Synthesis,Pharmacological Evaluation,and Docking Studies of Novel Pyridazinone‐Based Cannabinoid Receptor Type 2 Ligands |
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| Authors: | Dr. Giulio Ragusa Dr. Serena Bencivenni Dr. Paula Morales Dr. Tyra Callaway Dr. Dow P. Hurst Dr. Battistina Asproni Dr. Stefania Merighi Dr. Giovanni Loriga Prof. Gerard A. Pinna Prof. Patricia H. Reggio Prof. Stefania Gessi Prof. Gabriele Murineddu |
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| Affiliation: | 1. Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy;2. Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy;3. Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA;4. Institute of Translational Pharmacology, National Research Council, Cagliari, Italy |
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| Abstract: | In recent years, cannabinoid type 2 receptors (CB2R) have emerged as promising therapeutic targets in a wide variety of diseases. Selective ligands of CB2R are devoid of the psychoactive effects typically observed for CB1R 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 CB2R 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 CB2R affinity, with Ki values of 2.1 and 1.6 nm , respectively. In addition, functional assays of these compounds and other new active related derivatives revealed their pharmacological profiles as CB2R inverse agonists. Compound 22 displayed the highest CB2R 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. |
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| Keywords: | ADMET calculations cannabinoid receptors CB2 inverse agonism docking studies synthesis |
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