Discovery of 1-(3,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine, a dual serotonin and dopamine reuptake inhibitor

Liming Shao; Jianguo Ma; Fengjiang Wang; Scott C Malcolm; Michael C Hewitt; Una C Campbell; Nancy A Spicer; Larry W Hardy; Rudy Schreiber; Kerry L Spear; Mark A Varney

doi:10.1016/j.bmcl.2010.10.086

Discovery of 1-(3,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine, a dual serotonin and dopamine reuptake inhibitor

Bioorg Med Chem Lett. 2011 Jan 1;21(1):520-3. doi: 10.1016/j.bmcl.2010.10.086. Epub 2010 Oct 28.

Authors

Liming Shao¹, Jianguo Ma, Fengjiang Wang, Scott C Malcolm, Michael C Hewitt, Una C Campbell, Nancy A Spicer, Larry W Hardy, Rudy Schreiber, Kerry L Spear, Mark A Varney

Affiliation

¹ Discovery and Early Clinical Research, Sunovion Pharmaceuticals Inc, 84 Waterford Drive, Marlborough, MA 01752, USA. [email protected]

PMID: 21095126
DOI: 10.1016/j.bmcl.2010.10.086

Abstract

The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype.

MeSH terms

Animals
Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Dopamine Plasma Membrane Transport Proteins / metabolism
Dopamine Uptake Inhibitors / chemical synthesis
Dopamine Uptake Inhibitors / chemistry*
Dopamine Uptake Inhibitors / pharmacokinetics
Drug Evaluation, Preclinical
Humans
Mice
Microsomes / metabolism
Quinolines / chemical synthesis
Quinolines / chemistry*
Quinolines / pharmacokinetics
Selective Serotonin Reuptake Inhibitors / chemical synthesis
Selective Serotonin Reuptake Inhibitors / chemistry*
Selective Serotonin Reuptake Inhibitors / pharmacokinetics
Serotonin Plasma Membrane Transport Proteins / chemistry*
Serotonin Plasma Membrane Transport Proteins / metabolism

Substances

1-(3,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine
Dopamine Plasma Membrane Transport Proteins
Dopamine Uptake Inhibitors
Quinolines
Serotonin Plasma Membrane Transport Proteins
Serotonin Uptake Inhibitors