Journal
BEHAVIOURAL BRAIN RESEARCH
Volume 234, Issue 2, Pages 184-191Publisher
ELSEVIER
DOI: 10.1016/j.bbr.2012.06.023
Keywords
Adenosine; A(1) receptors; Non-xanthine antagonists; Purine receptors; Hippocampus
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Funding
- Proof of Concept award from Scottish Enterprise
- Synergy Fund of the Universities of Glasgow and Strathclyde
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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 A1 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. Crown Copyright (C) 2012 Published by Elsevier B.V. All rights reserved.
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