title: (S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity.
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.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Valentine
authors.forename: Gyöngyi N
authors.initials: GN
authors.lastname: Kiss
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Liu
authors.forename: Shuyu
authors.initials: S
authors.lastname: E
authors.forename: Mari
authors.initials: M
authors.lastname: Gotoh
authors.forename: Kimiko
authors.initials: K
authors.lastname: Murakami-Murofushi
authors.forename: Truc Chi
authors.initials: TC
authors.lastname: Pham
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Baker
authors.forename: Abby L
authors.initials: AL
authors.lastname: Parrill
authors.forename: Xuequan
authors.initials: X
authors.lastname: Lu
authors.forename: Chaode
authors.initials: C
authors.lastname: Sun
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010755:Organophosphates / Q000494:pharmacology; D063065:Organophosphonates; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014753:Vinyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D000099189:Lysophospholipase D
chemical_list: D008246:Lysophospholipids; D010755:Organophosphates; D063065:Organophosphonates; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D014753:Vinyl Compounds; D000099189:Lysophospholipase D; C542743:((E)-3-amino-5-(4-heptylphenyl)-3-(hydroxymethyl)pent-1-enyl)phosphonic acid; C525008:FTY 720P; C060506:sphingosine 1-phosphate