Abstract
Adenosine receptors (ARs) trigger signal transduction pathways inside the cell when activated by extracellular adenosine. Selective modulation of the A₃AR subtype may be beneficial in controlling diseases such as colorectal cancer and rheumatoid arthritis. Here, we report the synthesis and evaluation of β-D-apio-D-furano- and α-D-apio-L-furanoadenosines and derivatives thereof. Introduction of a 2-methoxy-5-chlorobenzyl group at N(6) of β-D-apio-D-furanoadenosine afforded an A₃AR antagonist (10c, Ki=0.98 μM), while a similar modification of an α-D-apio-L-furanoadenosine gave rise to a partial agonist (11c, Ki=3.07 μM). The structural basis for this difference was examined by docking to an A₃AR model; the antagonist lacked a crucial interaction with Thr94.
Keywords:
Adenosine A(3) receptor; Apionucleosides; G protein-coupled receptor.
Published by Elsevier Ltd.
Publication types
-
Research Support, N.I.H., Intramural
MeSH terms
-
Adenosine / analogs & derivatives*
-
Adenosine A3 Receptor Agonists / chemical synthesis*
-
Adenosine A3 Receptor Agonists / chemistry
-
Adenosine A3 Receptor Agonists / metabolism
-
Animals
-
Binding Sites
-
CHO Cells
-
Cricetinae
-
Cricetulus
-
HEK293 Cells
-
Humans
-
Hydrogen Bonding
-
Molecular Docking Simulation
-
Protein Binding
-
Protein Structure, Tertiary
-
Receptor, Adenosine A1 / chemistry
-
Receptor, Adenosine A1 / genetics
-
Receptor, Adenosine A1 / metabolism
-
Receptor, Adenosine A3 / chemistry*
-
Receptor, Adenosine A3 / genetics
-
Receptor, Adenosine A3 / metabolism
-
Receptors, Adenosine A2 / chemistry
-
Receptors, Adenosine A2 / genetics
-
Receptors, Adenosine A2 / metabolism
-
Structure-Activity Relationship
Substances
-
Adenosine A3 Receptor Agonists
-
Receptor, Adenosine A1
-
Receptor, Adenosine A3
-
Receptors, Adenosine A2
-
Adenosine