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Insight into the Interactions between Novel Coumarin Derivatives and Human A 3 Adenosine Receptors
Author(s) -
Matos Maria João,
Vilar Santiago,
Kachler Sonja,
Fonseca André,
Santana Lourdes,
Uriarte Eugenio,
Borges Fernanda,
Tatonetti Nicholas P.,
Klotz KarlNorbert
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402205
Subject(s) - coumarin , chemistry , adenylyl cyclase , adme , docking (animal) , stereochemistry , adenosine receptor , receptor , binding site , combinatorial chemistry , drug discovery , ligand (biochemistry) , in vitro , biochemistry , organic chemistry , medicine , nursing , agonist
A study focused on the discovery of new chemical entities based on the 3‐arylcoumarin scaffold was performed with the aim of finding new adenosine receptor (AR) ligands. Thirteen synthesized compounds were evaluated by radioligand binding (A 1 , A 2A , and A 3 ) and adenylyl cyclase activity (A 2B ) assays in order to study their affinity for the four human AR (hAR) subtypes. Seven of the studied compounds proved to be selective A 3 AR ligands, with 3‐(4′‐methylphenyl)‐8‐(2‐oxopropoxy)coumarin ( 12 ) being the most potent ( K i =634 n M ). None of the compounds showed affinity for the A 2B receptor, while four compounds were found to be nonselective AR ligands for the other three subtypes. Docking simulations were carried out to identify the hypothetical binding mode and to rationalize the interaction of these types of coumarin derivatives with the binding site of the three ARs to which binding was observed. The results allowed us to conclude that the 3‐arylcoumarin scaffold composes a novel and promising class of A 3 AR ligands. ADME properties were also calculated, with the results suggesting that these compounds are promising leads for the identification of new drug candidates.