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.

Arena, Chiara; Gado, Francesca; Di Cesare Mannelli, Lorenzo; Cervetto, Chiara; Carpi, Sara; Reynoso-Moreno, Ines; Polini, Beatrice; Vallini, Erika; Chicca, Stefano; Lucarini, Elena; Bertini, Simone; D'Andrea, Felicia; Digiacomo, Maria; Poli, Giulio; Tuccinardi, Tiziano; Macchia, Marco; Gertsch, Jürg; Marcoli, Manuela; Nieri, Paola; Ghelardini, Carla; ... (2020). 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. European journal of medicinal chemistry, 208, p. 112858. Elsevier 10.1016/j.ejmech.2020.112858

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Reynoso, Ines del Carmen; Vallini, Erika; Gertsch, Jürg and Chicca, Andrea

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1768-3254

Publisher:

Elsevier

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

13 Jan 2021 16:32

Last Modified:

17 Jan 2021 02:55

Publisher DOI:

10.1016/j.ejmech.2020.112858

PubMed ID:

33002735

Uncontrolled Keywords:

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

BORIS DOI:

10.48350/150887

URI:

https://boris.unibe.ch/id/eprint/150887

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