Azepines and Piperidines with Dual Norepinephrine Dopamine Uptake Inhibition and Antidepressant Activity

• Published in: ACS medicinal chemistry letters Vol. 4; no. 1; pp. 46 - 51
• Main Authors: Brown, Dean G, Bernstein, Peter R, Wu, Ye, Urbanek, Rebecca A, Becker, Christopher W, Throner, Scott R, Dembofsky, Bruce T, Steelman, Gary B, Lazor, Lois A, Scott, Clay W, Wood, Michael W, Wesolowski, Steven S, Nugiel, David A, Koch, Stephanie, Yu, Jian, Pivonka, Donald E, Li, Shuang, Thompson, Carol, Zacco, Anna, Elmore, Charles S, Schroeder, Patricia, Liu, JianWei, Hurley, Christopher A, Ward, Stuart, Hunt, Hazel J, Williams, Karen, McLaughlin, Joseph, Hoesch, Valerie, Sydserff, Simon, Maier, Donna, Aharony, David
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.01.2013; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; norepinephrine; dopamine; uptake inhibitors; antidepressant; BINDING; NOMIFENSINE
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml300262e

Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay.