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

Autor: Giulia Puia, Brandon M. Brown, Piotr Draczkowski, Ana Belén Elgoyhen, Dominik Feuerbach, Juan Carlos Boffi, Federica Ravazzini, Hugo R. Arias, Katarzyna M. Targowska-Duda, Krzysztof Jozwiak, Dirk Montag, Agnieszka A. Kaczor
Rok vydání: 2016
Předmět:
0301 basic medicine
alpha7 Nicotinic Acetylcholine Receptor
Otras Ciencias Biológicas
Allosteric regulation
AMPA receptor
Biochemistry
Ciencias Biológicas
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Allosteric Regulation
stomatognathic system
Cell Line
Tumor
parasitic diseases
Serotonin type 3 and glutamate receptors
Animals
Humans
5-HT receptor
Ion channel
Acetylcholine receptor
Acetylcholinesterase
Molecular docking and molecular dynamics
α7 Nicotinic acetylcholine receptor positive allosteric modulators
β-Amyloid
Cell Biology
Amyloid beta-Peptides
Voltage-gated ion channel
receptores nicotíncos
moduladores alostéricos
Ligand-Gated Ion Channels
Peptide Fragments
Rats
030104 developmental biology
chemistry
embryonic structures
Biophysics
Ligand-gated ion channel
CIENCIAS NATURALES Y EXACTAS
030217 neurology & neurosurgery
Zdroj: The International Journal of Biochemistry & Cell Biology. 76:19-30
ISSN: 1357-2725
DOI: 10.1016/j.biocel.2016.04.015
Popis: tThe activity of positive allosteric modulators (PAMs) of 7 nicotinic acetylcholine receptors (AChRs),including 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), 3-furan-2-yl-N-o-tolylacrylamide (PAM-3), and3-furan-2-yl-N-phenylacrylamide (PAM-4), was tested on a variety of ligand- [i.e., human (h) 7, rat(r) 910, h3-containing AChRs, mouse (m) 5-HT3AR, and several glutamate receptors (GluRs)] andvoltage-gated (i.e., sodium and potassium) ion channels, as well as on acetylcholinesterase (AChE) and-amyloid (A) content. The functional results indicate that PAM-2 inhibits h3-containing AChRs(IC50= 26 ± 6 M) with higher potency than that for NR1aNR2B and NR1aNR2A, two NMDA-sensitiveGluRs. 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 r910 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 andGluR2, two AMPA-sensitive GluRs. PAM-2 does not change the levels of A42in an Alzheimer?s diseasemouse model (i.e., 5XFAD). The molecular docking and dynamics results using the h7 model suggest thatthe active sites for PAM-2 include the intrasubunit (i.e., PNU-120596 locus) and intersubunit sites. Theseresults support our previous study showing that these PAMs are selective for the 7 AChR, and clarifythat the procognitive/promnesic/antidepressant activity of PAM-2 is not mediated by other targets. Fil: Arias, Hugo R.. California Northstate University; Estados Unidos Fil: Ravazzini, Federica. Università Degli Studi Di Modena e Reggio Emilia; Argentina Fil: Targowska Duda, Katarzyna M.. Medical University of Lublin; Polonia Fil: Kaczor, Agnieszka A.. Medical University of Lublin; Polonia Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza Fil: Boffi, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: Draczkowski, Piotr. Medical University of Lublin; Polonia Fil: Montag, Dirk. Leibniz Institute for Neurobiology; Alemania Fil: Brown, Brandon M.. University of California; Estados Unidos Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: Jozwiak, Krzysztof. Medical University of Lublin; Polonia Fil: Puia, Giulia. Università Degli Studi Di Modena e Reggio Emilia; Argentina
Databáze: OpenAIRE
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