Abstract
A large series of N6-substituted-4'-thioadenosines were synthesized starting from D-gulonic-gamma-lactone, and structure-activity relationships were studied at the human A3 and other subtypes of adenosine receptors (ARs). 2-Chloro-substituted and 2-H analogues were compared. 2-Chloro-N6-methyl-4'-thioadenosine 19b was a highly potent and selective agonist (Ki=0.8+/-0.1 nM in binding) at the A3AR, and displayed the same relative efficacy in receptor activation as a known full agonist, Cl-IB-MECA. Most of N6-substituted-4'-thioadenosines were less potent in binding than the corresponding N6-substituted-adenosines or N6-substituted-4'-thioadenosine-5'-uronamides. N6-(3-Iodobenzyl) derivative 19g was demonstrated to be an A3AR-selective partial agonist displaying a Ki value of 3.2 nM.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / analogs & derivatives*
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Adenosine / chemical synthesis
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Adenosine / chemistry
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Adenosine / metabolism
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Adenosine / pharmacology
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Adenosine A3 Receptor Agonists*
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Animals
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CHO Cells
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Cricetinae
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Cyclic AMP / metabolism
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Drug Design
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Humans
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In Vitro Techniques
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Kinetics
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Ligands
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Magnetic Resonance Spectroscopy
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Receptor, Adenosine A1 / metabolism
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Receptor, Adenosine A2A / metabolism
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Recombinant Proteins / agonists
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Structure-Activity Relationship
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Thionucleosides / chemical synthesis*
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Thionucleosides / chemistry
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Thionucleosides / metabolism
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Thionucleosides / pharmacology*
Substances
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Adenosine A3 Receptor Agonists
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Ligands
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Receptor, Adenosine A1
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Receptor, Adenosine A2A
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Recombinant Proteins
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Thionucleosides
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Cyclic AMP
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Adenosine