Positive allosteric modulators of α7 nicotinic acetylcholine receptors affect neither the function of other ligand- and voltage-gated ion channels and acetylcholinesterase, nor β-amyloid content.

Abstract

The activity of positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (AChRs), including 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), 3-furan-2-yl-N-o-tolylacrylamide (PAM-3), and 3-furan-2-yl-N-phenylacrylamide (PAM-4), was tested on a variety of ligand- [i.e., human (h) α7, rat (r) α9α10, hα3-containing AChRs, mouse (m) 5-HT3AR, and several glutamate receptors (GluRs)] and voltage-gated (i.e., sodium and potassium) ion channels, as well as on acetylcholinesterase (AChE) and β-amyloid (Aβ) content. The functional results indicate that PAM-2 inhibits hα3-containing AChRs (IC50=26±6μM) with higher potency than that for NR1aNR2B and NR1aNR2A, two NMDA-sensitive GluRs. PAM-2 affects neither the activity of m5-HT3ARs, GluR5/KA2 (a kainate-sensitive GluR), nor AChE, and PAM-4 does not affect agonist-activated rα9α10 AChRs. Relevant clinical concentrations of PAM-2-4 do not inhibit Nav1.2 and Kv3.1 ion channels. These PAMs slightly enhance the activity of GluR1 and GluR2, two AMPA-sensitive GluRs. PAM-2 does not change the levels of Aβ42 in an Alzheimer's disease mouse model (i.e., 5XFAD). The molecular docking and dynamics results using the hα7 model suggest that the active sites for PAM-2 include the intrasubunit (i.e., PNU-120596 locus) and intersubunit sites. These results support our previous study showing that these PAMs are selective for the α7 AChR, and clarify that the procognitive/promnesic/antidepressant activity of PAM-2 is not mediated by other targets.

• Authors: Hugo R Arias, Federica Ravazzini, Katarzyna M Targowska-Duda, Agnieszka A Kaczor, Dominik Feuerbach, Juan C Boffi, Piotr Draczkowski, Dirk Montag, Brandon M Brown, Ana Belén Elgoyhen, Krzysztof Jozwiak, Giulia Puia
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 76 Pg. 19-30 (07 2016) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 27129924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Ligand-Gated Ion Channels
• Peptide Fragments
• alpha7 Nicotinic Acetylcholine Receptor
• amyloid beta-protein (1-42)
• Acetylcholinesterase

Topics

• Acetylcholinesterase (genetics, metabolism)
• Allosteric Regulation (drug effects)
• Amyloid beta-Peptides (genetics, metabolism)
• Animals
• Cell Line, Tumor
• Humans
• Ligand-Gated Ion Channels (genetics, metabolism)
• Mice
• Peptide Fragments (genetics, metabolism)
• Rats
• alpha7 Nicotinic Acetylcholine Receptor (agonists, genetics, metabolism)