From 2‑Triethylammonium Ethyl Ether of 4‑Stilbenol (MG624) to Selective Small-Molecule Antagonists of Human α9α10 Nicotinic Receptor by Modifications at the Ammonium Ethyl Residue

Nicotinic acetylcholine receptors containing α9
subunits
(α9*-nAChRs) are potential druggable targets arousing great
interest for pain treatment alternative to opioids. Nonpeptidic small
molecules selectively acting as α9*-nAChRs antagonists still
remain an unattained goal. Here, through modifications of the cationic
head and the ethylene linker, we have converted the 2-triethylammonium
ethyl ether of 4-stilbenol (MG624), a well-known α7- and α9*-nAChRs
antagonist, into some selective antagonists of human α9*-nAChR.
Among these, the compound with cyclohexyldimethylammonium head (7) stands out for having no α7-nAChR agonist or antagonist
effect along with very low affinity at both α7- and α3β4-nAChRs.
At supra-micromolar concentrations, 7 and the other selective
α9* antagonists behaved as partial agonists at α9*-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.