title: No differences observed among multiple clinical S1P1 receptor agonists (functional antagonists) in S1P1 receptor down-regulation and degradation.
abstract: Sphingosine-1-phosphate (S1P) is a bioactive metabolite with pleiotropic effects on multiple cellular processes in health and disease. Responses elicited by S1P are a result of binding to five specific G-protein-coupled receptors. We have developed multiple assays to systematically study the downstream signaling of these receptors, including early events such as direct receptor activation (GTPγS) as well as more distal events such as S1P1 receptor degradation. Employing such assays, we have characterized and compared multiple S1P1 agonists that are in clinical development including FTY720, BAF312, CS-0777, and other molecules from the S1P1 patent literature. Our parallel assessment has allowed us to compare their potency against S1P1, their selectivity against the four other S1P receptors, as well as species cross-reactivity. We note that all of the compounds studied signal in an identical manner through S1P1, leading to receptor degradation.
authors.affiliation: 1Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lukas
authors.forename: Lori
authors.initials: L
authors.lastname: Patnaude
authors.forename: Sokol
authors.initials: S
authors.lastname: Haxhinasto
authors.forename: Anthony
authors.initials: A
authors.lastname: Slavin
authors.forename: Melissa
authors.initials: M
authors.lastname: Hill-Drzewi
authors.forename: Josh
authors.initials: J
authors.lastname: Horan
authors.forename: Louise Kelly
authors.initials: LK
authors.lastname: Modis
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D010755:Organophosphates / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C525008:FTY 720P; D010755:Organophosphates; D049349:Receptors, Lysosphingolipid; D000242:Cyclic AMP; D013110:Sphingosine; D002118:Calcium
keywords: GTPγS; functional antagonist; multiple sclerosis; receptor degradation; receptor down-regulation; sphingosine-1-phosphate receptors; β-arrestin