Structure-activity relationships of pyrimidine nucleotides containing a 5'-α,β-methylene diphosphonate at the P2Y₆ receptor.

ABSTRACT: The G_q-coupled P2Y₆ receptor (P2Y₆R) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2Y₆R agonist and P2Y₁₄R partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,β-methylene bridge as P2Y₆R agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5'-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2Y₆R potency (MRS4554, 0

SUBMITTER: Oliva P 

PROVIDER: S-EPMC8276771 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature