Novel indolodioxanes with antihypertensive effects: potent ligands for the 5-HT1A receptor

J Med Chem. 1992 Aug 7;35(16):3058-66. doi: 10.1021/jm00094a021.


The synthesis and biological evaluation of a new family of tricyclic indolodioxanes is described. These compounds all contain the 2,3-dihydro-7H-1,4-dioxino[2,3-e]indole nucleus and bear substituents at the 2 and/or 8 positions. Thirteen members of this class were prepared and shown to be potent ligands for the 5-HT1A receptor, with several compounds displaying subnanomolar inhibition constants. These compounds also bind to the dopamine D-2 receptor, but generally with higher inhibition constants than those for 5-HT1A. Certain members of this novel structural class show in vivo activity in the mouse hypothermia assay. One of these compounds, U-86192A, has been shown to have antihypertensive effects in the cat, completely eliminating sympathetic nerve discharge at 1 mg/kg iv and lowering mean arterial pressure to 50% pretreatment levels. These effects can be reversed by the administration of spiperone, indicating that U-86192A is acting via a central serotonergic mechanism.

MeSH terms

  • Animals
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / metabolism
  • Antihypertensive Agents / pharmacology*
  • Cats
  • Dioxanes / chemistry
  • Dioxanes / metabolism
  • Dioxanes / pharmacology*
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Ligands
  • Male
  • Mice
  • Molecular Structure
  • Radioligand Assay
  • Receptors, Adrenergic, alpha / metabolism
  • Receptors, Dopamine / metabolism
  • Receptors, Dopamine D2
  • Receptors, Opioid / metabolism
  • Receptors, Serotonin / metabolism*


  • Antihypertensive Agents
  • Dioxanes
  • Indoles
  • Ligands
  • Receptors, Adrenergic, alpha
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • Receptors, Opioid
  • Receptors, Serotonin