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Correlating the Metabolic Stability of Psychedelic 5-HT2A Agonists with Anecdotal Reports of Human Oral Bioavailability

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A Publisher's Erratum to this article was published on 28 March 2014

Abstract

2,5-Dimethoxyphenethylamines and their N-benzylated derivatives are potent 5-HT2A agonists with psychedelic effects in humans. The N-benzylated derivatives are among the most selective 5-HT2A agonists currently available and their usage as biochemical and brain imaging tools is increasing, yet very little is known about the relationships between the structure of the ligands and their pharmacokinetic profile. In order to evaluate the potential of these compounds for in vivo applications we have determined the microsomal stability of 11 phenethylamines and 27 N-benzylated derivatives thereof using human liver microsomes. We found that the N-benzylated phenethylamines have much higher intrinsic clearance than the parent phenethylamines. We hypothesize that their low hepatic stability renders them orally inactive due to first pass metabolism, which is supported by anecdotal data from recreational use of these compounds.

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Conflict of interest

The authors declare no conflict of interest associated with the present study.

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Authors and Affiliations

  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark

    Sebastian Leth-Petersen, Martin Hansen & Jesper Langgaard Kristensen

  2. Department of Discovery Chemistry and DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Christoffer Bundgaard, Martin A. Carnerup & Jan Kehler

Authors
  1. Sebastian Leth-Petersen
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  2. Christoffer Bundgaard
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  3. Martin Hansen
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  4. Martin A. Carnerup
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  5. Jan Kehler
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  6. Jesper Langgaard Kristensen
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Correspondence to Jesper Langgaard Kristensen.

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Special Issue: In honor of Krogsgaard-Larsen.

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Leth-Petersen, S., Bundgaard, C., Hansen, M. et al. Correlating the Metabolic Stability of Psychedelic 5-HT2A Agonists with Anecdotal Reports of Human Oral Bioavailability. Neurochem Res 39, 2018–2023 (2014). https://doi.org/10.1007/s11064-014-1253-y

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  • DOI: https://doi.org/10.1007/s11064-014-1253-y

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