An update on sphingosine-1-phosphate receptor 1 modulators

Abstract

Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P1) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein–coupled receptor (GPCR) in an attempt to suppress autoimmune disorders. FTY720, also known as fingolimod, is the first oral disease-modifying therapy for MS on the market. In pursuit of improved stability, bioavailability, and efficiency, structural analogues of this initial prodrug have emerged over time. This review covers a brief introduction to the sphingolipid metabolism, the mechanism of action on S1P1, and an updated overview of synthetic sphingosine S1P1 agonists.

Positron Emission Tomography in the Inflamed Cerebellum: Addressing Novel Targets among G Protein-Coupled Receptors and Immune Receptors

“…Five subtypes of these receptor interacting with S1P (sphingosine 1 phosphate) as one of the endogenous ligands have been identified to date [ 39 , 40 ]. While the subtypes 1–3 are omnipresent in the body and have been detected in cerebral as well as cerebellar glia cells [ 41 , 42 ], subtypes 4 and 5 are expressed only in few kinds of cells [ 43 ], i.e., S1P5 receptor in the brain in oligodendrocytes only [ 41 ]. G i protein has been confirmed for signaling with all five subtypes.…”

“…Thus, actions of the S1P1 receptor are related to racGTPase-dependent activation of the cytoskeleton barrier function. The S1P3 receptor supports rohGTPase-regulated cytoskeleton rearrangement and disruption of the barrier function [ 43 ].…”

“…The change in the core structure of phosphonates and the introduction of a vinyl chain resulting in chirality of the molecule improved the stability and provides possibilities for enhancement of receptor affinity and desired pharmacological effects [ 43 ].…”

“…Regardless of useful physicochemical properties, the problem of early-response bradycardia [ 53 , 54 ] and general pharmacokinetically triggered efforts for the development of competitive as well as allosteric antagonists. Some of these compounds are also derivatives of sphingosine-1-phosphate [ 43 , 55 ], despite the fact that the pool of antagonists remains limited [ 43 , 44 ].…”

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

“…As such, unexpected adverse effects on lymphocyte counts differ for the individual DMTs. Some of these laboratory changes have been associated with an increased risk of infections or other adverse clinical events [9][10][11][12][13]. The total number of lymphocytes (extent of lymphopenia), distinct changes in the overall leukocyte subpopulations, as well as the timing and sequence of immune reconstitution following cell depletion, have been related to possible therapeutic risks that include secondary autoimmunity, infections, and impaired response to vaccinations.…”