Triple reuptake inhibitors: Design, synthesis and structure-activity relationship of benzylpiperidine-tetrazoles

Bioorg Med Chem. 2017 Oct 15;25(20):5278-5289. doi: 10.1016/j.bmc.2017.07.046.

Suresh Paudel ¹, Xiao Min ¹, Srijan Acharya ¹, Daulat Bikram Khadka ¹, Goo Yoon ², Kyeong-Man Kim ³, Seung Hoon Cheon ⁴

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: 28807575 DOI: 10.1016/j.bmc.2017.07.046

Abstract

Monoamine transporters are important targets in the treatment of various central nervous disorders. Several limitations of traditional reuptake inhibitors, like delayed onset of action, insomnia, and sexual dysfunction, have compelled the search for safer, more effective compounds. In this study, we have sought to identify novel monoamine reuptake inhibitors. Based upon the docking study of compounds that we had reported previously, aromatic rings (A1) were modified to generate a novel series of benzylpiperidine-tetrazoles. Thirty-one compounds were synthesized and evaluated for their triple reuptake inhibition of serotonin, norepinephrine and dopamine. Triple reuptake inhibitor, compound 2q, in particular, showed potent serotonin reuptake inhibition, validating our design approach.

Keywords

Benzylpiperidine–tetrazoles; Docking; Monoamine neurotransmitters; Norepinephrine and dopamine reuptake inhibitors; Serotonin.

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