Synthesis, Pharmacological Evaluation, and Docking Studies of Novel Pyridazinone-Based Cannabinoid Receptor Typeâ
2 Ligands.
ChemMedChem
; 13(11): 1102-1114, 2018 06 06.
Article
em En
| MEDLINE
| ID: mdl-29575721
ABSTRACT
In recent years, cannabinoid typeâ
2 receptors (CB2 R) have emerged as promising therapeutic targets in a wide variety of diseases. Selective ligands of CB2 R are devoid of the psychoactive effects typically observed for CB1 R ligands. Based on our recent studies on a class of pyridazinone 4-carboxamides, further structural modifications of the pyridazinone core were made to better investigate the structure-activity relationships for this promising scaffold with the aim to develop potent CB2 R ligands. In binding assays, two of the new synthesized compounds [6-(3,4-dichlorophenyl)-2-(4-fluorobenzyl)-cis-N-(4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (2) and 6-(4-chloro-3-methylphenyl)-cis-N-(4-methylcyclohexyl)-3-oxo-2-pentyl-2,3-dihydropyridazine-4-carboxamide (22)] showed high CB2 R affinity, with Ki values of 2.1 and 1.6â
nm, respectively. In addition, functional assays of these compounds and other new active related derivatives revealed their pharmacological profiles as CB2 R inverse agonists. Compound 22 displayed the highest CB2 R selectivity and potency, presenting a favorable inâ
silico pharmacokinetic profile. Furthermore, a molecular modeling study revealed how 22 produces inverse agonism through blocking the movement of the toggle-switch residue, W6.48.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Piridazinas
/
Receptor CB2 de Canabinoide
/
Antagonistas de Receptores de Canabinoides
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article