Subnanomolar Affinity and Selective Antagonism at alpha 7 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 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.