1 research outputs found
Structure–Activity Relationships of Lysophosphatidylserine Analogs as Agonists of G‑Protein-Coupled Receptors GPR34, P2Y10, and GPR174
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 (LPS<sub>2</sub>) and GPR174 (LPS<sub>3</sub>), which, together with previously
reported GPR34 (LPS<sub>1</sub>), comprise a LysoPS receptor family.
Herein, we examined the structure–activity 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-LysoPS, <b>1</b>), 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