Design, synthesis, and biological activity of N6-substituted-4'-thioadenosines at the human A3 adenosine receptor

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-...

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Published in:Bioorganic & medicinal chemistry 2006-07, Vol.14 (14), p.4718-4730
Main Authors: LAK SHIN JEONG, HYUK WOO LEE, GUNAGA, Prashantha, SANG KOOK LEE, DONG ZHE JIN, MOON WOO CHUN, HYUNG RYONG MOON, HEA OK KIM, JI YOUNG JUNG, GAO, Zhan-Guo, DUONG, Heng T, RAO, Srikar, JACOBSON, Kenneth A, DAE HONG SHIN, LEE, Jeong A
Format: Article
Language:English
Subjects:
Adenosine - analogs & derivatives
Adenosine - chemical synthesis
Adenosine - chemistry
Adenosine - metabolism
Adenosine - pharmacology
Adenosine A3 Receptor Agonists
Animals
Biological and medical sciences
CHO Cells
Cricetinae
Cyclic AMP - metabolism
Drug Design
Humans
In Vitro Techniques
Kinetics
Ligands
Magnetic Resonance Spectroscopy
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Receptor, Adenosine A1 - metabolism
Receptor, Adenosine A2A - metabolism
Recombinant Proteins - agonists
Structure-Activity Relationship
Thionucleosides - chemical synthesis
Thionucleosides - chemistry
Thionucleosides - metabolism
Thionucleosides - pharmacology
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2006.03.030