artículo
New Pyridone-Based Derivatives as Cannabinoid Receptor Type 2 Agonists
Fecha
2021Registro en:
10.3390/ijms222011212
1422-0067
MEDLINE:34681877
WOS:000715456600001
Autor
Faundez Parraguez, Manuel
Alarcon Miranda, Carlos
Cho, Young Hwa
Pessoa Mahana, Hernan
Gallardo Garrido, Carlos
Chung, Hery
Faundez, Mario
Pessoa Mahana, David
Institución
Resumen
The activation of the human cannabinoid receptor type II (CB2R) is known to mediate analgesic and anti-inflammatory processes without the central adverse effects related to cannabinoid receptor type I (CB1R). In this work we describe the synthesis and evaluation of a novel series of N-aryl-2-pyridone-3-carboxamide derivatives tested as human cannabinoid receptor type II (CB2R) agonists. Different cycloalkanes linked to the N-aryl pyridone by an amide group displayed CB2R agonist activity as determined by intracellular [cAMP] levels. The most promising compound 8d exhibited a non-toxic profile and similar potency (EC50 = 112 nM) to endogenous agonists Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) providing new information for the development of small molecules activating CB2R. Molecular docking studies showed a binding pose consistent with two structurally different agonists WIN-55212-2 and AM12033 and suggested structural requirements on the pyridone substituents that can satisfy the orthosteric pocket and induce an agonist response. Our results provide additional evidence to support the 2-pyridone ring as a suitable scaffold for the design of CB2R agonists and represent a starting point for further optimization and development of novel compounds for the treatment of pain and inflammation.</p>