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

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    21 Scopus citations

    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 (US)
    Pages (from-to)376-383
    Number of pages8
    JournalChemMedChem
    Volume1
    Issue number3
    DOIs
    StatePublished - Mar 1 2006

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    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

    Cite this

    Qian, L., Xu, Y., Simper, T., Jiang, G., Aoki, J., Umezu-Goto, M., Arai, H., Yu, S., Mills, G. B., Tsukahara, R., Makarova, N., Fujiwara, Y., Tigyi, G., & Prestwich, G. D. (2006). Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA 3 receptor-selective agonists. ChemMedChem, 1(3), 376-383. https://doi.org/10.1002/cmdc.200500042