Structure−Activity Relationships of the Cycloalkanol Ethylamine Scaffold: Discovery of Selective Norepinephrine Reuptake Inhibitors
| Autor: | Jennifer Leiter, An T. Vu, Yingru Zhang, Sharon Rosenzweig-Lipson, Fei Ye, Valerie Smith, Stephen Todd Cohn, Douglas M. Ho, Elizabeth Koury, Justin K. Belardi, Darlene C. Deecher, Cheryl A. Mugford, Grace H. Johnston, Gary Paul Stack, Kevin D. Burroughs, Eugene John Trybulski, Scott Cosmi, Jenifer A. Bray, Joseph Peter Sabatucci, Lori Krim Gavrin, Liza Leventhal, Paige Erin Mahaney, Brian J. Platt, Arthur A. Santilli |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
Models Molecular Pain Venlafaxine Pharmacology Cell Line Norepinephrine (medication) Mice Norepinephrine Structure-Activity Relationship Norepinephrine reuptake inhibitor Dopamine Drug Discovery Ethylamines medicine Animals Humans Serotonin transporter Dopamine transporter Molecular Structure Symporters biology Chemistry Cyclohexanols Rats biology.protein Molecular Medicine Female Serotonin WY-46824 medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 51:4038-4049 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm8002262 |
| Popis: | Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|