title: 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.
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.
authors: Institute of Pharmacy and Biological Sciences, University of Strathclyde, Glasgow, G4 0NR, UK.
authors: Alan L
authors: AL
authors: Harvey
authors: Louise C
authors: LC
authors: Young
authors: Edgar
authors: E
authors: Kornisiuk
authors: Marina
authors: M
authors: Snitcofsky
authors: Natalia
authors: N
authors: Colettis
authors: Carlos
authors: C
authors: Blanco
authors: Diana
authors: D
authors: Jerusalinsky
authors: Andrew G
authors: AG
authors: Jamieson
authors: Richard C
authors: RC
authors: Hartley
authors: Trevor W
authors: TW
authors: Stone
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D056547:CA1 Region, Hippocampal / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007266:Inhibition, Psychological; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D012153:Retention, Psychology / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000493:pharmacokinetics; D014230:Triazoles / Q000493:pharmacokinetics; D014316:Tritium / Q000493:pharmacokinetics; D014970:Xanthines / Q000493:pharmacokinetics
chemical_list: C577573:7-methyl-1-phenyl-1,8-dihydropyrazolo(3,4d)(1,2,4)-triazolo(1,5a)pyrimidin-4-one; D006575:Heterocyclic Compounds, 3-Ring; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; D014316:Tritium; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine