Subnanomolar Affinity and Selective Antagonism at alpha 7 Nicotinic Receptor by Combined Modifications of 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624)
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Subnanomolar Affinity and Selective Antagonism at alpha 7 Nicotinic Receptor by Combined Modifications of 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624). / Bavo, Francesco; Pallavicini, Marco; Pucci, Susanna; Appiani, Rebecca; Giraudo, Alessandro; Oh, Hyoungil; Kneisley, Dana L.; Eaton, Brek; Lucero, Linda; Gotti, Cecilia; Clementi, Francesco; Whiteaker, Paul; Bolchi, Cristiano.
I: Journal of Medicinal Chemistry, Bind 66, Nr. 1, 2023, s. 306–332.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Subnanomolar Affinity and Selective Antagonism at alpha 7 Nicotinic Receptor by Combined Modifications of 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624)
AU - Bavo, Francesco
AU - Pallavicini, Marco
AU - Pucci, Susanna
AU - Appiani, Rebecca
AU - Giraudo, Alessandro
AU - Oh, Hyoungil
AU - Kneisley, Dana L.
AU - Eaton, Brek
AU - Lucero, Linda
AU - Gotti, Cecilia
AU - Clementi, Francesco
AU - Whiteaker, Paul
AU - Bolchi, Cristiano
PY - 2023
Y1 - 2023
N2 - Modifications of the cationic head and the ethylene linker of 2(triethylammonium)ethyl ether of 4-stilbenol (MG624) have been proved to produce selective alpha 9*-nAChR antagonism devoid of any effect on the alpha 7-subtype. Here, single structural changes at the styryl portion of MG624 lead to prevailing alpha 7-nAChR antagonism without abolishing alpha 9*-nAChR antagonism. Nevertheless, rigidification of the styryl into an aromatic bicycle, better if including a H-bond donor NH, such as 5-indolyl (31), resulted in higher and more selective alpha 7-nAChR affinity. Hybridization of this modification with the constraint of the 2-triethylammoniumethyloxy portion into (R)-N,N-dimethyl-3-pyrrolidiniumoxy substructure, previously reported as the best modification for the alpha 7-nAChR affinity of MG624 (2), was a winning strategy. The resulting hybrid 33 had a subnanomolar alpha 7-nAChR affinity and was a potent and selective alpha 7-nAChR antagonist, producing at the alpha 7-, but not at the alpha 9*-nAChR, a profound loss of subsequent ACh function.
AB - Modifications of the cationic head and the ethylene linker of 2(triethylammonium)ethyl ether of 4-stilbenol (MG624) have been proved to produce selective alpha 9*-nAChR antagonism devoid of any effect on the alpha 7-subtype. Here, single structural changes at the styryl portion of MG624 lead to prevailing alpha 7-nAChR antagonism without abolishing alpha 9*-nAChR antagonism. Nevertheless, rigidification of the styryl into an aromatic bicycle, better if including a H-bond donor NH, such as 5-indolyl (31), resulted in higher and more selective alpha 7-nAChR affinity. Hybridization of this modification with the constraint of the 2-triethylammoniumethyloxy portion into (R)-N,N-dimethyl-3-pyrrolidiniumoxy substructure, previously reported as the best modification for the alpha 7-nAChR affinity of MG624 (2), was a winning strategy. The resulting hybrid 33 had a subnanomolar alpha 7-nAChR affinity and was a potent and selective alpha 7-nAChR antagonist, producing at the alpha 7-, but not at the alpha 9*-nAChR, a profound loss of subsequent ACh function.
KW - 4-OXYSTILBENE
KW - DERIVATIVES
U2 - 10.1021/acs.jmedchem.2c01256
DO - 10.1021/acs.jmedchem.2c01256
M3 - Journal article
C2 - 36526469
VL - 66
SP - 306
EP - 332
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 1
ER -
ID: 332931733