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. 2017 Jun 21;8(6):1397-1403.
doi: 10.1021/acschemneuro.7b00055. Epub 2017 Feb 27.

Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release

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

Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release

Abdelrahman R Shalabi et al. ACS Chem Neurosci. .

Abstract

Bupropion (1), an α-aminophenone uptake inhibitor at plasma membrane transporters for dopamine (DAT) and norepinephrine (NET), is a widely prescribed antidepressant and smoking cessation aid. Cathinone (2), a structurally simpler α-aminophenone, is a substrate-type releasing agent at the same transporters and a recognized drug of abuse. Our goal was to identify the structural features of α-aminophenones that govern the mechanistic transition from uptake inhibition to substrate-induced release. Deconstructed analogues of 1 were synthesized and compared for their ability to interact with DAT, NET, and the serotonin transporter (SERT) using in vitro assay methods. Bulky amine substituents resulted in compounds that function as DAT uptake inhibitors but not release agents, whereas smaller amine substituents result in relatively nonselective releasing agents at DAT and NET. Our findings add to empirical evidence supporting distinct molecular determinants for α-aminophenone- (i.e., cathinone-) related agents acting as transporter inhibitors versus those acting as releasers.

Keywords: Dopamine transporter; cathinone analogues; drug abuse; norepinephrine transporter; serotonin transporter; synthetic cathinones.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Effects of bupropion analogues on inhibition of [3H]transmitter uptake via DAT, NET, and SERT in rat brain synaptosomes. Uptake of [3H]dopamine (DAT assays), [3H]norepinephrine (NET assays), or [3H]5-HT (SERT assays) was examined in the absence or presence of test drugs across eight different drug concentrations to construct dose–response curves. Data are mean ± SD for N = 3 experiments each performed in triplicate, expressed as percent of maximal uptake. All compounds were examined as their salts; see Methods for specific salts used.
Figure 2.
Figure 2.
Effects of bupropion analogues on transporter-mediated release via DAT, NET and SERT in rat brain synaptosomes. Synaptosomes were preloaded with [3H]MPP+ (DAT and NET assays) or [3H]5-HT (SERT assays) to achieve steady state. Preloaded synaptosomes were incubated in the absence or presence of test drugs across 8 different concentrations to construct dose–response curves. Data are mean ± SD for N = 3 experiments performed in triplicate, expressed as a % of maximal release. Analogues producing release responses <30% of maximum are considered inactive. All compounds were examined as their salts; see Methods for specific salts used.
Figure 3.
Figure 3.
Structures of α-PVP (10), mephedrone (11), and methylone (12).
Scheme 1.
Scheme 1.
Synthesis of Compounds 6 and 7a aReagents and conditions: (i) CH3NH2, room temperature, 2 h; (ii) NaN3, room temperature, 20 h; (iii) SnCl2, room temperature, 2 h.
See this image and copyright information in PMC

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