Full Pharmacological Efficacy of a Novel S1P1 Agonist That Does Not Require S1P-Like Headgroup Interactions

@article{GonzalezCabrera2008FullPE,
  title={Full Pharmacological Efficacy of a Novel S1P1 Agonist That Does Not Require S1P-Like Headgroup Interactions},
  author={Pedro J. Gonzalez-Cabrera and Euijung Jo and M. Germana Sanna and Steven J Brown and Nora B. Leaf and David Marsolais and M T Schaeffer and Jacqueline V. Chapman and Michael D. Cameron and Miguel Guerrero and Edward Roberts and Hugh Rosen},
  journal={Molecular Pharmacology},
  year={2008},
  volume={74},
  pages={1308 - 1318}
}
Strong evidence exists for interactions of zwitterionic phosphate and amine groups in sphingosine-1 phosphate (S1P) to conserved Arg and Glu residues present at the extracellular face of the third transmembrane domain of S1P receptors. The contribution of Arg120 and Glu121 for high-affinity ligand-receptor interactions is essential, because single-point R120A or E121A S1P1 mutants neither bind S1P nor transduce S1P function. Because S1P receptors are therapeutically interesting, identifying… Expand
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References

SHOWING 1-10 OF 44 REFERENCES
S1P1-selective in vivo-active agonists from high-throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate.
TLDR
SEW2871 recapitulates the action of S1P in all the signaling pathways examined and overlaps in interactions with key headgroup binding receptor residues, presumably replacing salt-bridge interactions with ion-dipole interactions. Expand
Identification of the Hydrophobic Ligand Binding Pocket of the S1P1 Receptor*
TLDR
The now validated ligand binding pocket provided the pharmacophore model, which was used for in silico screening of the NCI, National Institutes of Health, Developmental Therapeutics chemical library, leading to the identification of two novel nonlipid agonists of S1P1. Expand
Mapping Pathways Downstream of Sphingosine 1-Phosphate Subtype 1 by Differential Chemical Perturbation and Proteomics*
TLDR
Compared signaling and fate of human S1P1-green fluorescent protein (GFP) in stable 293 cells, using AFD-R, a chiral analog of FTY720-P, SEW2871, and S 1P, suggest that the hierarchy of ubiquitin recruitment to S1p1 correlates with the efficiency of lysosomal receptor degradation and reflects intrinsic differences between agonists. Expand
Ligand-binding pocket shape differences between sphingosine 1-phosphate (S1P) receptors S1P1 and S1P3 determine efficiency of chemical probe identification by ultrahigh-throughput screening.
TLDR
Chemistry-space and shape-based analysis of the screening libraries in combination with the binding models explain the observed differential hit rates and enhanced efficiency for lead discovery for S1P1 versus S1p3 in this closely related receptor family. Expand
Discovery of 3-arylpropionic acids as potent agonists of sphingosine-1-phosphate receptor-1 (S1P1) with high selectivity against all other known S1P receptor subtypes.
TLDR
A series of 3-arylpropionic acids synthesized as S1P1 receptor agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin transplantation model, supporting that S 1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models. Expand
Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists.
TLDR
In vitro binding assays showed that the implementation of phosphonates as phosphate mimetics provided compounds with similar receptor binding affinities as compared to their phosphate precursors. Expand
Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate*
TLDR
S 1P1-selective agonists will be of broad utility in understanding cell functions in vitro, and vascular physiology in vivo, and the success of the chemical approach for S1P1 suggests that selective tools for the resolution of function across this broad lipid receptor family are now possible. Expand
Identification of Edg1 Receptor Residues That Recognize Sphingosine 1-Phosphate*
TLDR
This computational map of the ligand binding pocket provides information necessary for understanding the molecular pharmacology of this receptor, thus underlining the potential of the computational method in predicting ligand-receptor interactions. Expand
Synthesis and biological evaluation of γ-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists
Abstract The synthesis of N-arylamide phosphonates and related arylether and arylamine analogues provided potent, subtype-selective agonists and antagonists of the five known sphingosine 1-phosphateExpand
A Single Amino Acid Determines Lysophospholipid Specificity of the S1P1 (EDG1) and LPA1 (EDG2) Phospholipid Growth Factor Receptors*
TLDR
Computational modeling ofThese receptors provided valid information necessary for understanding the molecular pharmacology of these receptors and predicted that this residue might influence ligand recognition and specificity. Expand
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