ABSTRACT
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-1ß 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.
Subject(s)
Analgesics/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Multiple Sclerosis/drug therapy , Pyridones/therapeutic use , Analgesics/chemical synthesis , Analgesics/metabolism , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/metabolism , Female , Ligands , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Molecular Structure , Protein Binding , Pyridones/chemical synthesis , Pyridones/metabolism , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
Targeting type-2 cannabinoid receptor (CB2) is considered a feasible strategy to develop new drugs for the treatment of diseases like neuropathic pain, chronic inflammation, neurodegenerative disorders and cancer. Such drugs are devoid of the undesired central side effects that are typically mediated by the CB1 receptor. In this work we synthesized 18 biphenylic carboxamides as new CB2-selective ligands and evaluated their pharmacological profiles. The functional activity of these compounds is strongly influenced by the nature of the substituent at position 4' and 5 of the biphenyl scaffold. Position 5 seems to be responsible for the agonist or inverse agonist behaviour independently of the substituent in position 4', with the exception of the methoxyl group which transforms both full agonists and inverse agonists into neutral antagonists. This study provides a novel complete toolbox of CB2 functional modulators that derive from the same chemical scaffold. Such probes may be useful to investigate the biological role of CB2 receptors in cellular assays.