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

Misa Sayama, Akiharu Uwamizu, Masaya Ikubo, Luying Chen, Ge Yan, Yuko Otani, Asuka Inoue, Junken Aoki, Tomohiko Ohwada

Research output: Contribution to journalArticlepeer-review

Abstract

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-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.

Original languageEnglish
Pages (from-to)10059-10101
Number of pages43
JournalJournal of Medicinal Chemistry
Volume64
Issue number14
DOIs
Publication statusPublished - 2021 Jul 22

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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