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.2020 Jun 17;11(12):1762-1769.
doi: 10.1021/acschemneuro.9b00617. Epub 2020 May 27.

Investigation of the Optical Isomers of Methcathinone, and Two Achiral Analogs, at Monoamine Transporters and in Intracranial Self-Stimulation Studies in Rats

Investigation of the Optical Isomers of Methcathinone, and Two Achiral Analogs, at Monoamine Transporters and in Intracranial Self-Stimulation Studies in Rats

Rachel A Davies et al. ACS Chem Neurosci..

Abstract

Methcathinone (MCAT;1), the progenitor of numerous and widely abused "synthetic cathinone" central stimulants, exists as a pair of optical isomers. AlthoughS(-)MCAT is several-fold more potent thanR(+)MCAT in rodent locomotor stimulation and in stimulus generalization studies in rat drug discrimination assays, the individual optical isomers of MCAT have never been directly compared for their actions at monoamine transporters that seem to underlie their actions and have never been examined for their relative abuse potential. Here, we found that the isomers of MCAT are nearly equieffective at dopamine and norepinephrine transporters (DAT and NET, respectively) as transporter substrates (i.e., as releasing agents) and are ≥63-fold less potent at the serotonin transporter (SERT). In intracranial self-stimulation (ICSS) studies to evaluate abuse-related drug effects in rats,S(-)MCAT was approximately twice as potent as itsR-enantiomer. Achiral analogs, α-methyl MCAT (3) and α-des-methyl MCAT (4), also were DAT/NET substrates and also produced abuse-related ICSS effects, indicating that they retain abuse potential and that they might be useful for the further study of the stereochemistry of synthetic cathinone analogs with chiral β- (or other) substituents.

Keywords: DAT; ICSS; NET; SERT; Synthetic cathinones; achiral methcathinone; drug abuse; methcathinone optical isomers; monoamine transporters.

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Conflict of interest statement

The authors claim no conflicting financial interest.

Figures

Figure 1.
Figure 1.
Chemical structures of MCAT (1), methamphetamine (2), and achiral analogs3 and4.
Figure 2.
Figure 2.
Concentration-response curves for MCAT and its optical isomers (upper trace), and compounds3 and4 relative to racemic MCAT (lower trace), as DAT substrates. The potency of these compounds was estimated by evaluating the depolarizing action of releasing agents when they interact with DAT. Voltage-gated Ca2+ channels were used as voltage sensors and the opening of these channels results in Ca2+ signals proportional to the transporter depolarizing activity. The experimental points correspond to mean ± SEM of n ≥ 23 cells analyzed per concentration.
Figure 3.
Figure 3.
Dose-dependent ICSS facilitation by racemic MCAT,S(−)MCAT,R(+)MCAT,α-methyl MCAT, andα-des-methyl-MCAT. Panels A-E show drug effects by dose on full ICSS frequency-rate curves.Abscissae: Frequency of electrical brain stimulation in Hz (log scale).Ordinates: Percent maximal control reinforcement rate (%MCR). Legends indicate the drug name and doses. Filled points represent frequencies at which ICSS rate was statistically different from vehicle as determined by two-way repeated-measures ANOVA followed by a Holm-Sidakpost hoc test, p < 0.05. Panel F shows summary ICSS data expressed as percent baseline number of stimulations per component delivered across all brain-stimulation frequencies for all drugs.Abscissa: Drug dose in mg/kg (log scale).Ordinate: Percent baseline number of stimulations per component. Filled points represent significant difference compared to vehicle using a repeated-measures one-way ANOVA for each drug followed by a Holm-Sidakpost hoc test, p < 0.05. All points show mean ± SEM for six rats (n=6).
Figure 4.
Figure 4.
Time course of ICSS facilitation by racemic MCAT,S(−)MCAT,R(+)MCAT,α-methyl MCAT, andα-des-methyl-MCAT. Panels A-E show full frequency-rate curves determined 10, 30, 100, and 300-minute after drug injection.Abscissae: Frequency of electrical brain stimulation in Hz (log scale).Ordinates: Percent maximal control reinforcement rate (%MCR). Filled points represent frequencies at which ICSS rate was statistically different from baseline as determined by two-way repeated-measures ANOVA followed by a Holm-Sidakpost hoc test, p < 0.05. Panel F shows summary data for total stimulations per component compared to baseline for all drugs.Abscissa: Time after injection in minutes (log scale).Ordinate: Percent baseline number of stimulations per component. Filled points represent significant difference compared to baseline using a repeated-measures one-way ANOVA followed by a Holm-Sidakpost hoc test, p < 0.05. All points mean ± SEM for six rats (n=6) with the exception ofS(−)MCAT, which had five subjects (n=5).
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