title: Lymphopenia induced by a novel selective S1P(1) antagonist structurally unrelated to S1P.
abstract: Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking via type-1 S1P receptor (S1P(1)) and participates in many pathological conditions. We developed a novel type S1P(1)-selective antagonist, TASP0251078, which is structurally unrelated to S1P. This competitive antagonist inhibited binding of S1P to S1P(1) resulting in reduced signaling downstream of S1P(1), including GTPγS-binding and cAMP formation. TASP0251078 also inhibited S1P-induced cellular responses such as chemotaxis and receptor-internalization. Furthermore, when administered in vivo, TASP0251078 induced lymphopenia in blood, which is different from previously reported effects of other S1P(1)-antagonists. In a mouse contact hypersensitivity model, TASP0251078 effectively suppressed ear swelling, leukocyte infiltration, and hyperplasia. These findings provide the chemical evidence that S1P(1) antagonism is responsible for lymphocyte sequestration from the blood, and suggest that the effect of S1P(1) agonists on lymphocyte sequestration results from their functional antagonism.
authors.affiliation: Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Saitama-shi, Saitama 331-9520, Japan. y.fujii@po.rd.taisho.co.jp
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujii
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ohtake
authors.forename: Naoya
authors.initials: N
authors.lastname: Ono
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hara
authors.forename: Takanobu
authors.initials: T
authors.lastname: Sakurai
authors.forename: Syuya
authors.initials: S
authors.lastname: Takahashi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takayama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Fukasawa
authors.forename: Fumiyasu
authors.initials: F
authors.lastname: Shiozawa
authors.forename: Narutoshi
authors.initials: N
authors.lastname: Tsukahara
authors.forename: Takehiro
authors.initials: T
authors.lastname: Hirayama
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Ryo
authors.initials: R
authors.lastname: Goitsuka
mesh_terms: D000818:Animals; D016466:CHO Cells; D002633:Chemotaxis / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D003877:Dermatitis, Contact / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004423:Ear / Q000473:pathology; D004487:Edema / Q000517:prevention & control; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia / Q000517:prevention & control; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008231:Lymphopenia / Q000139:chemically induced / Q000378:metabolism*; D008246:Lysophospholipids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000096926:Benzenesulfonamides
chemical_list: D000242:Cyclic AMP; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D013449:Sulfonamides; D014230:Triazoles; C577887:3-chloro-N-((1R)-1-(4-ethyl-5-methoxy-4H-1,2,4-triazol-3-yl)ethyl)-4-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C060506:sphingosine 1-phosphate