Abstract
Virtual screening was performed against experimentally enabled homology models of the adenosine A(2A) receptor, identifying a diverse range of ligand efficient antagonists (hit rate 9%). By use of ligand docking and Biophysical Mapping (BPM), hits 1 and 5 were optimized to potent and selective lead molecules (11-13 from 5, pK(I) = 7.5-8.5, 13- to >100-fold selective versus adenosine A(1); 14-16 from 1, pK(I) = 7.9-9.0, 19- to 59-fold selective).
MeSH terms
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Adenosine A2 Receptor Antagonists / chemical synthesis
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Adenosine A2 Receptor Antagonists / chemistry*
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Adenosine A2 Receptor Antagonists / pharmacology
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Animals
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Binding Sites
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CHO Cells
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Chromones / chemical synthesis
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Chromones / chemistry
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Chromones / pharmacology
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Cricetinae
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Cricetulus
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Databases, Factual*
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HEK293 Cells
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Humans
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Models, Molecular*
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Piperazines / chemical synthesis
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Piperazines / chemistry
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Piperazines / pharmacology
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Radioligand Assay
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Receptor, Adenosine A2A / chemistry*
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Receptor, Adenosine A2A / metabolism
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Structure-Activity Relationship
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Triazines / chemical synthesis
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Triazines / chemistry
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Triazines / pharmacology
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Turkeys
Substances
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Adenosine A2 Receptor Antagonists
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Chromones
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Piperazines
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Receptor, Adenosine A2A
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Triazines