2. Academic Validation
  3. Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors

Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors

  • Bioorg Med Chem. 2017 Apr 1;25(7):2266-2276. doi: 10.1016/j.bmc.2017.02.051.
Suresh Paudel 1,  Srijan Acharya 1,  Goo Yoon 2,  Kyeong-Man Kim 3,  Seung Hoon Cheon 4
Affiliations

Affiliations

  • 1 College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
  • 2 College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea.
  • 3 College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address: kmkim@jnu.ac.kr.
  • 4 College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address: shcheon@jnu.ac.kr.
PMID: 28274674 DOI: 10.1016/j.bmc.2017.02.051
Abstract

Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC50=158.7nM for 5-HT, 99nM for NE and 97.5nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.

Keywords

Arylpiperazines; Benzylpiperidines; Central nervous system disorders; Dopamine reuptake inhibitor; Monoamine transporters; Neurotransmitters; Norepinephrine reuptake inhibitor; Serotonin reuptake inhibitor; Tetrazole.

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