title: Design, synthesis, and biological evaluation of arylpiperazine-benzylpiperidines with dual serotonin and norepinephrine reuptake inhibitory activities.
abstract: The limitations of established serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitors necessitate the development of safer and more effective therapeutic agents. Based on the structures of 4-benzylpiperidine carboxamides and trazodone, arylpiperazine-benzylpiperidines with chemical scaffolds different from those of marketed drugs were designed, synthesized, and evaluated for their neurotransmitter reuptake inhibitory activities. The majority of the synthesized compounds showed greater NE than 5-HT reuptake inhibition. The activities were even greater than those of the standard drug, venlafaxine hydrochloride were. The derivatives with a three-carbon linker showed better activities than the derivatives with a two-carbon linker. Among the newly synthesized compounds, 2d exhibited the strongest reuptake inhibition of the neurotransmitters (IC50=0.38 μM for NE and 1.18 μM for 5-HT). The biological activity data demonstrate that arylpiperazine-benzylpiperidines have the potential to be developed as a new class of therapeutic agents to treat neuropsychiatric and neurodegenerative disorders.
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Suresh
authors.initials: S
authors.lastname: Paudel
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Srijan
authors.initials: S
authors.lastname: Acharya
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: kmkim@jnu.ac.kr.
authors.forename: Kyeong-Man
authors.initials: KM
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: shcheon@jnu.ac.kr.
authors.forename: Seung Hoon
authors.initials: SH
authors.lastname: Cheon
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects*; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; D010880:Piperidines; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Arylpiperazine–benzylpiperidine; Dual serotonin and norepinephrine reuptake inhibitor; Neurodegenerative disorder; Neuropsychiatric disorder