Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator. S1P evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene receptor family. The recent development of S1P receptor agonists has revealed that S1P signaling is an important regulator of lymphocyte trafficking. Especially, the lead compound VPC 23019 behaves as a competitive antagonist at the S1P1 and S1P3 receptors. VPC25239 is one log order more potent at the S1P3 receptor. VPC 23019 lacks agonist activity at the S1P1 and S1P3 receptors.

S1P plays fundamental roles in morphogenetic mechanisms, such as collective cell migration, tissue inductive events, and biomechanical signaling. Researchers report that a subset of our aryl amide-containing compounds are antagonists at the S1P1 and S1P3 receptors. The endothelial cell differentiation gene receptors are G-protein coupled receptors that, upon stimulation, propagate second messenger signals via activation of heterotrimeric G-protein α subunits and β-γ dimers. Thus, VPC 23019 is devoid of agonist activity at the S1P1 and S1P3 receptors using both broken cell and whole-cell assays. VPC 23019 blocks agonist activity at the S1P1 and S1P3 receptors. Equally, VPC 23019 exhibits possible inverse agonist activity at the S1P1 or S1P3 receptors. Thus, VPC 23019 behaves as a competitive antagonist at both receptors.

Finally, VPC 23019 is devoid of agonist activity at the S1P2 receptor, and radioligand binding studies with the S1P2 receptor reveal that it does not influence the binding of [³²P]S1P to the S1P2 receptor at concentrations up to 0.010 mM. All in all, VPC 23019 is a competitive antagonist at the S1P1 and S1P3 receptors and an agonist at the S1P4 and S1P5 receptors. VPC 23019 provide leads for further S1P receptor antagonist development.

Reference:
Davis MD, et al. Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem. 2005 Mar 18;280(11):9833-41.