Designing rapid onset selective serotonin re-uptake inhibitors. Part 1: Structure-activity relationships of substituted (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine

Bioorg Med Chem Lett. 2006 Mar 1;16(5):1434-9. doi: 10.1016/j.bmcl.2005.11.031. Epub 2005 Nov 28.

Abstract

A series of sertraline analogues 4-39 which possess polar groups on the fused tetrahydronaphthalene ring, targeting reduced V(d) as a strategy to reduce T(max) and increase rate of elevation of central 5-HT levels, were prepared. These studies led to the successful identification of 22a, which demonstrated equivalent pharmacology and metabolic stability to 1, but which possessed greatly reduced V(d) leading to significantly shorter T(max), in rat pharmacokinetic studies.

MeSH terms

  • Animals
  • Brain / blood supply
  • Brain / drug effects
  • Caco-2 Cells
  • Drug Design*
  • Humans
  • Molecular Structure
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry*
  • Naphthalenes / pharmacology*
  • Rats
  • Regional Blood Flow
  • Selective Serotonin Reuptake Inhibitors / chemistry*
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Sensitivity and Specificity
  • Serotonin / metabolism*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Time Factors

Substances

  • (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine
  • Naphthalenes
  • Serotonin Uptake Inhibitors
  • Serotonin