Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 10, Pages 4204-4219Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm5020082
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Funding
- Ministry of Education, Science, Sports, and Culture of Japan
- PRESTO (Precursory Research for Embryonic Science and Technology) from Japan Science and Technology Agency (JST)
- CREST from JST
- Grants-in-Aid for Scientific Research [26104508, 25293010, 25460009] Funding Source: KAKEN
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Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-attivity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS,receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and L-Serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysolPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.
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