Dual NK(1) antagonists--serotonin reuptake inhibitors as potential antidepressants. Part 2: SAR and activity of benzyloxyphenethyl piperazine derivatives

Bioorg Med Chem Lett. 2002 Nov 4;12(21):3195-8. doi: 10.1016/s0960-894x(02)00563-2.

Abstract

The synthesis, structure-affinity relationship and activity of benzyloxyphenethyl piperazine derivatives combining NK(1) antagonism and serotonin reuptake inhibition is described. Compound 7u was shown to be active in animal models of 5-HT reuptake inhibition and central NK(1) receptor blockade, and was demonstrated to be orally active in an integrated model sensitive to both mechanisms. This class of compounds potentially represents a new generation of antidepressants.

MeSH terms

  • Alcohols / chemical synthesis
  • Alcohols / pharmacology
  • Antidepressive Agents, Second-Generation / chemical synthesis*
  • Antidepressive Agents, Second-Generation / pharmacology*
  • Carrier Proteins / drug effects
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism
  • Drug Evaluation, Preclinical
  • Humans
  • Membrane Glycoproteins / drug effects
  • Membrane Transport Proteins*
  • Nerve Tissue Proteins*
  • Neurokinin-1 Receptor Antagonists*
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacology*
  • Selective Serotonin Reuptake Inhibitors / chemical synthesis*
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Serotonin Plasma Membrane Transport Proteins
  • Structure-Activity Relationship

Substances

  • Alcohols
  • Antidepressive Agents, Second-Generation
  • Carrier Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Neurokinin-1 Receptor Antagonists
  • Piperazines
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • benzyloxyphenethyl piperazine