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Research ArticleNeuropharmacology

Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release

Amy J. Eshleman, Katherine M. Wolfrum, John F. Reed, Sunyoung O. Kim, Tracy Swanson, Robert A. Johnson and Aaron Janowsky
Journal of Pharmacology and Experimental Therapeutics January 2017, 360 (1) 33-47; DOI: https://doi.org/10.1124/jpet.116.236349
Amy J. Eshleman
Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon
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Katherine M. Wolfrum
Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon
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John F. Reed
Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon
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Sunyoung O. Kim
Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon
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Tracy Swanson
Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon
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Robert A. Johnson
Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon
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Aaron Janowsky
Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon
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Abstract

Synthetic cathinones are components of “bath salts” and have physical and psychologic side effects, including hypertension, paranoia, and hallucinations. Here, we report interactions of 20 “bath salt” components with human dopamine, serotonin, and norepinephrine transporters [human dopamine transporter (hDAT), human serotonin transporter (hSERT), and human norepinephrine transporter (hNET), respectively] heterologously expressed in human embryonic kidney 293 cells. Transporter inhibitors had nanomolar to micromolar affinities (Ki values) at radioligand binding sites, with relative affinities of hDAT>hNET>hSERT for α-pyrrolidinopropiophenone (α-PPP), α-pyrrolidinobutiophenone, α-pyrrolidinohexiophenone, 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, 3,4-methylenedioxy-α-pyrrolidinobutiophenone, 4-methyl-α-pyrrolidinopropiophenone, α-pyrrolidinovalerophenone, 4-methoxy-α-pyrrolidinovalerophenone, α-pyrrolidinopentiothiophenone (alpha-PVT), and α-methylaminovalerophenone, and hDAT>hSERT>hNET for methylenedioxypentedrone. Increasing the α-carbon chain length increased the affinity and potency of the α-pyrrolidinophenones. Uptake inhibitors had relative potencies of hDAT>hNET>hSERT except α-PPP and α-PVT, which had highest potencies at hNET. They did not induce [3H]neurotransmitter release. Substrates can enter presynaptic neurons via transporters, and the substrates methamphetamine and 3,4-methylenedioxymethylamphetamine are neurotoxic. We determined that 3-fluoro-, 4-bromo-, 4-chloro-methcathinone, and 4-fluoroamphetamine were substrates at all three transporters; 5,6-methylenedioxy-2-aminoindane (MDAI) and 4-methylethcathinone (4-MEC) were substrates primarily at hSERT and hNET; and 3,4-methylenedioxy-N-ethylcathinone (ethylone) and 5-methoxy-methylone were substrates only at hSERT and induced [3H]neurotransmitter release. Significant correlations between potencies for inhibition of uptake and for inducing release were observed for these and additional substrates. The excellent correlation of efficacy at stimulating release versus Ki/IC50 ratios suggested thresholds of binding/uptake ratios above which compounds were likely to be substrates. Based on their potencies at hDAT, most of these compounds have potential for abuse and addiction. 4-Bromomethcathinone, 4-MEC, 5-methoxy-methylone, ethylone, and MDAI, which have higher potencies at hSERT than hDAT, may have empathogen psychoactivity.

Footnotes

    • Received July 21, 2016.
    • Accepted October 25, 2016.
  • ↵1 Current affiliation: Uniformed Services University, Bethesda, Maryland.

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Interagency Agreement ADA12013 (A.J., A.J.E.) and Grant P50 DA018165 (A.J)], the Department of Justice Drug Enforcement Administration [Interagency Agreement D-15-OD-0002], and Veterans Affairs Merit Review and Career Scientist programs (A.J.).

  • The authors have no actual or potential conflicts of interest.

  • Portions of this work were presented at Eshleman, AJ, Wolfrum KM, Reed JF, Chou YK and Janowsky A. (2013) Synthetic methcathinones: Correlation of potencies for inhibition of uptake and stimulation of neurotransmitter release via biogenic amine transporters. Society for Neuroscience abstract. 213.05, Pharmacology of psychoactive designer “bath salts”, AJ Eshleman et al., abstract #150.

  • dx.doi.org/10.1124/jpet.116.236349.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 360 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 360, Issue 1
1 Jan 2017
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Research ArticleNeuropharmacology

Structure Activity Relationship among Substituted Cathinones

Amy J. Eshleman, Katherine M. Wolfrum, John F. Reed, Sunyoung O. Kim, Tracy Swanson, Robert A. Johnson and Aaron Janowsky
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 33-47; DOI: https://doi.org/10.1124/jpet.116.236349

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Research ArticleNeuropharmacology

Structure Activity Relationship among Substituted Cathinones

Amy J. Eshleman, Katherine M. Wolfrum, John F. Reed, Sunyoung O. Kim, Tracy Swanson, Robert A. Johnson and Aaron Janowsky
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 33-47; DOI: https://doi.org/10.1124/jpet.116.236349
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