Switching Lysophosphatidylserine G Protein-Coupled Receptor Agonists to Antagonists by Acylation of the Hydrophilic Serine Amine

Three
human G protein-coupled receptors (GPCRs)GPR34/LPS1, P2Y10/LPS2, and GPR174/LPS3are
activated specifically by lysophosphatidylserine (LysoPS), an endogenous
hydrolysis product of a cell membrane component, phosphatidylserine
(PS). LysoPS consists of l-serine, glycerol, and fatty acid
moieties connected by phosphodiester and ester linkages. We previously
generated potent and selective GPCR agonists by modification of the
three modules and the ester linkage. Here, we show that a novel modification
of the hydrophilic serine moiety, that is, N-acylations of the serine
amine, converted a GPR174 agonist to potent GPR174 antagonists. Structural
exploration of the amide functionality provided access to a range
of activities from agonist to partial agonist to antagonist. The present
study would provide a new strategy for the development of lysophospholipid
receptor antagonists.