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 SIP receptors: while being inactive on SIPI 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. (c) 2006 Elsevier Ltd. All rights reserved.