A recent perspective published in Frontiers of Pharmacology by Salomone and Waeber (2011) discussed the selectivity and specificity of sphingosine 1-phosphate (S1P) receptor ligands. This perspective surveyed the use of various S1P receptor ligands and attempted to reconcile a number of inconsistencies in the predicted biological outcomes: these were interpreted as “off-target” effects. Therefore the perspective cautioned against the use of these S1P receptor ligands. Here we highlight the complex pharmacology of S1P receptors, which along with “inside-out” signaling might provide an alternative explanation for “off-target” effects

Pyne, Nigel J.

Pyne, Susan

Frontiers in Pharmacology

English

PubMed

A recent perspective published in Frontiers of Pharmacology by Salomone and Waeber (2011) discussed the selectivity and specificity of sphingosine 1-phosphate (S1P) receptor ligands. This perspective surveyed the use of various S1P receptor ligands and attempted to reconcile a number of inconsistencies in the predicted biological outcomes: these were interpreted as "off-target" effects. Therefore the perspective cautioned against the use of these S1P receptor ligands. Here we highlight the complex pharmacology of S1P receptors, which along with "inside-out" signaling might provide an alternative explanation for "off-target" effects

University of Strathclyde Institutional Repository

Selectivity and specificity of sphingosine 1-phosphate receptor ligands : "off-targets" or complex pharmacology?

Nigel J. Pyne

Susan Pyne

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Selectivity and Specificity of Sphingosine 1-Phosphate Receptor Ligands: “Off-Targets” or Complex Pharmacology?

Pyne, Nigel J

Name not available

A recent perspective published in frontiers of Pharmacology by Salomone and Waeber (2011) discussed the selectivity and specificity of sphingosine 1-phosphate (S1P) receptor ligands.  This perspective surveyed the use of various S1P receptor ligands and attempted to reconcile a number of inconsistencies in the predicted biological outcomes: these were interpreted as ‘off-target’ effects.  Therefore the perspective cautioned against the use of these S1P receptor ligands.  Here we highlight the complex pharmacology of S1P receptors, which along with ‘inside-out’ signalling might provide an alternative explanation for ‘off-target’ effects

Nigel John Pyne

Susan ePyne

Directory of Open Access Journals

SELECTIVITY AND SPECIFICITY OF SPHINGOSINE 1-PHOSPHATE RECEPTOR LIGANDS: ‘OFF-TARGETS’ OR COMPLEX PHARMACOLOGY?

Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor null mice and pharmacological tools.

Blockade of sphingosine 1-phosphate receptor 2 signallingattenuatesstreptozotocininduced apoptosis of pancreatic beta-cells.

BML-241 fails to display selective antagonism at the sphingosine-1-phosphate receptor, S1P(3).

Cell migration activated by platelet-derived growth factor receptor is blocked by an inverse agonist of the sphingosine 1-phosphatereceptor-1.FASEBJ.20,

Ceramide synthesis is modulated by the sphingosine analogFTY720viaamixtureof uncompetitive and noncompetitive inhibition in an Acyl-CoA chain lengthdependent manner.

Development of novel EDG3 antagonists using a 3D database search and their structure- activity relationships.

Different response patterns of several ligands at the sphingosine1-phosphate recep-tor subtype 3 (S1P3).

Effects of phosphorylation of immunomodulatory agent FTY720 (ﬁngolimod) on antiproliferative activity against breast and colon cancer cells.

Enhancement of sphingosine 1-phosphate-induced migration of vascular endothelial cells and smooth muscle cells by an EDG-5 antagonist.

Essential roles of sphingosine-1-phosphatereceptor2inhumanmast cell activation,anaphylaxis,and pulmonary edema.

EstrogentransactivatesEGFRviathe sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1.

Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis.

FTY720 analogues as sphingosine kinase 1 inhibitors: Enzyme inhibition kinetics, allosterism, proteasomal degradation and actin rearrangementinMCF-7breastcancer cells.

FTY720 and (S)-FTY720 vinylphosphonate inhibit sphingosine kinase 1 and promotes its proteasomal degradation in human pulmonary artery smooth muscle, breast cancer and androgenindependent prostate cancer cells.

Gilenya (FTY720) inhibits acid sphingomyelinase by a mechanism similar to tricy-clic antidepressants.

Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery.

Inverse, protean, and ligand-selective agonism: matters of receptor conformation.

K.(2008).Sphingosine-1-phosphate receptor subtypes differentially regulatesmoothmusclecellphenotype.

Lipid phosphate phosphatases and lipid phosphate signalling.

Selectivity and speciﬁcity of sphingosine 1-phosphate receptor ligands: “off-targets” or complex pharmacology?.

Selectivity and speciﬁcity of sphingosine-1-phosphate receptor ligands: caveats and critical thinking in characterizing receptor-mediated effects.

Sphingosine 1 phosphate, lysophosphatidic acid and growth factor signalling and termination.

Sphingosine 1-phosphate (S1P) regulates vascular contraction via S1P3 receptor: investigation based on a new S1P3 receptor antagonist.

Sphingosine 1-phosphate analogs as receptor antagonists.

Sphingosine 1-phosphate and plateletderived growth factor (PDGF) act via PDGFbeta receptor-sphingosine 1-phosphate receptor complexes in airwaysmoothmuscle.J.Biol.Chem.

Sphingosine and FTY720 directly bind pro-survival 14-3-3 proteins to regulate their function.

Sphingosine kinase 1 induces tolerance to human epidermal growth factor receptor 2 and prevents formation of a migratory phenotype in response to sphingosine 1-phosphate in estrogen receptor positive breast cancer cells.

Statement: The authors declare that the research was conducted in the absence of any commercial or ﬁnancial relationships that could be construed as a potential conﬂict of interest. Received:06April2011;accepted:20May 2011; published online: 31

The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors.

The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein coupled receptors.

Vessel-speciﬁc role of sphingosine kinase 1 in the vasoconstriction of isolated basilar arteries.

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Selectivity and Specificity of Sphingosine 1-Phosphate Receptor Ligands: “Off-Targets” or Complex Pharmacology?

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University of Strathclyde Institutional Repository

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Directory of Open Access Journals