Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.119
Design, Synthesis, and Functional Evaluation of 1, 5-Disubstituted Tetrazoles as Monoamine Neurotransmitter Reuptake Inhibitors
Suresh Paudel1,†, Shuji Wang1,†, Eunae Kim2,†, Dooti Kundu1, Xiao Min1, Chan Young Shin3,* and Kyeong-Man Kim1,*
1College of Pharmacy, Chonnam National University, Gwangju 61186, 2College of Pharmacy, Chosun University, Gwangju 61452, 3Department of Pharmacology and Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul 05029, Republic of Korea
*E-mail: chanyshin@kku.ac.kr (Shin CY), kmkim@jnu.ac.kr (Kim KM)
Tel: +82-2-454-5630 (Shin CY), +82-62-530-2936 (Kim KM)
Fax: +82-2-2030-7899 (Shin CY), +82-62-530-2949 (Kim KM)
The first three authors contributed equally to this work.
Received: July 15, 2021; Revised: October 20, 2021; Accepted: October 26, 2021; Published online: November 18, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Tetrazoles were designed and synthesized as potential inhibitors of triple monoamine neurotransmitters (dopamine, norepinephrine, serotonin) reuptake based on the functional and docking simulation of compound 6 which were performed in a previous study. The compound structure consisted of a tetrazole-linker (n)-piperidine/piperazine-spacer (m)-phenyl ring, with tetrazole attached to two phenyl rings (R1 and R2). Altering the carbon number in the linker (n) from 3 to 4 and in the spacer (m) from 0 to 1 increased the potency of serotonin reuptake inhibition. Depending on the nature of piperidine/piperazine, the substituents at R1 and R2 exerted various effects in determining their inhibitory effects on monoamine reuptake. Docking study showed that the selectivity of tetrazole for different transporters was determined based on multiple interactions with various residues on transporters, including hydrophobic residues on transmembrane domains 1, 3, 6, and 8. Co-expression of dopamine transporter, which lowers dopamine concentration in the biophase by uptaking dopamine into the cells, inhibited the dopamine-induced endoctytosis of dopamine D2 receptor. When tested for compound 40 and 56, compound 40 which has more potent inhibitory activity on dopamine reuptake more strongly disinhibited the inhibitory activity of dopamine transporter on the endocytosis of dopamine D2 receptor. Overall, we identified candidate inhibitors of triple monoamine neurotransmitter reuptake and provided a theoretical background for identifying such neurotransmitter modifiers for developing novel therapeutic agents of various neuropsychiatric disorders.
Keywords: Tetrazoles, Triple reuptake, Transporter, Structure-activity relationship, Docking simulation, Receptor endocytosis


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