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Cognitive improvements in a mouse model with substituted 1,2,3-triazole agonists for nicotinic acetylcholine receptors

Academic Article
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Overview

authors

  • Arunrungichian, K.
  • Boonyarat, C.
  • Fokin, Valery
  • Taylor, P.
  • Vajragupta, O.

publication date

  • 2015

journal

  • ACS Chemical Neuroscience  Journal

abstract

  • The α7 nicotinic acetylcholine receptor (nAChR) is a recognized drug target for dementias of aging and certain developmental disorders. Two selective and potent α7-nAChR agonists, winnowed from a list of 43 compounds characterized in a companion article (DOI: 10.1021/acschemneuro.5b00058), 5-((quinuclid-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indole (IND8) and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (QND8), were evaluated for cognitive improvement in both short- and long-term memory. Tacrine, a centrally active acetylcholinesterase inhibitor, and PNU-282987, a congeneric α7 nAChR agonist, were employed as reference standards. Three behavioral tests, modified Y-maze, object recognition test (ORT), and water maze, were performed in scopolamine-induced amnesic mice. Intraperitoneal injection of these two compounds significantly improved the cognitive impairment in a modified Y-maze test (5 μmol/kg for IND8 and 10 μmol/kg for QND8), ORT (10 μmol/kg), and water maze test (25 μmol/kg). For delay induced memory deficit or natural memory loss in mice, IND8 and QND8 at 10 μmol/kg were able to enhance memory comparable to PNU-282987 when evaluated using ORT time delay model. Cognitive enhancement of IND8 and QND8 was mediated through α7-nAChRs as evidenced by its complete abolition after pretreatment with a selective α7-nAChR antagonist, methyllycaconitine. These data demonstrate that IND8 and QND8 and their congeners are potential candidates for treatment of cognitive disorders, and the substituted triazole series formed by cycloaddition of alkynes and azides warrant further preclinical optimization.

subject areas

  • Animals
  • Benzamides
  • Bicyclo Compounds
  • Cholinesterase Inhibitors
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Humans
  • Injections, Intraperitoneal
  • Male
  • Maze Learning
  • Memory Disorders
  • Mice, Inbred ICR
  • Models, Chemical
  • Motor Activity
  • Nicotinic Agonists
  • Nootropic Agents
  • Recognition (Psychology)
  • Scopolamine Hydrobromide
  • Tacrine
  • alpha7 Nicotinic Acetylcholine Receptor
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Identity

International Standard Serial Number (ISSN)

  • 1948-7193

Digital Object Identifier (DOI)

  • 10.1021/acschemneuro.5b00059

PubMed ID

  • 25978789
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Additional Document Info

start page

  • 1331

end page

  • 1340

volume

  • 6

issue

  • 8

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