3-[3-(Phenalkylamino)cyclohexyl]phenols: Synthesis,biological activity,and in silico investigation of a naltrexone-derived novel class of MOR-antagonists |
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Authors: | Graziella Tocco Antonio Laus Maksims Vanejevs Anastasija Ture Rafaela Mostallino Nicholas Pintori Maria Antonietta De Luca M Paola Castelli Gaetano Di Chiara |
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Institution: | 1. Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy;2. Laboratory of CNS Active Compounds, Latvian Institute of Organic Chemistry, Riga, Latvia;3. Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy;4. Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy
Neuroscience Institute, National Research Council of Italy (CNR), Cagliari, Italy |
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Abstract: | 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. |
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Keywords: | [3H]DAMGO binding assay 3-[3-(phenalkylamino)cyclohexyl]phenols GTPγS assay in silico study MOR antagonists |
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