Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder

J Med Chem. 2011 May 12;54(9):3206-21. doi: 10.1021/jm101459g. Epub 2011 Apr 12.

Abstract

The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic β(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.

MeSH terms

  • Animals
  • Antidepressive Agents / chemical synthesis*
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology
  • Cell Line
  • Depressive Disorder, Major / drug therapy*
  • Drug Partial Agonism
  • Drug Stability
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver / metabolism
  • Oocytes / drug effects
  • Oocytes / physiology
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptor, Serotonin, 5-HT2C / metabolism
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin, 5-HT1 / metabolism
  • Receptors, Serotonin, 5-HT3 / metabolism
  • Recombinant Proteins / agonists
  • Recombinant Proteins / antagonists & inhibitors
  • Serotonin / metabolism
  • Serotonin 5-HT1 Receptor Agonists / chemical synthesis
  • Serotonin 5-HT1 Receptor Agonists / chemistry
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Serotonin 5-HT3 Receptor Antagonists / chemical synthesis
  • Serotonin 5-HT3 Receptor Antagonists / chemistry
  • Serotonin 5-HT3 Receptor Antagonists / pharmacology
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Serotonin Uptake Inhibitors / chemical synthesis
  • Serotonin Uptake Inhibitors / chemistry
  • Serotonin Uptake Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Sulfides / chemical synthesis*
  • Sulfides / chemistry
  • Sulfides / pharmacology
  • Vortioxetine
  • Xenopus

Substances

  • Antidepressive Agents
  • Piperazines
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Receptors, Serotonin, 5-HT3
  • Recombinant Proteins
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT3 Receptor Antagonists
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Sulfides
  • serotonin 7 receptor
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Vortioxetine