3‐[3‐(Phenalkylamino)cyclohexyl]phenols: Synthesis, biological activity, and in silico investigation of a naltrexone‐derived novel class of MOR‐antagonists

The development of novel μ‐opioid receptor (MOR) antagonists is one of the main objectives of drug discovery and development. Based on a simplified version of the morphinan scaffold, 3‐[3‐(phenalkylamino)cyclohexyl]phenol analogs were designed, synthesized, and evaluated for their MOR antagonist act...

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Veröffentlicht in:Archiv der Pharmazie (Weinheim) 2023-01, Vol.356 (1), p.e2200432-n/a
Hauptverfasser: Tocco, Graziella, Laus, Antonio, Vanejevs, Maksims, Ture, Anastasija, Mostallino, Rafaela, Pintori, Nicholas, De Luca, Maria Antonietta, Castelli, M. Paola, Di Chiara, Gaetano
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Sprache:eng
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Zusammenfassung:The development of novel μ‐opioid receptor (MOR) antagonists is one of the main objectives of drug discovery and development. Based on a simplified version of the morphinan scaffold, 3‐[3‐(phenalkylamino)cyclohexyl]phenol analogs were designed, synthesized, and evaluated for their MOR antagonist activity in vitro and in silico. At the highest concentrations, the compounds decreased by 52% to 75% DAMGO‐induced GTPγS stimulation, suggesting that they acted as antagonists. Moreover, Extra‐Precision Glide and Generalized‐Born Surface Area experiments provided useful information on the nature of the ligand–receptor interactions, indicating a peculiar combination of C‐1 stereochemistry and N‐substitutions as feasibly essential for MOR–ligand complex stability. Interestingly, compound 9 showed the best experimental binding affinity, the highest antagonist activity, and the finest MOR–ligand complex stability. In silico experiments also revealed that the most promising stereoisomer (1R, 3R, 5S) 9 retained 1,3‐cis configuration with phenol ring equatorial oriented. Further studies are needed to better characterize the pharmacodynamics and pharmacokinetic properties of these compounds. Based on a simplified version of the morphinan scaffold, 3‐[3‐(phenalkylamino)cyclohexyl]phenol analogues were designed, synthesized and evaluated for their µ‐opioid receptor (MOR) antagonist activity in vitro and in silico. Docking studies indicate a peculiar combination of C‐1 stereochemistry and N‐substitutions as feasibly essential for MOR‐ligand complex stability.
ISSN:0365-6233
1521-4184
DOI:10.1002/ardp.202200432