Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment

Br J Pharmacol. 2012 Nov;167(5):1021-34. doi: 10.1111/j.1476-5381.2011.01770.x.

Abstract

Background and purpose: The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective.

Experimental approach: We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430).

Key results: DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects.

Conclusions and implications: DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Adult
  • Animals
  • Antidepressive Agents / administration & dosage*
  • Brain / drug effects
  • Brain / physiology
  • Depressive Disorder, Major / drug therapy*
  • Drug Therapy, Combination
  • Female
  • Fluoxetine / administration & dosage*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Piperazines / administration & dosage*
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / physiology*
  • Serotonin Antagonists / administration & dosage*
  • Serotonin Receptor Agonists / pharmacology
  • Thiazoles / administration & dosage*

Substances

  • Antidepressive Agents
  • Piperazines
  • Pyridines
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Thiazoles
  • Fluoxetine
  • Receptor, Serotonin, 5-HT1A
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • 1,2-benzisothiazol-3(2H)-one, 2-(4-(4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl)butyl)-, 1,1-dioxide

Associated data

  • ClinicalTrials.gov/NCT01119430