Abstract
The synthesis and preliminary in vitro evaluation of five metabolites of the A2A antagonist ST1535 (1) are reported. The metabolites, originating in vivo from enzymatic oxidation of the 2-butyl group of the parent compound, were synthesized from 6-chloro-2-iodo-9-methyl-9H-purine (2) by selective C-C bond formation via halogen/magnesium exchange reaction and/or palladium-catalyzed reactions. The metabolites behaved in vitro as antagonist ligands of cloned human A2A receptor with affinities (Ki 7.5-53 nM) comparable to that of compound 1 (Ki 10.7 nM), thus showing that the long duration of action of 1 could be in part due to its metabolites. General behavior after oral administration in mice was also analyzed.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives*
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Adenine / chemical synthesis
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Adenine / metabolism
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Adenine / pharmacology
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Adenosine A2 Receptor Antagonists / chemical synthesis
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Adenosine A2 Receptor Antagonists / metabolism
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Adenosine A2 Receptor Antagonists / pharmacology*
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Animals
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Behavior, Animal / drug effects
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Binding, Competitive
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CHO Cells
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Cricetinae
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Cricetulus
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HEK293 Cells
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Humans
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Mice
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Models, Chemical
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Molecular Structure
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Parkinson Disease / metabolism
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Parkinson Disease / prevention & control*
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Radioligand Assay
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Receptor, Adenosine A2A / genetics
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Receptor, Adenosine A2A / metabolism*
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Time Factors
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Triazoles / chemical synthesis
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Triazoles / metabolism
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Triazoles / pharmacology*
Substances
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2-n-butyl-9-methyl-8-(1,2,3)triazol-2-yl-9H-purin-6-ylamine
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Adenosine A2 Receptor Antagonists
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Receptor, Adenosine A2A
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Triazoles
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Adenine