Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors

Liming Shao; Fengjiang Wang; Scott C Malcolm; Jianguo Ma; Michael C Hewitt; Una C Campbell; Larry R Bush; Nancy A Spicer; Sharon R Engel; Lakshmi D Saraswat; Larry W Hardy; Patrick Koch; Rudy Schreiber; Kerry L Spear; Mark A Varney

doi:10.1016/j.bmc.2010.10.034

Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors

Bioorg Med Chem. 2011 Jan 1;19(1):663-76. doi: 10.1016/j.bmc.2010.10.034. Epub 2010 Oct 21.

Authors

Liming Shao¹, Fengjiang Wang, Scott C Malcolm, Jianguo Ma, Michael C Hewitt, Una C Campbell, Larry R Bush, Nancy A Spicer, Sharon R Engel, Lakshmi D Saraswat, Larry W Hardy, Patrick Koch, Rudy Schreiber, Kerry L Spear, Mark A Varney

Affiliation

¹ Discovery and Early Clinical Research, Sepracor Inc., 84 Waterford Drive, Marlborough, MA 01752, USA. liming.shao@sepracor.com

PMID: 21093273
DOI: 10.1016/j.bmc.2010.10.034

Abstract

The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.

MeSH terms

Animals
Antidepressive Agents / chemical synthesis
Antidepressive Agents / pharmacology
Disease Models, Animal
Dopamine / metabolism
Drug Evaluation, Preclinical
Mice
Naphthalenes / chemical synthesis*
Naphthalenes / pharmacology*
Neurotransmitter Uptake Inhibitors / chemical synthesis*
Neurotransmitter Uptake Inhibitors / pharmacology*
Norepinephrine / metabolism
Serotonin / metabolism

Substances

Antidepressive Agents
Naphthalenes
Neurotransmitter Uptake Inhibitors
Serotonin
Dopamine
Norepinephrine