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
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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. / Bavo, Francesco; Pallavicini, Marco; Pucci, Susanna; Appiani, Rebecca; Giraudo, Alessandro; Eaton, Brek; Lucero, Linda; Gotti, Cecilia; Moretti, Milena; Whiteaker, Paul; Bolchi, Cristiano.
In: Journal of Medicinal Chemistry, Vol. 65, No. 14, 2022, p. 10079-10097.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - 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
AU - Bavo, Francesco
AU - Pallavicini, Marco
AU - Pucci, Susanna
AU - Appiani, Rebecca
AU - Giraudo, Alessandro
AU - Eaton, Brek
AU - Lucero, Linda
AU - Gotti, Cecilia
AU - Moretti, Milena
AU - Whiteaker, Paul
AU - Bolchi, Cristiano
N1 - Funding Information: This work was supported by Università degli Studi of Milan.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1021/acs.jmedchem.2c00746
DO - 10.1021/acs.jmedchem.2c00746
M3 - Journal article
C2 - 35834819
AN - SCOPUS:85135378044
VL - 65
SP - 10079
EP - 10097
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 14
ER -
ID: 318514694