Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity

August 16, 2017


Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and ‘pharmacoterrorism’ in the Middle East1,2,3,4. Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure5,6. These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system7,8,9. Although the psychoactive properties of fenethylline have been reported to differ from those of other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects10,11. Here we develop a ‘dissection through vaccination’ approach, called DISSECTIV, to mitigate the psychoactive effects of fenethylline and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against a single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacological activity. We anticipate that DISSECTIV will be used to expose unidentified active chemical species and resolve pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples and natural product extracts.


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Funding Source

This work was supported by a grant from the NIH (DA024705-06). We thank M. Gooyit for supplying reagents, B. Ellis for assistance with tissue collection and M. Taffe for providing DEA licensing (RT0485537). This is manuscript 29481 from The Scripps Research Institute.

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This article is cited by 3 publications

  1. Zheng, Z., Kyzer, J. L., Worob, A., & Wenthur, C. J. (2021). Family of Structurally Related Bioconjugates Yields Antibodies with Differential Selectivity against Ketamine and 6-Hydroxynorketamine. ACS chemical neuroscience, 12(21), 4113–4122.
  2. Wang, Y. Q., Lin, W. W., Wu, N., Wang, S. Y., Chen, M. Z., Lin, Z. H., Xie, X. Q., & Feng, Z. W. (2019). Structural insight into the serotonin (5-HT) receptor family by molecular docking, molecular dynamics simulation and systems pharmacology analysis. Acta pharmacologica Sinica, 40(9), 1138–1156.
  3. Wu, N., Feng, Z., He, X., Kwon, W., Wang, J., & Xie, X. Q. (2019). Insight of Captagon Abuse by Chemogenomics Knowledgebase-guided Systems Pharmacology Target Mapping Analyses. Scientific reports, 9(1), 2268.