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Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo
TLDR
Chemical modulation reveals differences in S1P-S1P1 'set points' among tissues and highlights both mechanistic advantages (lymphocyte sequestration) and risks (pulmonary edema) of therapeutic intervention. Expand
Sphingosine 1-phosphate receptor signaling.
TLDR
The sphingosine 1-phosphate (S1P) receptor signaling system, based in part on receptor subtype-selectivity and on differential attenuation of deleterious signals, now appears to be on the cusp of meaningful therapy for multiple sclerosis. Expand
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
Full Pharmacological Efficacy of a Novel S1P1 Agonist That Does Not Require S1P-Like Headgroup Interactions
TLDR
Data show that CYM-5442 activates S1P1-dependent pathways in vitro and to levels of full efficacy in vivo through a hydrophobic pocket separate from the orthosteric site of S 1P binding that is headgroup-dependent. Expand
Enhanced hypo-osmoregulation induced by warm-acclimation in antarctic fish is mediated by increased gill and kidney Na+/K(+)-ATPase activities.
TLDR
The results indicate that acclimation to 4 degrees C induced a decrease in serum osmolality which resulted from the positive compensation of Na+/K(+)-ATPase in osmoregulatory tissues, suggesting that energy expenditure in antarctic fish may be lessened, in part, by maintaining a reduced seawater-to-ECF osmotic gradient. Expand
Actions of a picomolar short-acting S1P1 agonist in S1P1-eGFP knock-in mice
TLDR
Differential downregulation of S1P1 on lymphocytes and endothelia following agonist treatment is demonstrated and elucidate physiological and agonist-perturbed changes in expression of S 1P1 at a subcellular level in vivo. Expand
S1P1 Receptor Modulation with Cyclical Recovery from Lymphopenia Ameliorates Mouse Model of Multiple Sclerosis
TLDR
S1P1-selective agonists that induce reversible lymphopenia while persisting in the CNS may be effective MS treatments. Expand
Tipping the gatekeeper: S1P regulation of endothelial barrier function.
TLDR
This personal perspective highlights the pivotal control points regulated by constitutive and induced S1P receptor tone at vascular endothelial and lymphatic endothelial barriers, through which S 1P agonism impacts on both innate and adaptive immunity. Expand
Phe-308 and Phe-312 in transmembrane domain 7 are major sites of alpha 1-adrenergic receptor antagonist binding. Imidazoline agonists bind like antagonists.
TLDR
The identification of two phenylalanine residues in transmembrane domain 7 of the alpha(1a)-adrenergic receptor (Phe-312 and Phe-308) that are a major site of antagonist affinity are reported, confirming previous evidence that this class of ligand binds differently than phenethylamine-type agonists and may be more antagonist-like. Expand
S1P signaling: new therapies and opportunities
TLDR
Proof-of-concept studies across validated animal models with S1P receptor modulators highly selective for S 1P1, and emerging clinical trials for safety and efficacy in humans, particularly in MS, ulcerative colitis (UC) and psoriasis, have set the stage for the company to consider additional testing in various other autoimmune diseases. Expand
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