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

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

Research output: Contribution to journalArticle

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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 ± 6 μM) 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.

Original languageEnglish
Pages (from-to)19-30
Number of pages12
JournalInternational Journal of Biochemistry and Cell Biology
Volume76
DOIs
StatePublished - 1 Jul 2016
Externally publishedYes

Fingerprint

Ligand-Gated Ion Channels
Nicotinic Receptors
Cholinergic Receptors
Acetylcholinesterase
Ion Channels
Amyloid
Modulators
Glutamate Receptors
Ligands
Electric potential
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Acrylamide
Sodium Channels
Kainic Acid
Potassium Channels
N-Methylaspartate
Molecular Dynamics Simulation
Antidepressive Agents
Inhibitory Concentration 50
Catalytic Domain

Keywords

  • Acetylcholinesterase
  • Molecular docking and molecular dynamics
  • Serotonin type 3 and glutamate receptors
  • α7 Nicotinic acetylcholine receptor positive allosteric modulators
  • β-Amyloid

Cite this

Arias, Hugo R. ; Ravazzini, Federica ; Targowska-Duda, Katarzyna M. ; Kaczor, Agnieszka A. ; Feuerbach, Dominik ; Boffi, Juan C. ; Draczkowski, Piotr ; Montag, Dirk ; Brown, Brandon M. ; Elgoyhen, Ana Belén ; Jozwiak, Krzysztof ; Puia, Giulia. / 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. In: International Journal of Biochemistry and Cell Biology. 2016 ; Vol. 76. pp. 19-30.
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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 ± 6 μM) 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.",
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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. / Arias, Hugo R.; Ravazzini, Federica; Targowska-Duda, Katarzyna M.; Kaczor, Agnieszka A.; Feuerbach, Dominik; Boffi, Juan C.; Draczkowski, Piotr; Montag, Dirk; Brown, Brandon M.; Elgoyhen, Ana Belén; Jozwiak, Krzysztof; Puia, Giulia.

In: International Journal of Biochemistry and Cell Biology, Vol. 76, 01.07.2016, p. 19-30.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Arias, Hugo R.

AU - Ravazzini, Federica

AU - Targowska-Duda, Katarzyna M.

AU - Kaczor, Agnieszka A.

AU - Feuerbach, Dominik

AU - Boffi, Juan C.

AU - Draczkowski, Piotr

AU - Montag, Dirk

AU - Brown, Brandon M.

AU - Elgoyhen, Ana Belén

AU - Jozwiak, Krzysztof

AU - Puia, Giulia

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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 ± 6 μM) 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.

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KW - Acetylcholinesterase

KW - Molecular docking and molecular dynamics

KW - Serotonin type 3 and glutamate receptors

KW - α7 Nicotinic acetylcholine receptor positive allosteric modulators

KW - β-Amyloid

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