Substituted methcathinones differ in transporter and receptor interactions - PubMed (original) (raw)

Comparative Study

Substituted methcathinones differ in transporter and receptor interactions

Amy J Eshleman et al. Biochem Pharmacol. 2013.

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-HT(1A) receptor partial agonists, (2) h5-HT(2A) receptor antagonists, (3) weak h5-HT(2C) 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.

Published by Elsevier Inc.

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Conflict of interest statement

The authors have no actual or potential conflicts of interest.

Figures

Figure 1

Figure 1

Structures of substituted methcathinones, MDMA, and METH.

Figure 2

Figure 2

Time courses of [3H]neurotransmitter release induced by the substituted methcathinones 4-FMC, mephedrone and methylone from HEK-hDAT, -hSERT and -hNET cells. Data shown are representative experiments. Data are normalized to percent release of [3H]neurotransmitter remaining in cells at each time point. The last three buffer fractions prior to addition of drug and the 12 fractions in the presence of drug are shown.

Figure 3

Figure 3

Substituted methcathinones, METH, and MDMA dose-response curves for release of [3H]neurotransmitter from HEK-hDAT (A,B), -hSERT (C,D) and -hNET (E,F) cells. The area under the curve (AUC) for each drug concentration was normalized to the maximal effect of METH for that experiment (hDAT and hNET) or the maximal effect of PCA (hSERT). A, C and E: Data show the lack of effect of minimal releasers compared to METH, methcathinone, MDMA and, for SERT, PCA. B, D, and F: Data show the effects of releasers at each or the transporters compared to METH.

Figure 4

Figure 4

Effects of substituted methcathinones, METH and MDMA on h5-HT1A and h5-HT2A function. A. The h5-HT1A agonist assay, stimulation of [35S]GTPγS binding. The methcathinones were full to partial agonists, tested at concentrations ranging from 100 nM to 1 mM. B. The h5-HT2A antagonist assay, inhibition of 100 nM-5-HT-stimulated inositol-1-phosphate formation. The compounds had no agonist activity (data not shown). The substituted methcathinones were weak to full antagonists and were tested at concentrations ranging from 100 nM to 1 mM. The percent inhibition by each compound at 100 µM and 1 mM concentrations is shown.

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