Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA 3 receptor-selective agonists

Lian Qian, Yong Xu, Ted Simper, Guowei Jiang, Junken Aoki, Makiko Umezu-Goto, Hiroyuki Arai, Shuangxing Yu, Gordon B. Mills, Ryoko Tsukahara, Natalia Makarova, Yuko Fujiwara, Gabor Tigyi, Glenn D. Prestwich

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

The metabolically stabilized LPA analogue 1-oleoyl-2-O-methyl-rac- glycerophosphorothioate (OMPT) was recently shown to be a potent subtype-selective agonist for LPA3, a G-protein-coupled receptor (GPCR) in the endothelial differentiation gene (EDG) family. Further stabilization was achieved by replacing the sn-1 O-acyl group with an O-alkyl ether. A new synthetic route for the enantiospecific synthesis of the resulting alkyl LPA phosphorothioate analogues is described. The pharmacological properties of the alkyl OMPT analogues were characterized for subtype-specific agonist activity using Ca2+-mobilization assays in RH7777 cells expressing the individual EDG family LPA receptors. Alkyl OMPT analogues induced cell migration in cancer cells mediated through LPA1. Alkyl OMPT analogues also activated Ca2+ release through LPA2 activation but with less potency than sn-1-oleoyl LPA. In contrast, alkyl OMPT analogues were potent LPA3 agonists. The alkyl OMPTs 1 and 3 induced cell proliferation at submicromolar concentrations in 10T1/2 fibroblasts. Interestingly, the absolute configuration of the sn-2 methoxy group of the alkyl OMPT analogues was not recognized by any of the LPA receptors in the EDG family. By using a reporter gene assay for the LPA-activated nuclear transcription factor PPARγ, we demonstrated that phosphorothioate diesters have agonist activity that is independent of their ligand properties at the LPA-activated GPCRs. The availability of new alkyl LPA analogues expands the scope of structure-activity studies and will further refine the molecular nature of ligand-receptor interactions for this class of GPCRs.

Original languageEnglish
Pages (from-to)376-383
Number of pages8
JournalChemMedChem
Volume1
Issue number3
DOIs
Publication statusPublished - 2006 Mar

Keywords

  • Calcium
  • Cell migration
  • EDG receptors
  • PPARγ
  • Synthetic methods

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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