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

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 21; pp. 5546 - 5555
• Main Authors: Paudel, Suresh, Acharya, Srijan, Yoon, Goo, Kim, Kyeong-Man, Cheon, Seung Hoon
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2016; Elsevier
• Subjects: Arylpiperazine–tetrazoles; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dopamine - metabolism; Dopamine reuptake inhibitors; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Life Sciences & Biomedicine; Molecular Structure; Norepinephrine - antagonists & inhibitors; Norepinephrine - metabolism; Norepinephrine reuptake inhibitors; Pharmacology & Pharmacy; Physical Sciences; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Science & Technology; Selective norepinephrine and dopamine reuptake inhibitors; Structure-Activity Relationship; Tetrazoles - chemical synthesis; Tetrazoles - chemistry; Tetrazoles - pharmacology; Norepinephrine reuptake inhibitors; Selective norepinephrine and dopamine reuptake inhibitors; Dopamine reuptake inhibitors; Arylpiperazine–tetrazoles; ANTIDEPRESSANT; DESIGN; BUPROPION; NOMIFENSINE; DISORDER; SEROTONIN; Arylpiperazine-tetrazoles; CHILDREN
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.09.005

[Display omitted] 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.