Novel positive allosteric modulators of the human α7 nicotinic acetylcholine receptor

Hugo R. Arias, Ruo Xu Gu, Dominik Feuerbach, Bao Bao Guo, Yong Ye, Dong Qing Wei

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The pharmacological activity of a series of novel amide derivatives was characterized on several nicotinic acetylcholine receptors (AChRs). Ca 2+ influx results indicate that these compounds are not agonists of the human (h) α4β2, α3β4, α7, and α1β1- 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.

Original languageEnglish
Pages (from-to)5263-5278
Number of pages16
JournalBiochemistry
Volume50
Issue number23
DOIs
StatePublished - 14 Jun 2011
Externally publishedYes

Fingerprint

Nicotinic Receptors
Cholinergic Receptors
Modulators
epibatidine
Amides
Binding Sites
Torpedo
Phencyclidine
Imipramine
Molecular Dynamics Simulation
Ion Channels
Molecular dynamics
Hydrogen
Hydrogen bonds
Pharmacology
Derivatives

Cite this

Arias, Hugo R. ; Gu, Ruo Xu ; Feuerbach, Dominik ; Guo, Bao Bao ; Ye, Yong ; Wei, Dong Qing. / Novel positive allosteric modulators of the human α7 nicotinic acetylcholine receptor. In: Biochemistry. 2011 ; Vol. 50, No. 23. pp. 5263-5278.
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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, Yong; Wei, Dong Qing.

In: Biochemistry, Vol. 50, No. 23, 14.06.2011, p. 5263-5278.

Research output: Contribution to journalArticle

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