jwh-133 and Multiple-Sclerosis

Multiple sclerosis is a chronic inflammatory demyelinating disorder of the central nervous system that eventually leads to progressive neurodegeneration and disability. Recent findings highlighted the emerging role of each target of the endocannabinoid system in controlling the symptoms and disease progression of multiple sclerosis. Therefore, multi-target modulators of the endocannabinoid system could provide a more effective pharmacological strategy as compared to the single target modulation. In this work, N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide (B2) was identified as the most promising compound with dual agonism at cannabinoid receptors type-1 and cannabinoid receptors type-2 and good drug-like properties. In in vitro assays, B2 reduced glutamate release from rat synaptosomes through interaction with cannabinoid receptors type-1 and modulated the production of the pro- and anti-inflammatory cytokines (interleukins IL-1β and IL-6 and interleukin IL-10 respectively) via cannabinoid receptors type-2 activation. Furthermore, B2 demonstrated antinociceptive effects in an animal model of neuropathic pain and efficacy in an experimental autoimmune encephalomyelitis model of multiple sclerosis.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Female; Ligands; Male; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Multiple Sclerosis; Protein Binding; Pyridones; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship

A combination of molecular modeling and structure-activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among others, cannabinoid binding assays, functional studies, and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB2 agonist isoxazole derivative, was tested in the acute phase of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV.

Topics: Dose-Response Relationship, Drug; HEK293 Cells; Humans; Models, Molecular; Molecular Structure; Multiple Sclerosis; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship

Several recent studies suggest that selective CB2 receptor agonists may represent a valid pharmacological approach in the treatment of various diseases due to the absence of relevant psychoactive side effect. In this study, we synthesized and tested a series of new quinoline-2(1H)-one- and 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine derivatives characterized by a 4-methylcyclohexylamido substituent in position 3 of the heterocyclic nucleus with high CB2 receptor affinity and selectivity. Two compounds showing the best binding and selectivity profile behaved as a full agonist and a partial agonist at the CB2 receptor and induced a concentration-dependent decrease of cell viability on LNCaP, a prostatic cancer cell line expressing CB2 receptor. Moreover considering that the CB2 receptor is mainly expressed in cells and organs of the immune system, the same compounds were studied for their potential immune-modulatory and anti-inflammatory effects in activated lymphocytes isolated from healthy controls and multiple sclerosis (MS) patients.

Topics: Amides; Anti-Inflammatory Agents; Antineoplastic Agents; Carboxylic Acids; Cell Line, Tumor; Cell Survival; Humans; Male; Molecular Structure; Multiple Sclerosis; Naphthyridines; Prostatic Neoplasms; Quinolines; Receptor, Cannabinoid, CB2; Reference Standards

Clinical trials investigating the analgesic efficacy of cannabinoids in multiple sclerosis have yielded mixed results, possibly due to psychotropic side effects mediated by cannabinoid CB1 receptors. We hypothesized that, a CB2-specific agonist (JWH-133) would decrease hyperalgesia in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Four weeks after induction of experimental autoimmune encephalomyelitis, we found that intrathecal administration of JWH-133 (10-100μg) dose-dependently reduced both mechanical and cold hypersensitivity without producing signs of sedation or ataxia. The anti-hyperalgesic effects of JWH-133 could be dose-dependently prevented by intrathecal co-administration of the CB2 antagonist, AM-630 (1-3μg). Our results suggest that JWH-133 acts at CB2 receptors, most likely within the dorsal horn of the spinal cord, to suppress the hypersensitivity associated with experimental autoimmune encephalomyelitis. These are the first pre-clinical studies to directly promote CB2 as a promising target for the treatment of central pain in an animal model of multiple sclerosis.

Topics: Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids; Encephalomyelitis, Autoimmune, Experimental; Female; Hyperalgesia; Indoles; Mice, Inbred C57BL; Multiple Sclerosis; Receptor, Cannabinoid, CB2

Cannabinoids may exhibit symptom control in multiple sclerosis (MS). We show here that cannabinoid receptor (CBR) agonists can also be immunosuppressive and neuroprotective in models of MS. Immunosuppression was associated with reduced: myelin-specific T cell responses; central nervous system infiltration and reduced clinical disease. This was found to be largely CB(1)R-dependent and only occurred at doses that induced significant cannabimimetic effects that would not be achieved clinically. Lower, non-immunosuppressive doses of cannabinoids however, slowed the accumulation of nerve loss and disability, despite failing to inhibit relapses. This further highlights the neuroprotective potential of cannabinoids to slow the progression of MS.

Topics: Animals; Benzoxazines; Cannabinoids; Encephalomyelitis, Autoimmune, Experimental; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; Morpholines; Multiple Sclerosis; Naphthalenes; Neuroprotective Agents; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; T-Lymphocytes