Synthesis of a novel and potent small-molecule antagonist of PAC1 receptor for the treatment of neuropathic pain.
Eur J Med Chem
; 186: 111902, 2020 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-31771828
ABSTRACT
We recently identified novel small-molecule antagonists of the PACAP type I (PAC1) receptor using docking-based in silico screening followed by in vitro/vivo pharmacological assays. In the present study, we synthesized 18 novel derivatives based on the structure of PA-9, a recently developed antagonist of the PAC1 receptor, with a view to obtain a panel of compounds with more potent antagonistic and analgesic activities. Among them, compound 3d showed improved antagonistic activities. Intrathecal injection of 3d inhibited both pituitary adenylate cyclase-activating polypeptide (PACAP) and spinal nerve ligation-induced mechanical allodynia. The effects were more potent than PA-9. Compound 3d also showed anti-allodynic effects following oral administration. Hence, our results suggest that 3d may become an orally available analgesic in the treatment of the neuropathic pain.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase
/
Bibliotecas de Moléculas Pequenas
/
Analgésicos
/
Neuralgia
Limite:
Animals
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2020
Tipo de documento:
Article