Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain.
ChemMedChem
; 13(19): 2090-2103, 2018 10 08.
Article
en En
| MEDLINE
| ID: mdl-30085402
ABSTRACT
The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-6-phenylhexylcarbamate (5 h) and 4-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-(6-phenylhexyl)carbamate (5 i) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB1 R), were selected for further studies. Results of cell-based studies on a neuroblastoma cell line (IMR32) demonstrated 5 h, 5 i, and our reference compound 3 ([3-(3-carbamoylpyrrol-1-yl)phenyl] N-(5-phenylpentyl)carbamate) to lack any cytotoxic effect, while all three showed the ability to decrease oxidative stress by reducing the expression of the redox-sensitive transcription factor NF-κB. Encouraged by these data, these compounds were studied in vivo and were dosed orally in a mouse model of neuropathic pain. At 10â
mg kg-1 all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Benzodiazepinonas
/
Inhibidores Enzimáticos
/
Amidohidrolasas
/
Neuralgia
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Italia