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.
LanguageEnglish
Pages184-191
Number of pages8
JournalBehavioural Brain Research
Volume234
Issue number2
DOIs
Publication statusPublished - 1 Oct 2012

Fingerprint

Adenosine
Hippocampus
Nootropic Agents
Avoidance Learning
Synaptic Potentials
Rodentia
Cognitive Dysfunction
7-methyl-1-phenyl-1,8-dihydropyrazolo(3,4d)(1,2,4)-triazolo(1,5a)pyrimidin-4-one

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

Cite this

Harvey, Alan L ; Young, Louise C ; Kornisiuk, Edgar ; Snitcofsky, Marina ; Colettis, Natalia ; Blanco, Carlos ; Jerusalinsky, Diana ; Jamieson, Andrew G ; Hartley, Richard C ; Stone, Trevor W. / 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. In: Behavioural Brain Research. 2012 ; Vol. 234, No. 2. pp. 184-191.
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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.",
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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. / Harvey, Alan L; Young, Louise C; Kornisiuk, Edgar; Snitcofsky, Marina; Colettis, Natalia; Blanco, Carlos; Jerusalinsky, Diana; Jamieson, Andrew G; Hartley, Richard C; Stone, Trevor W.

In: Behavioural Brain Research, Vol. 234, No. 2, 01.10.2012, p. 184-191.

Research output: Contribution to journalArticle

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AU - Kornisiuk, Edgar

AU - Snitcofsky, Marina

AU - Colettis, Natalia

AU - Blanco, Carlos

AU - Jerusalinsky, Diana

AU - Jamieson, Andrew G

AU - Hartley, Richard C

AU - Stone, Trevor W

N1 - Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

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N2 - 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.

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KW - electric stimulation

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KW - pyrimidines

KW - CHO cells

KW - retention (psychology)

KW - triazoles

KW - male

KW - inhibition (Psychology)

KW - drug administration schedule

KW - cricetulus

KW - dose-response relationship, drug

KW - triazines

KW - xanthines

KW - heterocyclic compounds, 3-Ring

KW - protein binding

KW - structure-activity relationship

KW - purinergic P1 receptor antagonists

KW - tritium

KW - excitatory postsynaptic potentials

KW - rats, wistar

KW - adenosine

KW - cricetinae

KW - reaction time

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