Subnanomolar Affinity and Selective Antagonism at α7 Nicotinic Receptor by Combined Modifications of 2‑Triethylammonium Ethyl Ether of 4‑Stilbenol (MG624)

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.