DOI: 10.1021/acs.jmedchem.5c02173
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 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.

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