Modulation of adenosine receptor affinity and intrinsic efficacy in adenine nucleosides substituted at the 2-position

We have studied the structural determinants of binding affinity and efficacy of adenosine receptor (AR) agonists. Substituents at the 2-position of adenosine have been combined with N 6-substitutions known to enhance human A 3AR affinity. The environment surrounding the 2-position within the putativ...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2004-06, Vol.12 (11), p.2995-3007
Main Authors: Ohno, Michihiro, Gao, Zhan-Guo, Van Rompaey, Philippe, Tchilibon, Susanna, Kim, Soo-Kyung, Harris, Brian A, Gross, Ariel S, Duong, Heng T, Van Calenbergh, Serge, Jacobson, Kenneth A
Format: Article
Language:English
Subjects:
Adenosine - agonists
Adenosine - analogs & derivatives
Adenosine - chemistry
Agonists
Antagonists
Binding
Binding Sites
Biological and medical sciences
Cyclic AMP
Deoxyadenosines - chemical synthesis
Deoxyadenosines - chemistry
Deoxyadenosines - metabolism
GPCR
Humans
Medical sciences
Models, Molecular
Molecular modeling
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Purinergic P1 Receptor Agonists
Purines
Receptors, Purinergic P1 - genetics
Receptors, Purinergic P1 - metabolism
Recombinant Proteins - metabolism
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:We have studied the structural determinants of binding affinity and efficacy of adenosine receptor (AR) agonists. Substituents at the 2-position of adenosine have been combined with N 6-substitutions known to enhance human A 3AR affinity. The environment surrounding the 2-position within the putative A 3AR binding site was explored using rhodopsin-based homology modeling and ligand docking. We studied the structural determinants of binding affinity and efficacy of adenosine receptor (AR) agonists. Substituents at the 2-position of adenosine were combined with N 6-substitutions known to enhance human A 3AR affinity. Selectivity of binding of the analogues and their functional effects on cAMP production were studied using recombinant human A 1, A 2A, A 2B, and A 3ARs. Mainly sterically small substituents at the 2-position modulated both the affinity and intrinsic efficacy at all subtypes. The 2-cyano group decreased hA 3AR affinity and efficacy in the cases of N 6-(3-iodobenzyl) and N 6-( trans-2-phenyl-1-cyclopropyl), for which a full A 3AR agonist was converted into a selective antagonist; the 2-cyano- N 6-methyl analogue was a full A 3AR agonist. The combination of N 6-benzyl and various 2-substitutions (chloro, trifluoromethyl, and cyano) resulted in reduced efficacy at the A 1AR. The environment surrounding the 2-position within the putative A 3AR binding site was explored using rhodopsin-based homology modeling and ligand docking.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2004.03.031