Novel Sigma 1 Receptor Antagonists as Potential Therapeutics for Pain Management.
J Med Chem
; 64(1): 890-904, 2021 01 14.
Artículo
en Inglés
| MEDLINE | ID: covidwho-997768
ABSTRACT
The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound 10 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable in vitro metabolic stability, slow clearance in liver microsomes, and excellent blood-brain barrier permeability in rats. Further in vivo studies in rats showed that 10 exhibited negligible acute toxicity in the rotarod test and statistically significant analgesic effects in the formalin test for acute inflammatory pain and paclitaxel-induced neuropathic pain models during cancer chemotherapy. These encouraging results promote further development of our triazole-based S1R antagonists as novel treatments for pain of different etiologies.
Texto completo:
Disponible
Colección:
Bases de datos internacionales
Base de datos:
MEDLINE
Asunto principal:
Triazoles
/
Receptores sigma
/
Manejo del Dolor
Tipo de estudio:
Estudio de etiologia
/
Estudio experimental
Límite:
Animales
/
Humanos
Idioma:
Inglés
Revista:
J Med Chem
Asunto de la revista:
Química
Año:
2021
Tipo del documento:
Artículo
País de afiliación:
Acs.jmedchem.0c01964
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