Constrained azacyclic analogues of the immunomodulatory agent FTY720 as molecular probes for sphingosine 1-phosphate receptors.
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.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-ville, Montréal, Que., Canada H3C 3J7. stephen.hanessian@umontreal.ca
Charron
Guillaume
G
Billich
Andreas
A
Guerini
Danilo
D
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002855:Chromatography, Thin Layer; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000378:metabolism; D015195:Drug Design; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000494:pharmacology*; D010766:Phosphorylation; D011409:Propylene Glycols / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D001372:Aza Compounds; D007155:Immunologic Factors; D007202:Indicators and Reagents; D015335:Molecular Probes; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D002118:Calcium