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Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters

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Abstract

Rationale

New psychoactive substances (NPSs), including substituted cathinones and other stimulants, are synthesized, sold on the Internet, and ingested without knowledge of their pharmacological activity and/or toxicity. In vitro pharmacology plays a role in therapeutic drug development, drug-protein in silico interaction modeling, and drug scheduling.

Objectives

The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability.

Methods

Affinities to displace the radioligand [125I]RTI-55 and potencies to inhibit [3H]neurotransmitter uptake for 22 cathinones, 6 benzofurans and another stimulant were characterized using human embryonic kidney cells stably expressing recombinant human transporters for dopamine, norepinephrine, or serotonin (hDAT, hNET, or hSERT, respectively). Selected compounds were tested for potencies and efficacies at inducing [3H]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters.

Results

Most α-pyrrolidinophenones had high hDAT potencies and selectivities in uptake assays, with hDAT/hSERT uptake selectivity ratios of 83–360. Other substituted cathinones varied in their potencies and selectivities, with N-ethyl-hexedrone and N-ethyl-pentylone having highest hDAT potencies and N-propyl-pentedrone having highest hDAT selectivity. 4-Cl-ethcathinone and 3,4-methylenedioxy-N-propylcathinone had higher hSERT selectivity. Benzofurans generally had low hDAT selectivity, especially 1-(2,3-dihydrobenzofuran-5-yl)-N-methylpropan-2-amine, with 25-fold higher hSERT potency. Consistent with this selectivity, the benzofurans were releasers at hSERT. Modeling indicated key amino acids in the transporters’ binding pockets that influence drug affinities.

Conclusions

The α-pyrrolidinophenones, with high hDAT selectivity, have high abuse potential. Lower hDAT selectivity among benzofurans suggests similarity to methylenedioxymethamphetamine, entactogens with lower stimulant activity.

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Acknowledgments

We thank the OHSU Medicinal Chemistry Core for the drug-transporter modeling and analysis.

Role of funding source

DEA project officers contributed to the study design and reviewed the manuscript. They had no further role in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Funding

Funding for this study was provided by the Department of Justice Drug Enforcement Administration (D-15-OD-0002), Veterans Affairs Merit Review (I01BX002758) and Career Scientist (14S-RCS-006) programs, the Methamphetamine Abuse Research Center (P50 DA018165), and National Institutes of Health/National Institute on Drug Abuse (ADA12013). The contents do not represent the views of the United States Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

  1. Research Service, VA Portland Health Care System, 3710 SW US Veterans Hospital Rd., Portland, OR, 97239, USA

    Amy J. Eshleman, Katherine M. Wolfrum, John F. Reed, Tracy L. Swanson, Aaron Nilsen & Aaron Janowsky

  2. Departments of Behavioral Neuroscience and Psychiatry, Oregon Health & Science University, Portland, OR, 97239, USA

    Amy J. Eshleman, Tracy L. Swanson & Aaron Janowsky

  3. Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR, 97239, USA

    Shanthi Nagarajan & Aaron Nilsen

  4. The Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, 97239, USA

    Aaron Janowsky

Authors
  1. Amy J. Eshleman
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  2. Shanthi Nagarajan
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  3. Katherine M. Wolfrum
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  4. John F. Reed
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  5. Tracy L. Swanson
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  6. Aaron Nilsen
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  7. Aaron Janowsky
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Contributions

Participated in the research design: Eshleman, Janowsky, Nagarajan, and Nilsen

Conducted the experiments: Eshleman, Wolfrum, Reed, and Swanson

Performed the data analysis: Eshleman, Wolfrum, Reed, Swanson, and Nagarajan

Wrote or contributed to the writing of the manuscript: Eshleman, Janowsky, Nagarajan, and Nilsen

Corresponding author

Correspondence to Amy J. Eshleman.

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The authors declare that they have no conflicts of interest.

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This article belongs to a Special Issue on Bath Salts

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Eshleman, A.J., Nagarajan, S., Wolfrum, K.M. et al. Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters. Psychopharmacology 236, 939–952 (2019). https://doi.org/10.1007/s00213-018-5059-5

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  • DOI: https://doi.org/10.1007/s00213-018-5059-5

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