Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.233
Structural Requirements for Modulating 4-Benzylpiperidine Carboxamides from Serotonin/Norepinephrine Reuptake Inhibitors to Triple Reuptake Inhibitors
Suresh Paudel1,†, Eunae Kim2,†, Anlin Zhu1,†, Srijan Acharya1, Xiao Min1, Seung Hoon Cheon1 and Kyeong-Man Kim1,*
1College of Pharmacy, Chonnam National University, Gwangju 61186,
2College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
*E-mail: kmkim@jnu.ac.kr
Tel: +82-62-530-2936, Fax: +82-62-530-2949
The first three authors contributed equally to this work.
Received: December 28, 2020; Revised: April 1, 2021; Accepted: April 2, 2021; Published online: May 31, 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
In this study, we determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA), and characterized their structure–activity relationship. The compounds with a two-carbon linker inhibited DA reuptake with much higher potency than those with a three-carbon linker. Among the aromatic ring substituents, biphenyl and diphenyl groups played a critical role in determining the selectivity of the 4-benzylpiperidine carboxamides toward the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. Compounds with a 2-naphthyl ring were found to exhibit a higher degree of inhibition on the norepinephrine transporter (NET) and SERT than those with a 1-naphthyl ring. A docking simulation using a triple reuptake inhibitor 8k and a serotonin/norepinephrine reuptake inhibitor 7j showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound 8k bound tightly to the binding pocket of all three monoamine reuptake transporters; however, 7j showed poor docking with DAT. Co-expression of DAT with the dopamine D2 receptor (D2R) significantly inhibited DA-induced endocytosis of D2R probably by reuptaking DA into the cells. Pretreatment of the cells with 8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D2R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D2R function.
Keywords: 4-Benzylpiperidine carboxamides, Serotonin reuptake inhibitor, Norepinephrine reuptake inhibitor, Triple reuptake inhibitor, Docking, Dopamine D2 receptor endocytosis


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