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


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.

SUBMITTER: Toti KS 

PROVIDER: S-EPMC5798474 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Pyrimidine Nucleotides Containing a (S)-Methanocarba Ring as P2Y<sub>6</sub> Receptor Agonists.

Toti Kiran S KS   Jain Shanu S   Ciancetta Antonella A   Balasubramanian Ramachandran R   Chakraborty Saibal S   Surujdin Ryan R   Shi Zhen-Dan ZD   Jacobson Kenneth A KA  

MedChemComm 20170906 10


Both agonists and antagonists of the UDP-activated P2Y<sub>6</sub> receptor (P2Y<sub>6</sub>R) 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 P2Y<sub>6</sub>R agonists in a calcium mobilization assay. The (S)-methanocarba modification was compatible with either a 5-iodo or  ...[more]

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