biostudies-literatureSorrentino JPNIGMS NIH HHS707-713https://www.ebi.ac.uk/biostudies/studies/S-EPMC9014517biostudies-literatureUnknown13(4)Aryl-methyl ethers, while present in many bioactive compounds, are subject to rapid O-dealkylation, which can generate bioinactive or toxic metabolites. Such is the case for dextromethorphan, which readily undergoes P450 mediated O-dealkylation to provide the psychoactive phenolic metabolite dextrorphan, an <i>N</i>-methyl-d-aspartate (NMDA) receptor antagonist that causes hallucinations and encourages recreational abuse. As a general strategy to minimize this undesired degradation, both deuteration and fluorination strategies might be exploited, though such strategies have rarely been compared in matched series. In this manuscript, we designed, synthesized, and evaluated <i>in vitro</i> and <i>in vivo</i> new fluoroalkyl analogs of dextromethorphan and D₃-dextromethorphan that ACS medicinal chemistry lettersFluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability.PMC9014517P20 GM103418R35 GM124661Sorrentino JPAltman RAfalseFluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability.Aryl-methyl ethers, while present in many bioactive compounds, are subject to rapid O-dealkylation, which can generate bioinactive or toxic metabolites. Such is the case for dextromethorphan, which readily undergoes P450 mediated O-dealkylation to provide the psychoactive phenolic metabolite dextrorphan, an <i>N</i>-methyl-d-aspartate (NMDA) receptor antagonist that causes hallucinations and encourages recreational abuse. As a general strategy to minimize this undesired degradation, both deuteration and fluorination strategies might be exploited, though such strategies have rarely been compared in matched series. In this manuscript, we designed, synthesized, and evaluated <i>in vitro</i> and <i>in vivo</i> new fluoroalkyl analogs of dextromethorphan and D₃-dextromethorphan that 2022-01-01T00:00:00Z2022 Apr2025-04-04T14:23:50.93Z2025-04-04T14:23:50.93ZS-EPMC90145173545037910.1021/acsmedchemlett.2c00055