title: Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes.
abstract: Three novel families of A2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2(1H)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A2B ligand that exhibits complete selectivity toward A1, A2A, and A3 receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A2A receptor.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: El Maatougui
authors.forename: Jhonny
authors.initials: J
authors.lastname: Azuaje
authors.forename: Manuel
authors.initials: M
authors.lastname: González-Gómez
authors.forename: Gabriel
authors.initials: G
authors.lastname: Miguez
authors.forename: Abel
authors.initials: A
authors.lastname: Crespo
authors.forename: Carlos
authors.initials: C
authors.lastname: Carbajales
authors.forename: Luz
authors.initials: L
authors.lastname: Escalante
authors.forename: Xerardo
authors.initials: X
authors.lastname: García-Mera
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University , Uppsala SE-75124, Sweden.
authors.forename: Hugo
authors.initials: H
authors.lastname: Gutiérrez-de-Terán
authors.forename: Eddy
authors.initials: E
authors.lastname: Sotelo
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011744:Pyrimidinones; D043704:Receptor, Adenosine A2B