title: 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.affiliation: Department of Medical Education, California Northstate University College of Medicine, Elk Grove, CA, USA. Electronic address: hugo.arias@cnsu.edu.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Arias
authors.affiliation: Department of Life Science, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Ravazzini
authors.affiliation: Department of Biopharmacy, Medical University of Lublin, Lublin, Poland.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Targowska-Duda
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Medical University of Lublin, Lublin, Poland; Department of Pharmaceutical Chemistry, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kaczor
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N. Torres, CONICET, Buenos Aires, Argentina.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Boffi
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Medical University of Lublin, Lublin, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Draczkowski
authors.affiliation: Neurogenetics Special Laboratory, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Montag
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Brown
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N. Torres, CONICET, Buenos Aires, Argentina.
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Elgoyhen
authors.affiliation: Department of Biopharmacy, Medical University of Lublin, Lublin, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.affiliation: Department of Life Science, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Puia
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000494:Allosteric Regulation / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D058446:Ligand-Gated Ion Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D058446:Ligand-Gated Ion Channels; D010446:Peptide Fragments; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Molecular docking and molecular dynamics; Serotonin type 3 and glutamate receptors; α7 Nicotinic acetylcholine receptor positive allosteric modulators; β-Amyloid