sew2871 and Multiple-Sclerosis

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 (S1P

Topics: Autoimmune Diseases; Biological Availability; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Oxadiazoles; Receptors, Lysosphingolipid; Sphingolipids

Multiple sclerosis (MS) is an autoimmune-inflammatory neurodegenerative disease that is often accompanied by a debilitating neuropathic pain. Disease-modifying agents slow down the progression of multiple sclerosis and prevent relapses, yet it remains unclear if they yield analgesia. We explored the analgesic potential of fingolimod (FTY720), an agonist and/or functional antagonist at the sphingosine-1-phosphate receptor 1 (S1PR1), because it reduces hyperalgesia in models of peripheral inflammatory and neuropathic pain. We used a myelin oligodendrocyte glycoprotein 35 to 55 (MOG35-55) mouse model of experimental autoimmune encephalomyelitis, modified to avoid frank paralysis, and thus, allow for assessment of withdrawal behaviors to somatosensory stimuli. Daily intraperitoneal fingolimod reduced behavioral signs of central neuropathic pain (mechanical and cold hypersensitivity) in a dose-dependent and reversible manner. Both autoimmune encephalomyelitis and fingolimod changed hyperalgesia before modifying motor function, suggesting that pain-related effects and clinical neurological deficits were modulated independently. Fingolimod also reduced cellular markers of central sensitization of neurons in the dorsal horn of the spinal cord: glutamate-evoked Ca signaling and stimulus-evoked phospho-extracellular signal-related kinase ERK (pERK) expression, as well as upregulation of astrocytes (GFAP) and macrophage/microglia (Iba1) immunoreactivity. The antihyperalgesic effects of fingolimod were prevented or reversed by the S1PR1 antagonist W146 (1 mg/kg daily, i.p.) and could be mimicked by either repeated or single injection of the S1PR1-selective agonist SEW2871. Fingolimod did not change spinal membrane S1PR1 content, arguing against a functional antagonist mechanism. We conclude that fingolimod behaves as an S1PR1 agonist to reduce pain in multiple sclerosis by reversing central sensitization of spinal nociceptive neurons.

Topics: Anilides; Animals; Central Nervous System Sensitization; Disease Models, Animal; eIF-2 Kinase; Female; Fingolimod Hydrochloride; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Motor Activity; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Neuralgia; Organophosphonates; Oxadiazoles; Pain Threshold; Peptide Fragments; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors; Spinal Cord; Spinal Nerve Roots; Subcellular Fractions; Thiophenes

We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.070 μM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 μM; 5: EC(50)=1.5 μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.

Topics: Animals; Area Under Curve; Cardiovascular Diseases; Chemistry, Physical; Drug Design; Female; Humans; Immunosuppressive Agents; In Vitro Techniques; Kinetics; Lymphocytes; Models, Chemical; Multiple Sclerosis; Quinolones; Rats; Rats, Inbred Lew; Receptors, Lysosphingolipid; Structure-Activity Relationship