Abstract
Receptors for sphingosine-1-phosphate (S1P) have been identified only recently. Their medicinal chemistry is therefore still in its infancy, and few selective agonists or antagonists are available. Furthermore, the selectivity of S1P receptor agonists or antagonists is not well established. JTE-013 and BML-241 (also known as CAY10444), used extensively as specific S1P2 and S1P3 receptors antagonists respectively, are cases in point. When analyzing S1P-induced vasoconstriction in mouse basilar artery, we observed that JTE-013 inhibited not only the effect of S1P, but also the effect of U46619, endothelin-1 or high KCl; JTE-013 strongly inhibited responses to S1P in S1P2 receptor knockout mice. Similarly, BML-241 has been shown to inhibit increases in intracellular Ca2+ concentration via P2 receptor or α1A-adrenoceptor stimulation and α1A-adrenoceptor-mediated contraction of rat mesenteric artery, while it did not affect S1P3-mediated decrease of forskolin-induced cyclic AMP accumulation. Another putative S1P1/3 receptor antagonist, VPC23019, does not inhibit S1P3-mediated vasoconstriction. With these examples in mind, we discuss caveats about relying on available pharmacological tools to characterize receptor subtypes.
Highlights
Receptors for sphingosine-1-phosphate (S1P) have been identified only recently.Their medicinal chemistry is still in its infancy, and few selective agonists or antagonists are available
An old antiprotozoal drug, was used as S1P3 receptor antagonist (Ancellin and Hla, 1999; Salomone et al, 2003), but its usefulness was limited because it lacked specificity (Voogd et al, 1993)
It is possible that the BML-241/CAY10444 concentration used in these studies was too low to block S1P3 receptors to a significant extent; using a β-arrestin recruitment assay, Wetter et al (2009) showed that their S1P3 cell line response to S1P was inhibited to 78% of the receptor response by 100 μM
Summary
We chose to focus this Perspective on JTE-013 and BML-241 because they are commonly used despite reports of their lack of specificity. It is possible that the BML-241/CAY10444 concentration used in these studies was too low to block S1P3 receptors to a significant extent; using a β-arrestin recruitment assay, Wetter et al (2009) showed that their S1P3 cell line response to S1P was inhibited to 78% of the receptor response by 100 μM. It is increasingly recognized that S1P, generated intracellularly by SPK, can be released into the extracellular space and thereby stimulate membrane S1P receptors, establishing an autocrine loop (Kim et al, 2009; Takabe et al, 2010) When this occurs, even a specific S1P receptor antagonist might inhibit the response to an agonist other than S1P. Autocrine loops might account for the fact that JTE-013 and BML-241 inhibit responses to U46619, endothelin-1 and high KCl, and to purinergic P2 receptor or α1Aadrenoceptor stimulation, respectively. When studying the effects of S1P on vascular tone, we found that VPC23019 potentiated S1P-induced contractile response in both rat and mouse basilar arteries with intact endothelium, while it failed to do so in preparations without
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