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Medchemcomm. 2017 Oct 1;8(10):1897-1908. doi: 10.1039/C7MD00397H. Epub 2017 Sep 6.

Pyrimidine Nucleotides Containing a (S)-Methanocarba Ring as P2Y6 Receptor Agonists.

Author information

1
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA.
2
Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, MD 20850 USA.

Abstract

Both agonists and antagonists of the UDP-activated P2Y6 receptor (P2Y6R) have been proposed for therapeutic use, in conditions such as cancer, inflammation, neurodegeneration and diabetes. Uracil nucleotides containing a South-bicyclo[3.1.0]hexane ((S)-methanocarba) ring system in place of the ribose ring were synthesized and shown to be potent P2Y6R agonists in a calcium mobilization assay. The (S)-methanocarba modification was compatible with either a 5-iodo or 4-methoxyimino group on the pyrimidine, but not with a α,β-methylene 5´-diphosphate. (S)-Methanocarba dinucleotide potency was compatible with a N4-methoxy modification on the proximal nucleoside that is assumed to bind at the P2Y6R similarly to UDP; (N)-methanocarba was preferred on the distal nucleoside moiety. This suggests that the distal dinucleotide P2Y6R binding site prefers a ribose-like group that can attain a (N) conformation, rather than (S). Dinucleotide binding was modeled by homology modeling, docking and molecular dynamics simulations, which suggested the same ribose conformational preferences found empirically.

KEYWORDS:

G protein-coupled receptor; P2Y6 receptor; dinucleotides; structure activity relationship; uracil nucleotides

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