New Pyridone-Based Derivatives as Cannabinoid Receptor Type 2 Agonists

Faundez-Parraguez, Manuel; Alarcón-Miranda, Carlos; Cho, Young Hwa; Pessoa-Mahana, Hernán; Gallardo-Garrido, Carlos; Chung, Hery; Faúndez, Mario A.; Pessoa-Mahana, David

Keywords: synthesis, Cannabinoids, 2-pyridone, CB2R agonists

Abstract

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.

Más información

Título de la Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volumen: 22
Editorial: Multidisciplinary Digital Publishing Institute
Fecha de publicación: 2021
Página de inicio: 11212
Idioma: inglés
URL: https://doi.org/10.3390/ijms222011212