title: Enantiospecific Recognition at the A2BAdenosine Receptor by Alkyl 2-Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates.
abstract: A novel family of structurally simple, potent, and selective nonxanthine A2BAR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (16) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (16) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(±)16b, Ki= 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A2BAR, with the (S)-16b enantiomer retaining all the affinity (Ki= 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A2Badenosine receptor and opens new possibilities in ligand design for this receptor.
authors.forename: Carlos
authors.initials: C
authors.lastname: Carbajales
authors.forename: Jhonny
authors.initials: J
authors.lastname: Azuaje
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University , Uppsala SE-75124, Sweden.
authors.forename: Ana
authors.initials: A
authors.lastname: Oliveira
authors.affiliation: Drug Screening Platform/Biofarma Research Group, Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela , 15782 Santiago de Compostela, Spain.
authors.forename: María I
authors.initials: MI
authors.lastname: Loza
authors.affiliation: Drug Screening Platform/Biofarma Research Group, Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela , 15782 Santiago de Compostela, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.affiliation: Drug Screening Platform/Biofarma Research Group, Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela , 15782 Santiago de Compostela, Spain.
authors.forename: María I
authors.initials: MI
authors.lastname: Cadavid
authors.forename: Christian F
authors.initials: CF
authors.lastname: Masaguer
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.identifier: 0000-0001-5571-2812
authors.initials: E
authors.lastname: Sotelo
mesh_terms: D066241:Carbon-13 Magnetic Resonance Spectroscopy; D066244:Proton Magnetic Resonance Spectroscopy; D011743:Pyrimidines / Q000737:chemistry*; D043704:Receptor, Adenosine A2B / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
chemical_list: D011743:Pyrimidines; D043704:Receptor, Adenosine A2B