Novel Positive Allosteric Modulators of the Human α7 Nicotinic Acetylcholine Receptor

The pharmacological activity of a series of novel amide derivatives was characterized on several nicotinic acetylcholine receptors (AChRs). Ca2+ influx results indicate that these compounds are not agonists of the human (h) alpha 4 beta 2, alpha 3 beta 4, alpha 7, and alpha 1 beta 1 gamma delta AChRs; compounds 2-4 are specific positive allosteric modulators (PAMs) of h alpha 7 AChRs, whereas compounds 1-4, 7, and 12 are noncompetitive antagonists of the other AChRs. Radioligand binding results indicate that PAMs do not inhibit binding of [H-3]methyllycaconitine but enhance binding of [H-3]epibatidine to h alpha 7 AChRs, indicating that these compounds do not directly, but allosterically, interact with the h alpha 7 agonist sites. Additional competition binding results indicate that the antagonistic action mediated by these compounds is produced by direct interaction with neither the phencyclidine site in the Torpedo AChR ion channel nor the imipramine and the agonist sites in the h alpha 4 beta 2 and h alpha 3 beta 4 AChRs. Molecular dynamics and docking results suggest that the binding site for compounds 2-4 is mainly located in the inner beta-sheet of the h alpha 7-alpha 7 interface, similar to 12 angstrom from the agonist locus. Hydrogen bond interactions between the amide group of the PAMs and the h alpha 7 AChR binding site are found to be critical for their activity. The dual PAM and antagonistic activities elicited by compounds 2-4 might be therapeutically important.