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1.
Eur J Med Chem ; 208: 112858, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33002735

RESUMO

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.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Piridonas/uso terapêutico , Analgésicos/síntese química , Analgésicos/metabolismo , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Feminino , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Piridonas/síntese química , Piridonas/metabolismo , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 116: 252-266, 2016 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-27078864

RESUMO

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.


Assuntos
Compostos de Bifenilo/síntese química , Compostos de Bifenilo/metabolismo , Desenho de Fármacos , Receptor CB2 de Canabinoide/metabolismo , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Células CHO , Técnicas de Química Sintética , Cricetinae , Cricetulus , Humanos , Ligantes , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade
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