The endocannabinoid system dual-target ligand N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide improves disease severity in a mouse model of multiple sclerosis.

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-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.

• Authors: Chiara Arena, Francesca Gado, Lorenzo Di Cesare Mannelli, Chiara Cervetto, Sara Carpi, Ines Reynoso-Moreno, Beatrice Polini, Erika Vallini, Stefano Chicca, Elena Lucarini, Simone Bertini, Felicia D'Andrea, Maria Digiacomo, Giulio Poli, Tiziano Tuccinardi, Marco Macchia, Jürg Gertsch, Manuela Marcoli, Paola Nieri, Carla Ghelardini, Andrea Chicca, Clementina Manera
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 208 Pg. 112858 (Dec 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 33002735 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Analgesics
• Anti-Inflammatory Agents
• Ligands
• Pyridones
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2

Topics

• Analgesics (chemical synthesis, metabolism, therapeutic use)
• Animals
• Anti-Inflammatory Agents (chemical synthesis, metabolism, therapeutic use)
• Female
• Ligands
• Male
• Mice, Inbred C57BL
• Molecular Docking Simulation
• Molecular Structure
• Multiple Sclerosis (drug therapy)
• Protein Binding
• Pyridones (chemical synthesis, metabolism, therapeutic use)
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1 (agonists, metabolism)
• Receptor, Cannabinoid, CB2 (agonists, metabolism)
• Structure-Activity Relationship