title: Development of novel adenosine receptor ligands based on the 3-amidocoumarin scaffold.
abstract: With the aim of finding new adenosine receptor (AR) ligands presenting the 3-amidocoumarin scaffold, a study focusing on the discovery of new chemical entities was carried out. The synthesized compounds 1-8 were evaluated in radioligand binding (A1, A2A and A3) and adenylyl cyclase activity (A2B) assays in order to determine their affinity for human AR subtypes. The 3-benzamide derivative 4 showed the highest affinity of the whole series and was more than 30-fold selective for the A3 AR (Ki=3.24 μM). The current study supported that small structural changes in this scaffold allowed modulating the affinity resulting in novel promising classes of A1, A2A, and/or A3 AR ligands. We also performed docking calculations in hA2A and hA3 to identify the hypothetical binding mode for the most active compounds. In addition, some ADME properties were calculated in order to better understand the potential of these compounds as drug candidates.
authors.affiliation: CIQUP, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal. Electronic address: mariacmatos@gmail.com.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Matos
authors.affiliation: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vilar
authors.affiliation: Institut für Pharmakologie und Toxikologie, Universität Würzburg, 97078 Würzburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kachler
authors.affiliation: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Celeiro
authors.affiliation: CIQUP, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal.
authors.forename: Saleta
authors.initials: S
authors.lastname: Vazquez-Rodriguez
authors.affiliation: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Santana
authors.affiliation: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
authors.affiliation: Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: George
authors.initials: G
authors.lastname: Hripcsak
authors.affiliation: CIQUP, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal. Electronic address: mfernandamborges@gmail.com.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.affiliation: Institut für Pharmakologie und Toxikologie, Universität Würzburg, 97078 Würzburg, Germany.
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
mesh_terms: D001665:Binding Sites; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D043682:Receptor, Adenosine A1 / Q000737:chemistry* / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000737:chemistry* / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D008024:Ligands; D043682:Receptor, Adenosine A1; D043684:Receptor, Adenosine A3; D043683:Receptors, Adenosine A2
keywords: 3-Amidocoumarins; Adenosine ligands; Molecular modeling calculations; Theoretical ADME properties