Discovery of a potent, selective, and less flexible selective norepinephrine reuptake inhibitor (sNRI).

The design, synthesis, and SAR of a series of ring-constrained norepinephrine reuptake inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC(50)=8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the norepinephrine transporter (NET).

[1]  L. Iversen.  Neurotransmitter transporters: fruitful targets for CNS drug discovery , 2000, Molecular Psychiatry.

[2]  S. Bembenek,et al.  Ligand binding efficiency: trends, physical basis, and implications. , 2008, Journal of medicinal chemistry.

[3]  D. Wong,et al.  Fluoxetine, a selective inhibitor of serotonin uptake , 1991, Medicinal research reviews.

[4]  K. Kinbara,et al.  Enantiopure trans- and cis-3-Aminoindan-1-ols: Preparation and Application as Novel Basic Resolving Agents , 2002 .

[5]  M. Detke,et al.  The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. , 2005, Current pharmaceutical design.

[6]  S. Ito,et al.  N,N,N',N'-tetramethylazodicarboxamide (TMAD), a new versatile reagent for Mitsunobu reaction, its application to synthesis of secondary amines , 1994 .

[7]  J. Wernicke,et al.  Treatment of Chronic Pain with Drugs that Modulate Central Nervous System Serotonin and Norepinephrine , 2007 .

[8]  S. Maiti,et al.  Norepinephrine reuptake inhibitors for depression, ADHD and other neuropsychiatric disorders , 2006 .

[9]  M. Walter.  Monoamine reuptake inhibitors: highlights of recent research developments , 2005 .

[10]  John-Michael Sauer,et al.  Clinical Pharmacokinetics of Atomoxetine , 2005, Clinical pharmacokinetics.

[11]  Jia Zhou.  Norepinephrine transporter inhibitors and their therapeutic potential. , 2004, Drugs of the future.

[12]  M. Jann,et al.  Antidepressant Agents for the Treatment of Chronic Pain and Depression , 2007, Pharmacotherapy.

[13]  J. Findlay,et al.  Discovery and structure-activity relationships of novel selective norepinephrine and dual serotonin/norepinephrine reuptake inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[14]  R. Wise,et al.  The neurobiology of addiction , 2019, Annals of the New York Academy of Sciences.