2. Academic Validation
  3. Switching Lysophosphatidylserine G Protein-Coupled Receptor Agonists to Antagonists by Acylation of the Hydrophilic Serine Amine

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

  • J Med Chem. 2021 Jul 22;64(14):10059-10101. doi: 10.1021/acs.jmedchem.1c00347.
Misa Sayama 1,  Akiharu Uwamizu 2 3,  Masaya Ikubo 1,  Luying Chen 1,  Ge Yan 1,  Yuko Otani 1,  Asuka Inoue 3 4 5,  Junken Aoki 2 3,  Tomohiko Ohwada 1
Affiliations

Affiliations

  • 1 Department of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 2 Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 3 AMED-LEAP, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan.
  • 4 Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
  • 5 AMED-PRIME, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan.
PMID: 34233115 DOI: 10.1021/acs.jmedchem.1c00347
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 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.

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