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Phosphorothioate Analogues of Alkyl Lysophosphatidic Acid as LPA 3 Receptor‐Selective Agonists
Author(s) -
Qian Lian,
Xu Yong,
Simper Ted,
Jiang Guowei,
Aoki Junken,
UmezuGoto Makiko,
Arai Hiroyuki,
Yu Shuangxing,
Mills Gordon B.,
Tsukahara Ryoko,
Makarova Natalia,
Fujiwara Yuko,
Tigyi Gabor,
Prestwich Glenn D.
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200500042
Subject(s) - g protein coupled receptor , agonist , lysophosphatidic acid , receptor , chemistry , ligand (biochemistry) , alkyl , biochemistry , stereochemistry , biology , organic chemistry
The metabolically stabilized LPA analogue 1‐oleoyl‐2‐O‐methyl‐rac‐glycerophosphorothioate (OMPT) was recently shown to be a potent subtype‐selective agonist for LPA 3 , 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 Ca 2+ ‐mobilization assays in RH7777 cells expressing the individual EDG family LPA receptors. Alkyl OMPT analogues induced cell migration in cancer cells mediated through LPA 1 . Alkyl OMPT analogues also activated Ca 2+ release through LPA 2 activation but with less potency than sn‐1‐oleoyl LPA. In contrast, alkyl OMPT analogues were potent LPA 3 agonists. The alkyl OMPTs 1 and 3 induced cell proliferation at submicromolar concentrations in 10T 1/2 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.

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