Novel Positive Allosteric Modulators of the Human α7 Nicotinic Acetylcholine Receptor

• Published in: Biochemistry (Easton) Vol. 50; no. 23; pp. 5263 - 5278
• Main Authors: Arias, Hugo R, Gu, Ruo-Xu, Feuerbach, Dominik, Guo, Bao-Bao, Ye, Yong, Wei, Dong-Qing
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.06.2011
• Subjects: Allosteric Regulation; alpha7 Nicotinic Acetylcholine Receptor; Animals; Binding Sites; Cells, Cultured; Humans; Hydrogen Bonding; Molecular Dynamics Simulation; Protein Conformation; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - metabolism; Torpedo - metabolism
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi102001m

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) α4β2, α3β4, α7, and α1β1γδ AChRs; compounds 2–4 are specific positive allosteric modulators (PAMs) of hα7 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 [3H]methyllycaconitine but enhance binding of [3H]epibatidine to hα7 AChRs, indicating that these compounds do not directly, but allosterically, interact with the hα7 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 hα4β2 and hα3β4 AChRs. Molecular dynamics and docking results suggest that the binding site for compounds 2–4 is mainly located in the inner β-sheet of the hα7−α7 interface, ∼12 Å from the agonist locus. Hydrogen bond interactions between the amide group of the PAMs and the hα7 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.