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

  • Eur J Med Chem. 2020 Dec 15;208:112858. doi: 10.1016/j.ejmech.2020.112858.
Chiara Arena  1 ,  Francesca Gado  2 ,  Lorenzo Di Cesare Mannelli  3 ,  Chiara Cervetto  4 ,  Sara Carpi  2 ,  Ines Reynoso-Moreno  5 ,  Beatrice Polini  2 ,  Erika Vallini  1 ,  Stefano Chicca  1 ,  Elena Lucarini  3 ,  Simone Bertini  2 ,  Felicia D'Andrea  2 ,  Maria Digiacomo  2 ,  Giulio Poli  2 ,  Tiziano Tuccinardi  2 ,  Marco Macchia  2 ,  Jürg Gertsch  5 ,  Manuela Marcoli  4 ,  Paola Nieri  2 ,  Carla Ghelardini  3 ,  Andrea Chicca  6 ,  Clementina Manera  7
Affiliations
  • 1. Department of Pharmacy, University of Pisa, 56126, Pisa, Italy; NCCR-TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012, Bern, Switzerland.
  • 2. Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
  • 3. Department of Neuroscience, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, 50139, Florence, Italy.
  • 4. Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genova, 16126, Genova, Italy.
  • 5. NCCR-TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012, Bern, Switzerland.
  • 6. NCCR-TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012, Bern, Switzerland. Electronic address: [email protected].
  • 7. Department of Pharmacy, University of Pisa, 56126, Pisa, Italy. Electronic address: [email protected].
PMID: 33002735 DOI: 10.1016/j.ejmech.2020.112858
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.

Keywords
1,2-Dihydropyridine-2-oxo-3-carboxamides; EAE mouse Model multiple sclerosis; Endocannabinoid system; Glutamate release; Microglial cell; Neuropathic pain.
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