Identification of 1S,2R-milnacipran analogs as potent norepinephrine and serotonin transporter inhibitors

Junko Tamiya; Brian Dyck; Mingzhu Zhang; Kasey Phan; Beth A Fleck; Anna Aparicio; Florence Jovic; Joe A Tran; Troy Vickers; Jonathan Grey; Alan C Foster; Chen Chen

doi:10.1016/j.bmcl.2008.04.025

Identification of 1S,2R-milnacipran analogs as potent norepinephrine and serotonin transporter inhibitors

Bioorg Med Chem Lett. 2008 Jun 1;18(11):3328-32. doi: 10.1016/j.bmcl.2008.04.025. Epub 2008 Apr 15.

Authors

Junko Tamiya¹, Brian Dyck, Mingzhu Zhang, Kasey Phan, Beth A Fleck, Anna Aparicio, Florence Jovic, Joe A Tran, Troy Vickers, Jonathan Grey, Alan C Foster, Chen Chen

Affiliation

¹ Department of Medicinal Chemistry, Neurocrine Bioscience, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

PMID: 18445525
DOI: 10.1016/j.bmcl.2008.04.025

Abstract

A series of milnacipran analogs were synthesized and studied as monoamine transporter inhibitors, and several potent compounds with moderate lipophilicity were identified from the 1S,2R-isomers. Thus, 15l exhibited IC(50) values of 1.7nM at NET and 25nM at SERT, which were, respectively, 20- and 13-fold more potent than 1S,2R-milnacipran 1-II.

MeSH terms

Antidepressive Agents / chemical synthesis*
Antidepressive Agents / chemistry
Antidepressive Agents / pharmacology*
Combinatorial Chemistry Techniques
Cyclopropanes / chemical synthesis*
Cyclopropanes / chemistry
Cyclopropanes / pharmacology*
Humans
Inhibitory Concentration 50
Milnacipran
Molecular Structure
Norepinephrine / antagonists & inhibitors*
Selective Serotonin Reuptake Inhibitors / chemical synthesis*
Selective Serotonin Reuptake Inhibitors / chemistry
Selective Serotonin Reuptake Inhibitors / pharmacology
Stereoisomerism
Structure-Activity Relationship

Substances

Antidepressive Agents
Cyclopropanes
Serotonin Uptake Inhibitors
Milnacipran
Norepinephrine