Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174

J Med Chem. 2015 May 28;58(10):4204-19. doi: 10.1021/jm5020082. Epub 2015 May 13.


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-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, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Chemistry Techniques, Synthetic
  • Drug Design
  • Drug Evaluation, Preclinical / methods
  • Glycerol / chemistry
  • HEK293 Cells
  • Humans
  • Lysophospholipids / chemistry*
  • Molecular Structure
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, Lysophospholipid / agonists*
  • Receptors, Purinergic P2 / drug effects*
  • Stress Fibers / drug effects
  • Stress Fibers / metabolism
  • Structure-Activity Relationship*
  • Transforming Growth Factor alpha / metabolism


  • Amino Acids
  • G-protein-coupled receptor 34
  • GPR174 protein, human
  • Lysophospholipids
  • P2RY10 protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Lysophospholipid
  • Receptors, Purinergic P2
  • Transforming Growth Factor alpha
  • lysophosphatidylserine
  • Glycerol