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Synthesis, Pharmacological Evaluation, and Docking Studies of Novel Pyridazinone‐Based Cannabinoid Receptor Type 2 Ligands
Author(s) -
Ragusa Giulio,
Bencivenni Serena,
Morales Paula,
Callaway Tyra,
Hurst Dow P.,
Asproni Battistina,
Merighi Stefania,
Loriga Giovanni,
Pinna Gerard A.,
Reggio Patricia H.,
Gessi Stefania,
Murineddu Gabriele
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800152
Subject(s) - chemistry , stereochemistry , docking (animal) , inverse agonist , cannabinoid , carboxamide , in silico , cannabinoid receptor , receptor , antagonist , biochemistry , medicine , gene , nursing
In recent years, cannabinoid type 2 receptors (CB 2 R) have emerged as promising therapeutic targets in a wide variety of diseases. Selective ligands of CB 2 R are devoid of the psychoactive effects typically observed for CB 1 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 CB 2 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 CB 2 R affinity, with K i values of 2.1 and 1.6 n m , respectively. In addition, functional assays of these compounds and other new active related derivatives revealed their pharmacological profiles as CB 2 R inverse agonists. Compound 22 displayed the highest CB 2 R selectivity and potency, presenting a favorable in 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.