From 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624) to Selective Small-Molecule Antagonists of Human alpha 9 alpha 10 Nicotinic Receptor by Modifications at the Ammonium Ethyl Residue

Nicotinic acetylcholine receptors containing alpha 9 subunits (alpha 9*- nAChRs) are potential druggable targets arousing great interest for pain treatment alternative to opioids. Nonpeptidic small molecules selectively acting as alpha 9*- nAChRs antagonists still remain an unattained goal. Here, through modifications of the cationic head and the ethylene linker, we have converted the 2triethylammonium ethyl ether of 4-stilbenol (MG624), a well-known alpha 7-and alpha 9*-nAChRs antagonist, into some selective antagonists of human alpha 9*-nAChR. Among these, the compound with cyclohexyldimethylammonium head (7) stands out for having no alpha 7-nAChR agonist or antagonist effect along with very low affinity at both alpha 7-and alpha 3 beta 4-nAChRs. At supra-micromolar concentrations, 7 and the other selective alpha 9* antagonists behaved as partial agonists at alpha 9*-nAChRs with a very brief response, followed by rebound current once the application is stopped and the channel is disengaged. The small or null postapplication activity of ACh seems to be related to the slow recovery of the rebound current.