Exploration of substituted arylpiperazine-tetrazoles as promising dual norepinephrine and dopamine reuptake inhibitors

Bioorg Med Chem. 2016 Nov 1;24(21):5546-5555. doi: 10.1016/j.bmc.2016.09.005. Epub 2016 Sep 3.

Abstract

In the search for potent dual norepinephrine and dopamine reuptake inhibitors, several substituted arylpiperazine-tetrazoles were designed, synthesized and evaluated for their neurotransmitter reuptake inhibitory activities. Various derivatives exhibited selective and strong neurotransmitter reuptake inhibitory activity. In particular, compounds with a three-carbon linker displayed selective and stronger potency than those with two-carbon and four-carbon linkers. Interestingly, six compounds, 9b, 9c, 9d, 9o, 9q and 9u displayed more effective activity than the standard drug, bupropion. The provided SAR data and potent biological activity can offer useful guidelines for designing dual norepinephrine and dopamine reuptake inhibitors as effective therapeutic agents for treatment of several central nervous system diseases.

Keywords: Arylpiperazine–tetrazoles; Dopamine reuptake inhibitors; Norepinephrine reuptake inhibitors; Selective norepinephrine and dopamine reuptake inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Norepinephrine / antagonists & inhibitors*
  • Norepinephrine / metabolism
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Structure-Activity Relationship
  • Tetrazoles / chemical synthesis
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology*

Substances

  • Piperazines
  • Tetrazoles
  • Dopamine
  • Norepinephrine