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Novel Positive Allosteric Modulators of the Human α7 Nicotinic Acetylcholine Receptor

Arias, Hugo R, Gu, Ruo-Xu, Feuerbach, Dominik, Guo, Bao-Bao, Ye, Young and Wei, Dong-Qing (2011) Novel Positive Allosteric Modulators of the Human α7 Nicotinic Acetylcholine Receptor. Biochemistry.


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, but compounds 2-4 are specific positive allosteric modulators (PAMs) of hα7 AChRs, whereas compounds 1-4, 7, and 12 are moderate antagonists of the other AChRs. Radioligand binding results indicate that these pharmacological actions are not produced by interactions to the agonist or the phencyclidine/imipramine site. Molecular dynamics and docking results suggest that the binding site for compounds 2-4 is mainly located in the inner -sheet of the hα7/α7 interface at a minimum distance of ~10 Å from the agonist locus. The amide group forms hydrogen bonds to both (+) and (-) faces, whereas the short alkyl group found in compounds 1 and 6-8 precludes this critical hydrogen bonding, and the larger molecular volumes of compounds 5 and 9-12 produce steric hindrance. The hα7 AChR specificity is ascribed to the absence of the hydrogen bond at the (-) face and on a naturally occurring smaller pocket at the hα4/β2 and hα3/β4 interfaces. The dual PAM and antagonistic activities elicited by compounds 2-4 could be important for the treatment of Alzheimer’s disease, drug addiction, and depression.

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46