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Novel positive allosteric modulators of the human α7 nicotinic acetylcholine receptor
Author(s) -
Miller Marc A.,
Gu Ruo-Xu,
Feuerbach Dominik,
Ye Yong,
Wei* Dong-Qing,
Arias Hugo R.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb578
Subject(s) - methyllycaconitine , allosteric regulation , phencyclidine , chemistry , epibatidine , allosteric modulator , nicotinic agonist , nicotinic acetylcholine receptor , pharmacology , acetylcholine receptor , agonist , radioligand , binding site , receptor , stereochemistry , biochemistry , nmda receptor , biology
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 α1β1γδ AChRs; but are specific positive allosteric modulators (PAMs) of hα7 AChRs. Radioligand binding results indicate that PAMs do not inhibit binding of [ 3 H]methyllycaconitine but enhance binding of [ 3 H]epibatidine to hα7 AChRs, indicating that these compounds do not directly, but allosterically, interact with the hα7 agonist sites. 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 these compounds might be therapeutically important in treating diseases such as depression and drug addiction. We thank the National Institute on Drug Abuse (NIDA) for the gift of phencyclidine.