title: Discovery of novel A3 adenosine receptor ligands based on chromone scaffold.
abstract: A project focused on the discovery of new chemical entities (NCEs) as AR ligands that incorporate a benzo-γ-pyrone [(4H)-1-benzopyran-4-one] substructure has been developed. Accordingly, two series of novel chromone carboxamides placed at positions C2 (compounds 2-13) and C3 (compounds 15-26) of the γ-pyrone ring were synthesized using chromone carboxylic acids (compounds 1 or 14) as starting materials. From this study and on the basis of the obtained structure-activity relationships it was concluded that the chromone carboxamide scaffold represent a novel class of AR ligands. The most remarkable chromones were compounds 21 and 26 that present a better affinity for A3AR (Ki = 3680 nM and Ki = 3750 nM, respectively). Receptor-driven molecular modeling studies provide information on the binding/selectivity data of the chromone. The data so far acquired are instrumental for future optimization of chromone carboxamide as a selective A3AR antagonist.
authors.affiliation: CIQUP/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gaspar
authors.forename: Joana
authors.initials: J
authors.lastname: Reis
authors.forename: Sonja
authors.initials: S
authors.lastname: Kachler
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D002867:Chromones / Q000737:chemistry*; D003001:Cloning, Molecular; D006224:Cricetinae; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011869:Radioligand Assay; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D002867:Chromones; D008024:Ligands; D043684:Receptor, Adenosine A3; D054852:Small Molecule Libraries