Sphingosine 1-phosphate pathway therapeutics: a lipid ligand-receptor paradigm

New insights have been gained into the therapeutic relevance of the sphingosine 1-phosphate (S1P) pathway, on the basis of reverse pharmacological approaches to defining the mechanism of action of the immunosuppressive agent FTY720. Natural and synthetic sphingosine 1-phosphate receptor agonists can make picomolar interactions with their cognate G-protein-coupled receptors, and provide chemical approaches to defining the contribution of distinct receptor subtypes to pathology, physiology and treatment. The chemistry of S1P receptors and their synthetic ligands present a paradigm for the understanding of lipid-receptor interactions and their contribution to physiology and pathology. These approaches can potentially be extended to a broad, related family of G-protein-coupled receptors that share ligands and ligand similarities.