Discovery of a New Series of Centrally Active Tricyclic Isoxazoles Combining Serotonin (5-HT) Reuptake Inhibition With alpha2-adrenoceptor Blocking Activity

J Med Chem. 2005 Mar 24;48(6):2054-71. doi: 10.1021/jm049619s.

Abstract

The synthesis and pharmacology of a new series of 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles that combine central serotonin (5-HT) reuptake inhibition with alpha(2)-adrenoceptor blocking activity is described as potential antidepressants. Four compounds were selected for further evaluation, and the combination of both activities was found to be stereoselective, residing mainly in one enantiomer. Reversal of the loss of righting induced by the alpha(2)-agonist medetomidine in rats confirmed the alpha(2)-adrenoceptor blocking activity in vivo and also demonstrated CNS penetration. Antagonism of p-chloroamphetamine (pCA)-induced excitation as well as blockade of the neuronal 5-HT depletion induced by p-CA administration in rats confirmed their ability to block the central 5-HTT, even after oral administration. Replacement of the oxygen atom at the 5-position of the tricyclic scaffold by a nitrogen or a carbon atom, as well as O-substitution at position 7, led also to active compounds, both in vitro and in vivo.

MeSH terms

  • Administration, Oral
  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-2 Receptor Antagonists*
  • Animals
  • Antidepressive Agents / chemical synthesis*
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Medetomidine / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Rats
  • Rats, Wistar
  • Reflex / drug effects
  • Serotonin Uptake Inhibitors / chemical synthesis*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / chemical synthesis
  • Tetrahydronaphthalenes / chemistry
  • Tetrahydronaphthalenes / pharmacology

Substances

  • 7,8-dimethoxy-3-(4-(2-methyl-3-phenyl-2-propen-1-yl)piperazin-1-ylmethyl)-3,3a,4,5-tetrahydroquinolino(4,3-c)isoxazole
  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-2 Receptor Antagonists
  • Antidepressive Agents
  • Heterocyclic Compounds, 3-Ring
  • Isoxazoles
  • Quinolines
  • Serotonin Uptake Inhibitors
  • Tetrahydronaphthalenes
  • Medetomidine