Substituted methcathinones differ in transporter and receptor interactions

Amy J. Eshleman, Katherine M. Wolfrum, Meagan G. Hatfield, Robert A. Johnson, Kevin V. Murphy, Aaron Janowsky

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

Abstract

The use of synthetic methcathinones, components of "bath salts," is a world-wide health concern. These compounds, structurally similar to methamphetamine (METH) and 3,4-methylendioxymethamphetamine (MDMA), cause tachycardia, hallucinations and psychosis. We hypothesized that these potentially neurotoxic and abused compounds display differences in their transporter and receptor interactions as compared to amphetamine counterparts. 3,4-Methylenedioxypyrovalerone and naphyrone had high affinity for radioligand binding sites on recombinant human dopamine (hDAT), serotonin (hSERT) and norepinephrine (hNET) transporters, potently inhibited [3H] neurotransmitter uptake, and, like cocaine, did not induce transporter-mediated release. Butylone was a lower affinity uptake inhibitor. In contrast, 4-fluoromethcathinone, mephedrone and methylone had higher inhibitory potency at uptake compared to binding and generally induced release of preloaded [ 3H]neurotransmitter from hDAT, hSERT and hNET (highest potency at hNET), and thus are transporter substrates, similar to METH and MDMA. At hNET, 4-fluoromethcathinone was a more efficacious releaser than METH. These substituted methcathinones had low uptake inhibitory potency and low efficacy at inducing release via human vesicular monoamine transporters (hVMAT2). These compounds were low potency (1) h5-HT1A receptor partial agonists, (2) h5-HT2A receptor antagonists, (3) weak h5-HT2C receptor antagonists. This is the first report on aspects of substituted methcathinone efficacies at serotonin (5-HT) receptors and in superfusion release assays. Additionally, the drugs had no affinity for dopamine receptors, and high-nanomolar to mid-micromolar affinity for hSigma1 receptors. Thus, direct interactions with hVMAT2 and serotonin, dopamine, and hSigma1 receptors may not explain psychoactive effects. The primary mechanisms of action may be as inhibitors or substrates of DAT, SERT and NET.

Original languageEnglish (US)
Pages (from-to)1803-1815
Number of pages13
JournalBiochemical Pharmacology
Volume85
Issue number12
DOIs
StatePublished - 2013

Keywords

  • Dopamine transporter
  • Methcathinone
  • Norepinephrine transporter
  • Serotonin receptor
  • Serotonin transporter

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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