Synthesis and pharmacological investigation of aralkyl diamine derivatives as potential triple reuptake inhibitors

Eur J Med Chem. 2014 Oct 30:86:219-34. doi: 10.1016/j.ejmech.2014.08.045. Epub 2014 Aug 14.

Abstract

A series of aralkyl diamine derivatives were designed, synthesized, and evaluated for their triple reuptake inhibitory abilities. Compounds 18c (5-HT, NE, DA, IC50 = 389, 69, 238 nM), 36a (5-HT, NE, DA, IC50 = 378, 477, 247 nM), and 36d (5-HT, NE, DA, IC50 = 501, 206, 357 nM) showed in vivo activities in the rat forced swim test at 5, 10, and 20 mg/kg PO. 36a was identified as the most promising candidate in this study. Specifically, 36a exhibited high selectivity for monoamine transporters over a number of CNS-related targets. Furthermore, 36a showed a good pharmacokinetic properties and acceptable safety profile in preclinical studies.

Keywords: Aralkyl diamine derivatives; Monoamine transporters; Triple reuptake inhibitory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diamines / chemical synthesis
  • Diamines / chemistry
  • Diamines / pharmacology*
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred Strains
  • Molecular Structure
  • Norepinephrine / antagonists & inhibitors*
  • Norepinephrine / metabolism
  • Rats
  • Serotonin / metabolism*
  • Structure-Activity Relationship

Substances

  • Diamines
  • Serotonin
  • Dopamine
  • Norepinephrine