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Dual Allosteric Modulators of Neuronal Nicotinic‐Acetylcholine and GABA‐A Receptors
Author(s) -
Gee Kelvin W,
Johnstone Timothy,
Hogenkamp Derk J,
Yoshimura Ryan,
Whittemore Edward R,
Gu Zhenglin,
Yakel Jerrel
Publication year - 2010
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.24.1_supplement.579.5
Subject(s) - allosteric regulation , long term potentiation , neuroscience , nicotinic agonist , gabaa receptor , chemistry , allosteric modulator , acetylcholine receptor , stimulation , receptor , tetanic stimulation , biology , biochemistry
Chemically induced LTP recorded in the CA1 hippocampal region can be induced by simultaneous activation of α7 nACh and inhibition of GABAA α5 receptors. This effect can be replicated by co‐applying molecules that exhibit similar activities at either receptor but not when each is applied alone. Our lab has designed an allosteric modulator that simultaneously modulates γ‐aminobutyric acid‐A (GABA A ) α5 AND α7 neuronal nicotinic‐acetylcholine receptors (nAChRs). This molecule designated 522‐054 is a proposed lead molecule for treating Alzheimer's disease with putative cognition enhancing properties derived from modulation of both GABA A and nAChRs. 522‐054 is a positive allosteric modulator of α7 nAChRs and negative allosteric modulator of GABA A α5 receptors. 522‐054 enhances CA1 hippocampal output after mossy fiber stimulation and enhances CA1 EPSCs to the point of LTP like that observed following high frequency tetanic stimulation. 522‐054 evoked LTP in CA1 region is differentially blocked by α7 nAChR or GABA A α5 receptor antagonism. In the radial arm maze, the compound enhances cognition as measured by working memory errors and % correct performance.