Structure-activity relationships of the cycloalkanol ethylamine scaffold: discovery of selective norepinephrine reuptake inhibitors.

Abstract

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.

• Authors: Paige E Mahaney, Lori K Gavrin, Eugene J Trybulski, Gary P Stack, T An Vu, Stephen T Cohn, Fei Ye, Justin K Belardi, Arthur A Santilli, Joseph P Sabatucci, Jennifer Leiter, Grace H Johnston, Jenifer A Bray, Kevin D Burroughs, Scott A Cosmi, Liza Leventhal, Elizabeth J Koury, Yingru Zhang, Cheryl A Mugford, Douglas M Ho, Sharon J Rosenzweig-Lipson, Brian Platt, Valerie A Smith, Darlene C Deecher
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 13 Pg. 4038-49 (Jul 10 2008) ISSN: 1520-4804 [Electronic] United States
• PMID: 18557608 (Publication Type: Journal Article)

Chemical References

• Cyclohexanols
• Ethylamines
• Symporters
• Norepinephrine
• ethylamine

Topics

• Animals
• Cell Line
• Cyclohexanols (chemistry)
• Ethylamines (chemistry, pharmacology, therapeutic use)
• Female
• Humans
• Male
• Mice
• Models, Molecular
• Molecular Structure
• Norepinephrine (metabolism)
• Pain (drug therapy)
• Rats
• Structure-Activity Relationship
• Symporters (antagonists & inhibitors, metabolism)