Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [37]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family [3,45], the receptors are currently designated as S1P₁R through S1P₅R [3,30,45]. Their gene nomenclature has been codified as human S1PR1, S1PR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and S1pr1, S1pr2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function. All S1P receptors (S1PRs) have been knocked-out in mice constitutively and in some cases, conditionally.

S1PRs, particularly S1P₁, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P₁ in multiple cell types [5,19]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems.

Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P₁R activation [38-39]. The structures of S1P₁ [29,40,64,66], S1P₂ [12], S1P₃[43,68], and S1P₅ [41,67] are solved, and confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [4,29]. Fingolimod (FTY720), the first FDA-approved drug to target any of the lysophospholipid receptors, binds as a phosphorylated metabolite to four of the five S1PRs, and was the first oral therapy for multiple sclerosis (MS) [13]. Second-generation S1PR modulators siponimod, ozanimod, and ponesimod that target S1P₁ and S1P₅ are also FDA approved for the treatment of various MS forms [3,45]. In 2021, ozanimod became the first S1PR modulator to be FDA approved for the treatment of ulcerative colitis [56]. The mechanisms of action of fingolimod and other S1PR-modulating drugs now in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [14,26-27,54].

The FDA-approved immunomodulator fingolimod (FTY720) is phosphorylated in vivo [1] to generate an agonist with activity at S1P₁, S1P₃, S1P₄ and S1P₅ receptors [7,44]. Many of the physiological consequences of fingolimod-phosphate administration, as well as those of other currently described S1P₁ agonists, may involve functional antagonism via ubiquitination and subsequent degradation of S1P₁ [3,48]. Additionally, receptor specificities of the different compounds may depend on the functional assay system utilized and from which species the receptor sequence originated.

* Key recommended reading is highlighted with an asterisk

* Cartier A, Hla T. (2019) Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science, 366 (6463). DOI: 10.1126/science.aar5551 [PMID:31624181]

* Chew WS, Wang W, Herr DR. (2016) To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling. Pharmacol Res, 113 (Pt A): 521-532. [PMID:27663260]

* Chun J, Hla T, Lynch KR, Spiegel S, Moolenaar WH. (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol Rev, 62 (4): 579-87. [PMID:21079037]

Kihara Y, Mizuno H, Chun J. (2015) Lysophospholipid receptors in drug discovery. Exp Cell Res, 333 (2): 171-7. [PMID:25499971]

Mutoh T, Rivera R, Chun J. (2012) Insights into the pharmacological relevance of lysophospholipid receptors. Br J Pharmacol, 165 (4): 829-44. [PMID:21838759]

O'Sullivan C, Dev KK. (2013) The structure and function of the S1P1 receptor. Trends Pharmacol Sci, 34 (7): 401-12. [PMID:23763867]

* Pyne NJ, Pyne S. (2017) Sphingosine 1-Phosphate Receptor 1 Signaling in Mammalian Cells. Molecules, 22 (3). [PMID:28241498]

* Rosen H, Stevens RC, Hanson M, Roberts E, Oldstone MB. (2013) Sphingosine-1-phosphate and its receptors: structure, signaling, and influence. Annu Rev Biochem, 82: 637-62. [PMID:23527695]

Spiegel S, Milstien S. (2011) The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol, 11 (6): 403-15. [PMID:21546914]

* Yanagida K, Hla T. (2017) Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. Annu Rev Physiol, 79: 67-91. [PMID:27813829]

1. Albert R, Hinterding K, Brinkmann V, Guerini D, Müller-Hartwieg C, Knecht H, Simeon C, Streiff M, Wagner T, Welzenbach K et al.. (2005) Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer. J Med Chem, 48 (16): 5373-7. [PMID:16078855]

2. Ancellin N, Hla T. (1999) Differential pharmacological properties and signal transduction of the sphingosine 1-phosphate receptors EDG-1, EDG-3, and EDG-5. J Biol Chem, 274 (27): 18997-9002. [PMID:10383399]

3. Blaho VA. (2020) Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities. Adv Exp Med Biol, 1274: 101-135. [PMID:32894509]

4. Blaho VA, Chun J. (2018) 'Crystal' Clear? Lysophospholipid Receptor Structure Insights and Controversies. Trends Pharmacol Sci, 39 (11): 953-966. [PMID:30343728]

5. Blaho VA, Galvani S, Engelbrecht E, Liu C, Swendeman SL, Kono M, Proia RL, Steinman L, Han MH, Hla T. (2015) HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature, 523 (7560): 342-6. [PMID:26053123]

6. Bolli MH, Abele S, Binkert C, Bravo R, Buchmann S, Bur D, Gatfield J, Hess P, Kohl C, Mangold C et al.. (2010) 2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. J Med Chem, 53 (10): 4198-211. [PMID:20446681]

7. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P et al.. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem, 277 (24): 21453-7. [PMID:11967257]

8. Buvinic S, Briones R, Huidobro-Toro JP. (2002) P2Y(1) and P2Y(2) receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed. Br J Pharmacol, 136 (6): 847-56. [PMID:12110609]

9. Buzard DJ, Kim SH, Lopez L, Kawasaki A, Zhu X, Moody J, Thoresen L, Calderon I, Ullman B, Han S et al.. (2014) Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor. ACS Med Chem Lett, 5 (12): 1313-7. [PMID:25516790]

10. Cahalan SM, Gonzalez-Cabrera PJ, Sarkisyan G, Nguyen N, Schaeffer MT, Huang L, Yeager A, Clemons B, Scott F, Rosen H. (2011) Actions of a picomolar short-acting S1P₁ agonist in S1P₁-eGFP knock-in mice. Nat Chem Biol, 7 (5): 254-6. [PMID:21445057]

11. Cencetti F, Bernacchioni C, Tonelli F, Roberts E, Donati C, Bruni P. (2013) TGFβ1 evokes myoblast apoptotic response via a novel signaling pathway involving S1P4 transactivation upstream of Rho-kinase-2 activation. FASEB J, 27 (11): 4532-46. [PMID:23913862]

12. Chen H, Chen K, Huang W, Staudt LM, Cyster JG, Li X. (2022) Structure of S1PR2-heterotrimeric G₁₃ signaling complex. Sci Adv, 8 (13): eabn0067. [PMID:35353559]

13. Chun J, Kihara Y, Jonnalagadda D, Blaho VA. (2019) Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders. Annu Rev Pharmacol Toxicol, 59: 149-170. [PMID:30625282]

14. Cohen JA, Chun J. (2011) Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann Neurol, 69 (5): 759-77. [PMID:21520239]

15. Davis MD, Clemens JJ, Macdonald TL, Lynch KR. (2005) Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem, 280 (11): 9833-41. [PMID:15590668]

16. Di Pardo A, Castaldo S, Amico E, Pepe G, Marracino F, Capocci L, Giovannelli A, Madonna M, van Bergeijk J, Buttari F et al.. (2018) Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease. Hum Mol Genet, 27 (14): 2490-2501. [PMID:29688337]

17. Forrest M, Sun SY, Hajdu R, Bergstrom J, Card D, Doherty G, Hale J, Keohane C, Meyers C, Milligan J et al.. (2004) Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J Pharmacol Exp Ther, 309 (2): 758-68. [PMID:14747617]

18. Foss FW, Snyder AH, Davis MD, Rouse M, Okusa MD, Lynch KR, Macdonald TL. (2007) Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg Med Chem, 15 (2): 663-77. [PMID:17113298]

19. Galvani S, Sanson M, Blaho VA, Swendeman SL, Obinata H, Conger H, Dahlbäck B, Kono M, Proia RL, Smith JD et al.. (2015) HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci Signal, 8 (389): ra79. [PMID:26268607]

20. Gates E. (1998) A complement to care. Nurs Times, 94 (9): 55-7. [PMID:9735753]

21. Gergely P, Nuesslein-Hildesheim B, Guerini D, Brinkmann V, Traebert M, Bruns C, Pan S, Gray NS, Hinterding K, Cooke NG et al.. (2012) The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol, 167 (5): 1035-47. [PMID:22646698]

22. Gilmore JL, Xiao HY, Dhar TGM, Yang M, Xiao Z, Yang X, Taylor TL, McIntyre KW, Warrack BM, Shi H et al.. (2021) Bicyclic Ligand-Biased Agonists of S1P₁: Exploring Side Chain Modifications to Modulate the PK, PD, and Safety Profiles. J Med Chem, 64 (3): 1454-1480. [PMID:33492963]

23. Gilmore JL, Xiao HY, Dhar TGM, Yang MG, Xiao Z, Xie J, Lehman-McKeeman LD, Gong L, Sun H, Lecureux L et al.. (2019) Identification and Preclinical Pharmacology of ((1 R,3 S)-1-Amino-3-(( S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986166): A Differentiated Sphingosine-1-phosphate Receptor 1 (S1P₁) Modulator Advanced into Clinical Trials. J Med Chem, 62 (5): 2265-2285. [PMID:30785748]

24. Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, Peter van Marle S, Legangneux E, Borell H, James AD et al.. (2018) Metabolism and Disposition of Siponimod, a Novel Selective S1P₁/S1P₅ Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism. Drug Metab Dispos, 46 (7): 1001-1013. [PMID:29735753]

25. Gonzalez-Cabrera PJ, Jo E, Sanna MG, Brown S, Leaf N, Marsolais D, Schaeffer MT, Chapman J, Cameron M, Guerrero M et al.. (2008) Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions. Mol Pharmacol, 74 (5): 1308-18. [PMID:18708635]

26. Groves A, Kihara Y, Chun J. (2013) Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci, 328 (1-2): 9-18. [PMID:23518370]

27. Groves A, Kihara Y, Jonnalagadda D, Rivera R, Kennedy G, Mayford M, Chun J. (2018) A Functionally Defined In Vivo Astrocyte Population Identified by c-Fos Activation in a Mouse Model of Multiple Sclerosis Modulated by S1P Signaling: Immediate-Early Astrocytes (ieAstrocytes). eNeuro, 5 (5). [PMID:30255127]

28. Guerrero M, Urbano M, Velaparthi S, Zhao J, Schaeffer MT, Brown S, Rosen H, Roberts E. (2011) Discovery, design and synthesis of the first reported potent and selective sphingosine-1-phosphate 4 (S1P4) receptor antagonists. Bioorg Med Chem Lett, 21 (12): 3632-6. [PMID:21570287]

29. Hanson MA, Roth CB, Jo E, Griffith MT, Scott FL, Reinhart G, Desale H, Clemons B, Cahalan SM, Schuerer SC et al.. (2012) Crystal structure of a lipid G protein-coupled receptor. Science, 335 (6070): 851-5. [PMID:22344443]

30. Hla T, Maciag T. (1990) An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. J Biol Chem, 265 (16): 9308-13. [PMID:2160972]

31. Hobson AD, Harris CM, van der Kam EL, Turner SC, Abibi A, Aguirre AL, Bousquet P, Kebede T, Konopacki DB, Gintant G et al.. (2015) Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders. J Med Chem, 58 (23): 9154-70. [PMID:26509640]

32. Hong CH, Ko MS, Kim JH, Cho H, Lee CH, Yoon JE, Yun JY, Baek IJ, Jang JE, Lee SE et al.. (2022) Sphingosine 1-Phosphate Receptor 4 Promotes Nonalcoholic Steatohepatitis by Activating NLRP3 Inflammasome. Cell Mol Gastroenterol Hepatol, 13 (3): 925-947. [PMID:34890841]

33. Im DS, Heise CE, Ancellin N, O'Dowd BF, Shei GJ, Heavens RP, Rigby MR, Hla T, Mandala S, McAllister G et al.. (2000) Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. J Biol Chem, 275 (19): 14281-6. [PMID:10799507]

34. Imeri F, Stepanovska Tanturovska B, Zivkovic A, Enzmann G, Schwalm S, Pfeilschifter J, Homann T, Kleuser B, Engelhardt B, Stark H et al.. (2021) Novel compounds with dual S1P receptor agonist and histamine H₃ receptor antagonist activities act protective in a mouse model of multiple sclerosis. Neuropharmacology, 186: 108464. [PMID:33460688]

35. Jo E, Bhhatarai B, Repetto E, Guerrero M, Riley S, Brown SJ, Kohno Y, Roberts E, Schürer SC, Rosen H. (2012) Novel selective allosteric and bitopic ligands for the S1P(3) receptor. ACS Chem Biol, 7 (12): 1975-83. [PMID:22971058]

36. Kennedy PC, Zhu R, Huang T, Tomsig JL, Mathews TP, David M, Peyruchaud O, Macdonald TL, Lynch KR. (2011) Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J Pharmacol Exp Ther, 338 (3): 879-89. [PMID:21632869]

37. Kihara Y, Maceyka M, Spiegel S, Chun J. (2014) Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br J Pharmacol, 171 (15): 3575-94. [PMID:24602016]

38. Kono M, Conlon EG, Lux SY, Yanagida K, Hla T, Proia RL. (2017) Bioluminescence imaging of G protein-coupled receptor activation in living mice. Nat Commun, 8 (1): 1163. [PMID:29079828]

39. Kono M, Tucker AE, Tran J, Bergner JB, Turner EM, Proia RL. (2014) Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo. J Clin Invest, 124 (5): 2076-86. [PMID:24667638]

40. Liu S, Paknejad N, Zhu L, Kihara Y, Ray M, Chun J, Liu W, Hite RK, Huang XY. (2022) Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate. Nat Commun, 13 (1): 731. [PMID:35136060]

41. Lyapina E, Marin E, Gusach A, Orekhov P, Gerasimov A, Luginina A, Vakhrameev D, Ergasheva M, Kovaleva M, Khusainov G et al.. (2022) Structural basis for receptor selectivity and inverse agonism in S1P₅ receptors. Nat Commun, 13 (1): 4736. [PMID:35961984]

42. Ma B, Guckian KM, Liu XG, Yang C, Li B, Scannevin R, Mingueneau M, Drouillard A, Walzer T. (2021) Novel Potent Selective Orally Active S1P5 Receptor Antagonists. ACS Med Chem Lett, 12 (3): 351-355. [PMID:33738061]

43. Maeda S, Shiimura Y, Asada H, Hirata K, Luo F, Nango E, Tanaka N, Toyomoto M, Inoue A, Aoki J et al.. (2021) Endogenous agonist-bound S1PR3 structure reveals determinants of G protein-subtype bias. Sci Adv, 7 (24). [PMID:34108205]

44. Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C et al.. (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science, 296 (5566): 346-9. [PMID:11923495]

45. Mizuno H, Kihara Y. (2020) Druggable Lipid GPCRs: Past, Present, and Prospects. Adv Exp Med Biol, 1274: 223-258. [PMID:32894513]

46. Murakami A, Takasugi H, Ohnuma S, Koide Y, Sakurai A, Takeda S, Hasegawa T, Sasamori J, Konno T, Hayashi K et al.. (2010) Sphingosine 1-phosphate (S1P) regulates vascular contraction via S1P3 receptor: investigation based on a new S1P3 receptor antagonist. Mol Pharmacol, 77 (4): 704-13. [PMID:20097776]

47. Okamoto H, Takuwa N, Gonda K, Okazaki H, Chang K, Yatomi Y, Shigematsu H, Takuwa Y. (1998) EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. J Biol Chem, 273 (42): 27104-10. [PMID:9765227]

48. Oo ML, Thangada S, Wu MT, Liu CH, Macdonald TL, Lynch KR, Lin CY, Hla T. (2007) Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem, 282 (12): 9082-9. [PMID:17237497]

49. Osada M, Yatomi Y, Ohmori T, Ikeda H, Ozaki Y. (2002) Enhancement of sphingosine 1-phosphate-induced migration of vascular endothelial cells and smooth muscle cells by an EDG-5 antagonist. Biochem Biophys Res Commun, 299 (3): 483-7. [PMID:12445827]

50. Pan S, Gray NS, Gao W, Mi Y, Fan Y, Wang X, Tuntland T, Che J, Lefebvre S, Chen Y et al.. (2013) Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator. ACS Med Chem Lett, 4 (3): 333-7. [PMID:24900670]

51. Pan S, Mi Y, Pally C, Beerli C, Chen A, Guerini D, Hinterding K, Nuesslein-Hildesheim B, Tuntland T, Lefebvre S et al.. (2006) A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chem Biol, 13 (11): 1227-34. [PMID:17114004]

52. Piali L, Birker-Robaczewska M, Lescop C, Froidevaux S, Schmitz N, Morrison K, Kohl C, Rey M, Studer R, Vezzali E et al.. (2017) Cenerimod, a novel selective S1P₁receptor modulator with unique signaling properties. Pharmacol Res Perspect, 5 (6). [PMID:29226621]

53. Poirier B, Briand V, Kadereit D, Schäfer M, Wohlfart P, Philippo MC, Caillaud D, Gouraud L, Grailhe P, Bidouard JP et al.. (2020) A G protein-biased S1P₁ agonist, SAR247799, protects endothelial cells without affecting lymphocyte numbers. Sci Signal, 13 (634). [PMID:32487716]

54. Proia RL, Hla T. (2015) Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest, 125 (4): 1379-87. [PMID:25831442]

55. Quancard J, Bollbuck B, Janser P, Angst D, Berst F, Buehlmayer P, Streiff M, Beerli C, Brinkmann V, Guerini D et al.. (2012) A potent and selective S1P(1) antagonist with efficacy in experimental autoimmune encephalomyelitis. Chem Biol, 19 (9): 1142-51. [PMID:22999882]

56. Sandborn WJ, Feagan BG, D'Haens G, Wolf DC, Jovanovic I, Hanauer SB, Ghosh S, Petersen A, Hua SY, Lee JH et al.. (2021) Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med, 385 (14): 1280-1291. [PMID:34587385]

57. Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, Peterson MS, Webb B, Lefebvre S, Chun J, Gray N et al.. (2004) Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem, 279 (14): 13839-48. [PMID:14732717]

58. Sanna MG, Wang SK, Gonzalez-Cabrera PJ, Don A, Marsolais D, Matheu MP, Wei SH, Parker I, Jo E, Cheng WC et al.. (2006) Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol, 2 (8): 434-41. [PMID:16829954]

59. Stepanovska Tanturovska B, Zivkovic A, Imeri F, Homann T, Kleuser B, Stark H, Huwiler A. (2021) ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P₁ Agonist and Functional Antagonist Potency In Vitro and In Vivo. Molecules, 26 (17). [PMID:34500564]

60. Urbano M, Guerrero M, Rosen H, Roberts E. (2013) Modulators of the Sphingosine 1-phosphate receptor 1. Bioorg Med Chem Lett, 23 (23): 6377-89. [PMID:24125884]

61. Urbano M, Guerrero M, Velaparthi S, Crisp M, Chase P, Hodder P, Schaeffer MT, Brown S, Rosen H, Roberts E. (2011) Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype. Bioorg Med Chem Lett, 21 (22): 6739-45. [PMID:21982495]

62. Van Brocklyn JR, Gräler MH, Bernhardt G, Hobson JP, Lipp M, Spiegel S. (2000) Sphingosine-1-phosphate is a ligand for the G protein-coupled receptor EDG-6. Blood, 95 (8): 2624-9. [PMID:10753843]

63. Vutukuri R, Koch A, Trautmann S, Schreiber Y, Thomas D, Mayser F, Meyer Zu Heringdorf D, Pfeilschifter J, Pfeilschifter W, Brunkhorst R. (2020) S1P d20:1, an endogenous modulator of S1P d18:1/S1P₂ -dependent signaling. FASEB J, 34 (3): 3932-3942. [PMID:31944406]

64. Xu Z, Ikuta T, Kawakami K, Kise R, Qian Y, Xia R, Sun MX, Zhang A, Guo C, Cai XH et al.. (2022) Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism. Nat Chem Biol, 18 (3): 281-288. [PMID:34937912]

65. Yamamoto R, Okada Y, Hirose J, Koshika T, Kawato Y, Maeda M, Saito R, Hattori K, Harada H, Nagasaka Y et al.. (2014) ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile. PLoS ONE, 9 (10): e110819. [PMID:25347187]

66. Yu L, He L, Gan B, Ti R, Xiao Q, Hu H, Zhu L, Wang S, Ren R. (2022) Structural insights into sphingosine-1-phosphate receptor activation. Proc Natl Acad Sci U S A, 119 (16): e2117716119. [PMID:35412894]

67. Yuan Y, Jia G, Wu C, Wang W, Cheng L, Li Q, Li Z, Luo K, Yang S, Yan W et al.. (2021) Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition. Cell Res, 31 (12): 1263-1274. [PMID:34526663]

68. Zhao C, Cheng L, Wang W, Wang H, Luo Y, Feng Y, Wang X, Fu H, Cai Y, Yang S et al.. (2022) Structural insights into sphingosine-1-phosphate recognition and ligand selectivity of S1PR3-Gi signaling complexes. Cell Res, 32 (2): 218-221. [PMID:34545189]

Subcommittee members: Jerold Chun (Chairperson) Sanford Burnham Prebys Medical Discovery Institute 10901 North Torrey Pines Road La Jolla CA, 92037 USA Victoria Blaho Sanford Burnham Prebys Medical Discovery Institute 10901 North Torrey Pines Road La Jolla CA, 92037 USA Yasuyuki Kihara Sanford Burnham Prebys Medical Discovery Institute 10901 North Torrey Pines Road La Jolla CA, 92037 USA Danielle Jones (Editorial assistant to chairperson) Sanford Burnham Prebys Medical Discovery Institute 10901 North Torrey Pines Road La Jolla CA, 92037 USA

Other contributors: Deron Herr San Diego State University San Diego USA