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(S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity

Valentine, W.J. and Kiss, G.N. and Liu, J. and E, Shuyu and Gotoh, M. and Murakami-Murofushi, K. and Pham, T.C. and Baker, D.L. and Parrill, A.L. and Lu, X. and Sun, C. and Bittman, R. and Pyne, N.J. and Tigyi, G. (2010) (S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity. Cellular Signalling, 22 (10). pp. 1543-1553. ISSN 0898-6568

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Abstract

FTY720 (Fingolimod), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P(1) receptor internalization and targeting to the proteasomal degradative pathway, and thus functions as an antagonist of S1P(1) by depleting the functional S1P(1) receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P(1) (EC(50) 20+/-3 nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P(1,3,4) (K(i) 384 nM, 39 nM, and 1190 nM, respectively) and a partial antagonist of S1P(2), and S1P(5). Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with K(i) values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P(2) transcripts and traces of S1P(5). (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.

Item type: Article
ID code: 28081
Notes: Copyright 2010 Elsevier Inc. All rights reserved.
Keywords: animals, cell line, humans, lysophospholipids, mice, phosphodiesterase inhibitors, phosphoric acid esters, phosphoric diester hydrolases, rats, receptors, signal transduction, sphingosine, stereoisomerism, vinyl compounds, Therapeutics. Pharmacology, Cell Biology
Subjects: Medicine > Therapeutics. Pharmacology
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Faculty of Engineering > Electronic and Electrical Engineering
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Depositing user: Miss Shauna Thompson
Date Deposited: 13 Oct 2010 12:28
Last modified: 27 Mar 2014 09:00
URI: http://strathprints.strath.ac.uk/id/eprint/28081

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