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. 2019 Jan 16;10(1):740-745.
doi: 10.1021/acschemneuro.8b00524. Epub 2018 Nov 7.

Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents

Donna Walther  1 , Abdelrahman R Shalabi  2 , Michael H Baumann  1 , Richard A Glennon  2
Affiliations

Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents

Donna Walther et al. ACS Chem Neurosci. .

Abstract

Methcathinone analogs are appearing on the clandestine market at a rate nearly out-pacing the ability of investigators to examine them on an individual basis. To formulate structure-activity relationship (SAR) generalities, we examined the releasing ability of several simple methcathinone analogs at the three monoamine transporters (i.e., the dopamine, norepinephrine, and serotonin transporters, DAT, NET, and SERT, respectively) using in vitro assay methods. The analogs included methcathinone and 14 other compounds monosubstituted at the 2-, 3-, or 4-position. In general, (a) the 2-substituted analogs were less potent than either the 3- or 4-substituted analogs, (b) the 3- and 4-substituted analogs were relatively similar in potency, (c) methcathinone was the most selective as a DAT-releasing agent, and (d) the 3- and 4-CF3 analogs were the least DAT-selective. For the 15 compounds, there was a significant correlation ( r > 0.9) between DAT and NET potency, suggesting relatively similar structure-activity relationships (at least for the compounds examined here). Several of the compounds have appeared on the clandestine market since our studies were initiated, and the present results provide new information on how they might act.

Keywords: DAT; NET; SERT; drug abuse; synaptosomes; synthetic cathinones.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
A comparison of DAT and NET release potencies for compounds shown in Table 1 (n = 15, r = 0.950); DAT and NET data for methcathinone were only considered once, IC50 = 21 and 22 nM, respectively).
Scheme 1.
Scheme 1.
Synthesis of 2- and 3-substituted methcathinone analogs.a aReagents and conditions: (i) N-benzyl-N-methylamine, THF, reflux, 18–23 h; (ii) (a) 1-chloroethyl chloroformate, CH2Cl2, reflux, 2 h; (b) CH3OH, reflux, 1 h; (c) Et2O, room temperature, 18 h.
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