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Enantiospecific Recognition at the A(2B) Adenosine Receptor by Alkyl 2-Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates
Univ Santiago de Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
Univ Santiago de Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
Univ Santiago de Compostela, Drug Screening Platform Biofarma Res Grp, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 15782, Spain..
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2017 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 8, 3372-3382 p.Article in journal (Refereed) Published
Abstract [en]

A novel family of structurally simple, potent, and selective nonxanthine A(2B)AR 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, K-i = 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 A(2B)AR, with the (S)-16b enantiomer retaining all the affinity (K-i = 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A(2B) adenosine receptor and opens new possibilities in ligand design for this receptor.

Place, publisher, year, edition, pages
2017. Vol. 60, no 8, 3372-3382 p.
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-323455DOI: 10.1021/acs.jmedchem.7b00138ISI: 000400538900011PubMedID: 28368607OAI: oai:DiVA.org:uu-323455DiVA: diva2:1106521
Funder
Swedish Research CouncileSSENCE - An eScience Collaboration
Available from: 2017-06-07 Created: 2017-06-07 Last updated: 2017-06-07Bibliographically approved

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Oliveira, AnaGutiérrez-de-Terán, Hugo
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Computational Biology and BioinformaticsDepartment of Cell and Molecular Biology
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