A novel dihydro-pyrazolo(3,4d)(1,2,4)triazolo(1,5a)pyrimidin-4-one (AJ23) is an antagonist at adenosine A(1) receptors and enhances consolidation of step-down avoidance

Alan L Harvey, Louise C Young, Edgar Kornisiuk, Marina Snitcofsky, Natalia Colettis, Carlos Blanco, Diana Jerusalinsky, Andrew G Jamieson, Richard C Hartley, Trevor W Stone

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Adenosine A(1) receptor antagonists are of potential value in the treatment of cognitive dysfunction. We have developed compound AJ23 (7-methyl-1-phenyl-1,8-dihydro-pyrazolo-(3,4d)(1,2,4)-triazolo(1,5a)-pyrimidin-4-one) as a novel, non-xanthine based antagonist at A(1) receptors. It has micromolar affinity at human A(1) receptors with a 45-fold selectivity for A(1) over A(2A) receptors and little affinity for many other receptors and transporters tested in a screening panel. AJ23 blocks A(1) receptors in the rat hippocampus, increasing the baseline size of excitatory post-synaptic potentials and blocking the inhibitory effects of adenosine. When administered directly into the rodent hippocampus this compound improves consolidation in a step-down avoidance learning task. The results suggest that AJ23 or derivatives may represent possible leads for further chemical development towards a chemically novel group of antagonists at A(1) receptors with potential value as cognitive enhancers.
Original languageEnglish
Pages (from-to)184-191
Number of pages8
JournalBehavioural Brain Research
Volume234
Issue number2
DOIs
Publication statusPublished - 1 Oct 2012

Keywords

  • animals
  • drug interactions
  • analysis of variance
  • HEK293 Cells
  • humans
  • electric stimulation
  • avoidance learning
  • rats
  • CA1 region, hippocampal
  • pyrimidines
  • CHO cells
  • retention (psychology)
  • triazoles
  • male
  • inhibition (Psychology)
  • drug administration schedule
  • cricetulus
  • dose-response relationship, drug
  • triazines
  • xanthines
  • heterocyclic compounds, 3-Ring
  • protein binding
  • structure-activity relationship
  • purinergic P1 receptor antagonists
  • tritium
  • excitatory postsynaptic potentials
  • rats, wistar
  • adenosine
  • cricetinae
  • reaction time

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