Subnanomolar Affinity
and Selective Antagonism at
α7 Nicotinic Receptor by Combined Modifications of 2‑Triethylammonium
Ethyl Ether of 4‑Stilbenol (MG624)
posted on 2022-12-17, 03:03authored byFrancesco Bavo, Marco Pallavicini, Susanna Pucci, Rebecca Appiani, Alessandro Giraudo, Hyoungil Oh, Dana L. Kneisley, Brek Eaton, Linda Lucero, Cecilia Gotti, Francesco Clementi, Paul Whiteaker, Cristiano Bolchi
Modifications of
the cationic head and the ethylene linker of 2-(triethylammonium)ethyl
ether of 4-stilbenol (MG624) have been proved to produce selective
α9*-nAChR antagonism devoid of any effect on the α7-subtype.
Here, single structural changes at the styryl portion of MG624 lead
to prevailing α7-nAChR antagonism without abolishing α9*-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 α7-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 α7-nAChR affinity
of MG624 (2), was a winning strategy. The resulting hybrid 33 had a subnanomolar α7-nAChR affinity and was a potent
and selective α7-nAChR antagonist, producing at the α7-,
but not at the α9*-nAChR, a profound loss of subsequent ACh
function.