Biomolecules & Therapeutics
Potential Functional Role of Phenethylamine Derivatives in Inhibiting Dopamine Reuptake: Structure–Activity Relationship
Dooti Kundu1,†, Anlin Zhu1,†, Eunae Kim2,†, Suresh Paudel1, Choon-Gon Jang3, Yong Sup Lee4, Kyeong-Man Kim1,*
1College of Pharmacy, Chonnam National University, Gwangju 61146,
2College of Pharmacy, Chosun University, Gwangju 61452,
3College of Pharmacy, Sungkyunkwan University, Suwon 16419,
4College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
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The first three authors contributed equally to this work.
Received: April 10, 2022; Revised: July 25, 2022; Accepted: August 3, 2022; Published online: September 13, 2022.
© The Korean Society of Applied Pharmacology. All rights reserved.

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Numerous psychotropic and addictive substances possess structural features similar to those of β-phenethylamine (β-PEA). In this study, we selected 29 β-PEA derivatives and determined their structure–activity relationship (SAR) to their ability to inhibit dopamine (DA) reuptake; conducted docking simulation for two selected compounds; and identified their potential functionals. The compounds were subdivided into arylethylamines, 2-(alkyl amino)-1-arylalkan-1-one derivatives and alkyl 2-phenyl-2-(piperidin-2- yl)acetate derivatives. An aromatic group, alkyl group, and alkylamine derivative were attached to the arylethylamine and 2-(alkyl amino)-1-arylalkan-1-one derivatives. The inhibitory effect of the compounds on dopamine reuptake increased in the order of the compounds substituted with phenyl, thiophenyl, and substituted phenyl groups in the aromatic position; compounds with longer alkyl groups and smaller ring-sized compounds at the alkylamine position showed stronger inhibitory activities. Docking simulation conducted for two compounds, 9 and 28, showed that the (S)-form of compound 9 was more stable than the (R)-form, with a good fit into the binding site covered by helices 1, 3, and 6 of human dopamine transporter (hDAT). In contrast, the (R, S)-configuration of compound 28 was more stable than that of other isomers and was firmly placed in the binding pocket of DAT bound to DA. DA-induced endocytosis of dopamine D2 receptors was inhibited when they were co-expressed with DAT, which lowered extracellular DA levels, and uninhibited when they were pretreated with compound 9 or 28. In summary, this study revealed critical structural features responsible for the inhibition of DA reuptake and the functional role of DA reuptake inhibitors in regulating D2 receptor function.
Keywords: Phenethylamine, Drug addiction, Dopamine transporter, Dopamine D2 receptor, Docking simulation, Structure activity relationship

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