Artículos de revistas
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
Fecha
2016-07Registro en:
Arias, Hugo R.; Ravazzini, Federica; Targowska Duda, Katarzyna M.; Kaczor, Agnieszka A.; Feuerbach, Dominik; et al.; 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; Pergamon-Elsevier Science Ltd; International Journal of Biochemistry and Cellular Biology; 76; 7-2016; 19-30
1357-2725
CONICET Digital
CONICET
Autor
Arias, Hugo R.
Ravazzini, Federica
Targowska Duda, Katarzyna M.
Kaczor, Agnieszka A.
Feuerbach, Dominik
Boffi, Juan Carlos
Draczkowski, Piotr
Montag, Dirk
Brown, Brandon M.
Elgoyhen, Ana Belen
Jozwiak, Krzysztof
Puia, Giulia
Resumen
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.