| First Author | Arias HR | Year | 2016 |
| Journal | Int J Biochem Cell Biol | Volume | 76 |
| Pages | 19-30 | PubMed ID | 27129924 |
| Mgi Jnum | J:319226 | Mgi Id | MGI:6863235 |
| Doi | 10.1016/j.biocel.2016.04.015 | Citation | Arias HR, et al. (2016) Positive allosteric modulators of alpha7 nicotinic acetylcholine receptors affect neither the function of other ligand- and voltage-gated ion channels and acetylcholinesterase, nor beta-amyloid content. Int J Biochem Cell Biol 76:19-30 |
| abstractText | The activity of positive allosteric modulators (PAMs) of alpha7 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) alpha7, rat (r) alpha9alpha10, halpha3-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 beta-amyloid (Abeta) content. The functional results indicate that PAM-2 inhibits halpha3-containing AChRs (IC50=26+/-6muM) 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 ralpha9alpha10 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 Abeta42 in an Alzheimer's disease mouse model (i.e., 5XFAD). The molecular docking and dynamics results using the halpha7 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 alpha7 AChR, and clarify that the procognitive/promnesic/antidepressant activity of PAM-2 is not mediated by other targets. |
