Abstract
A molecular simplification approach of previously reported 2-arylpyrazolo[3,4-c]quinolin-4-ones was applied to design 2-arylpyrazolo[4,3-d]pyrimidin-7-one derivatives as new human A(3) adenosine receptor antagonists. Substituents with different lipophilicity and steric hindrance were introduced at the 5-position of the bicyclic scaffold (R(5) = H, Me, Et, Ph, CH(2)Ph) and on the 2-phenyl ring (OMe, Me). Most of the synthesized derivatives were highly potent hA(3) adenosine receptor antagonists, the best being the 2-(4-methoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-one (K(i) = 1.2 nM). The new compounds were also highly selective, being completely devoid of affinity toward hA(1), hA(2A), and hA(2B) adenosine receptors. On the basis of the recently published human A(2A) receptor crystallographic information, we propose a novel receptor-driven hypothesis to explain both A(3) AR affinity and A(3) versus A(2A) selectivity profiles of these new antagonists.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine A2 Receptor Antagonists
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Adenosine A3 Receptor Antagonists*
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Amino Acid Sequence
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Animals
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CHO Cells
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Cricetinae
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Cricetulus
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Humans
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Models, Molecular
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Molecular Conformation
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Molecular Sequence Data
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Protein Binding
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Pyrazoles / chemistry
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Pyrazoles / metabolism*
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Pyrazoles / pharmacology*
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Pyrimidines / chemistry
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Pyrimidines / metabolism*
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Pyrimidines / pharmacology*
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Pyrimidinones / chemistry
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Pyrimidinones / metabolism*
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Pyrimidinones / pharmacology*
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Receptor, Adenosine A2A / chemistry
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Receptor, Adenosine A2A / metabolism
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Receptor, Adenosine A3 / chemistry
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Receptor, Adenosine A3 / metabolism*
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Substrate Specificity
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Triazines / metabolism
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Triazines / pharmacology
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Triazoles / metabolism
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Triazoles / pharmacology
Substances
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Adenosine A2 Receptor Antagonists
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Adenosine A3 Receptor Antagonists
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Pyrazoles
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Pyrimidines
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Pyrimidinones
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Receptor, Adenosine A2A
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Receptor, Adenosine A3
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Triazines
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Triazoles
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ZM 241385
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pyrimidine