Structural Requirements for Modulating 4-Benzylpiperidine Carboxamides from Serotonin/Norepinephrine Reuptake Inhibitors to Triple Reuptake Inhibitors

Suresh Paudel; Eunae Kim; Anlin Zhu; Srijan Acharya; Xiao Min; Seung Hoon Cheon; Kyeong-Man Kim

doi:10.4062/biomolther.2020.233

Structural Requirements for Modulating 4-Benzylpiperidine Carboxamides from Serotonin/Norepinephrine Reuptake Inhibitors to Triple Reuptake Inhibitors

Biomol Ther (Seoul). 2021 Jul 1;29(4):392-398. doi: 10.4062/biomolther.2020.233.

Authors

Suresh Paudel¹, Eunae Kim², Anlin Zhu¹, Srijan Acharya¹, Xiao Min¹, Seung Hoon Cheon¹, Kyeong-Man Kim¹

Affiliations

¹ College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.
² College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.

Abstract

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; Docking; Dopamine D₂ receptor endocytosis; Norepinephrine reuptake inhibitor; Serotonin reuptake inhibitor; Triple reuptake inhibitor.