Abstract
Constrained azacyclic analogues of FTY720 were prepared starting with d- and l-pyroglutamic acids. One enantiomer was shown to be a substrate for sphingosine kinase 2, being phosphorylated 4-fold more efficiently than FTY720. Among the corresponding phosphates, two were found to have unusual specificity in binding to S1P receptors: while being inactive on S1P1 and S1P3, they acted as potent agonists on S1P4 and S1P5. The phosphates may be useful to explore the biology and binding site of these receptors.
MeSH terms
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Animals
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Aza Compounds / chemical synthesis*
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Aza Compounds / pharmacology*
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CHO Cells / metabolism
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Calcium / metabolism
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Cell Line
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Chromatography, Thin Layer
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Cricetinae
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Cricetulus
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Cytoplasm / metabolism
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Drug Design
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Fingolimod Hydrochloride
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Humans
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Immunologic Factors / chemical synthesis*
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Immunologic Factors / pharmacology*
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Indicators and Reagents
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Magnetic Resonance Spectroscopy
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Molecular Probes / chemical synthesis*
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Molecular Probes / pharmacology*
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Phosphorylation
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Propylene Glycols / pharmacology*
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Receptors, Lysosphingolipid / drug effects*
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
Substances
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Aza Compounds
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Immunologic Factors
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Indicators and Reagents
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Molecular Probes
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Propylene Glycols
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Receptors, Lysosphingolipid
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Fingolimod Hydrochloride
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Sphingosine
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Calcium