title: Insight into the interactions between novel coumarin derivatives and human A3 adenosine receptors.
abstract: 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 (A1, A2A, and A3) and adenylyl cyclase activity (A2B) assays in order to study their affinity for the four human AR (hAR) subtypes. Seven of the studied compounds proved to be selective A3 AR ligands, with 3-(4'-methylphenyl)-8-(2-oxopropoxy)coumarin (12) being the most potent (Ki =634 nM). None of the compounds showed affinity for the A2B 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 A3 AR ligands. ADME properties were also calculated, with the results suggesting that these compounds are promising leads for the identification of new drug candidates.
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Avda. das Ciencias, 15782 Santiago de Compostela (Spain); CIQUP, Department of Chemistry & Biochemistry, Faculty of Science, University of Porto, Rua do Campo Alegre 687, 4169-007 Porto (Portugal). mariacmatos@gmail.com.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Matos
authors.forename: Santiago
authors.initials: S
authors.lastname: Vilar
authors.forename: Sonja
authors.initials: S
authors.lastname: Kachler
authors.forename: André
authors.initials: A
authors.lastname: Fonseca
authors.forename: Lourdes
authors.initials: L
authors.lastname: Santana
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Tatonetti
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
mesh_terms: D003374:Coumarins / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D003374:Coumarins; D043684:Receptor, Adenosine A3; C030123:coumarin
keywords: 3-arylcoumarin scaffold; ADME properties; adenosine receptor ligands; docking studies; radioligand binding