New Pyridone-Based Derivatives as Cannabinoid Receptor Type 2 Agonists

• Published in: International journal of molecular sciences 2021-10, Vol.22 (20), p.11212
• Main Authors: Faúndez-Parraguez, Manuel, Alarcón-Miranda, Carlos, Cho, Young Hwa, Pessoa-Mahana, Hernán, Gallardo-Garrido, Carlos, Chung, Hery, Faúndez, Mario, Pessoa-Mahana, David
• Format: Article
• Language: English
• Subjects: 2-Arachidonoylglycerol; 2-pyridone; Agonists; Analgesics; Anandamide; Animals; Arachidonic Acids - chemistry; Arachidonic Acids - pharmacology; Aromatic compounds; Benzoxazines - chemistry; Benzoxazines - pharmacology; Binding Sites; Cannabinoid CB1 receptors; Cannabinoid CB2 receptors; Cannabinoid Receptor Agonists - chemical synthesis; Cannabinoid Receptor Agonists - chemistry; Cannabinoid Receptor Agonists - pharmacology; cannabinoids; CB2R agonists; Cell Survival - drug effects; CHO Cells; Cricetulus; Cyclic AMP - metabolism; Drug Evaluation, Preclinical; Endocannabinoids - chemistry; Endocannabinoids - pharmacology; Glycerides - chemistry; Glycerides - pharmacology; Hep G2 Cells; HL-60 Cells; Humans; Inflammation; Ligands; Molecular docking; Molecular Docking Simulation; Morpholines - chemistry; Morpholines - pharmacology; Naphthalenes - chemistry; Naphthalenes - pharmacology; Polyunsaturated Alkamides - chemistry; Polyunsaturated Alkamides - pharmacology; Pyridones - chemistry; Pyridones - pharmacology; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - chemistry; Receptor, Cannabinoid, CB2 - genetics; Receptor, Cannabinoid, CB2 - metabolism; Structure-Activity Relationship; synthesis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222011212

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 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.