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Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis
Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan
* Author to whom correspondence should be addressed.
Received: 5 April 2012; in revised form: 24 April 2012 / Accepted: 15 May 2012 / Published: 18 May 2012
Abstract: Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P1) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), as evinced by the inability of lymphocytes to exit from the SLO in mice lacking lymphocytic S1P1. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active, S1P receptor modulator with a structure closely related to sphingosine. FTY720 was first synthesized by chemical modification of a natural product, myriocin. FTY720 is effectively converted to an active metabolite, FTY720 phosphate (FTY720-P) by sphingosine kinases. FTY720-P shows high affinity to 4 of the S1P receptors (S1P1, S1P3, S1P4, and S1P5). In particular, FTY720-P strongly induces internalization and degradation of S1P1, inhibits S1P responsiveness of lymphocytes in the SLO, and acts as a functional antagonist at lymphocytic S1P1. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from the SLO to decrease circulation of lymphocytes including autoreactive Th17 cells and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Because FTY720 shows a superior efficacy in relapsing remitting MS patients compared to intramuscular interferon-β-1a (Avonex®), S1P1 is presumed to be a useful target for the therapy of MS.
Keywords: sphingosine 1-phasphate (S1P); S1P receptor 1 (S1P1); fingolimod (FTY720); lymphocyte egress; immunomodulator; experimental autoimmune encephalomyelitis (EAE); multiple sclerosis (MS); therapy
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Chiba, K.; Adachi, K. Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis. Pharmaceuticals 2012, 5, 514-528.
Chiba K, Adachi K. Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis. Pharmaceuticals. 2012; 5(5):514-528.
Chiba, Kenji; Adachi, Kunitomo. 2012. "Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis." Pharmaceuticals 5, no. 5: 514-528.