5-Methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole: a novel 5-HT2C/5-HT2B receptor antagonist with improved affinity, selectivity, and oral activity

J Med Chem. 1995 Jul 7;38(14):2524-30. doi: 10.1021/jm00014a004.

Abstract

The preparation of a series of conformationally restricted analogues of indolylurea 1, namely tetrahydropyrroloindoles and tetrahydropyrroloquinolines, is described. The binding affinities of these compounds at 5-HT2A, 5-HT2B, and 5-HT2C receptors were determined. Of these compounds, the 1,2,3,5-tetrahydropyrrolo[2,3-f]indole derivative, compound 11, was found to have high affinity for the 5-HT2C (pKI 8.0) and 5-HT2B receptors (pA2 8.5), with excellent selectivity over the 5-HT2A and various other receptors (pKI < 6). 11 is also considerably more active than 1 in both an in vitro functional model, 5-HT-stimulated phosphoinositol hydrolysis (pKB 8.8), and an in vivo functional model, mCPP-induced hypolocomotion (ID50 5.5 mg/kg po). 11 should therefore be of significant utility as a pharmacological tool to delineate the functional significance of blockade of 5-HT2B and 5-HT2C receptors.

MeSH terms

  • Administration, Oral
  • Animals
  • Indoles / administration & dosage
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Pyridines / administration & dosage
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Receptor, Serotonin, 5-HT2B
  • Receptors, Serotonin
  • Serotonin Antagonists / administration & dosage
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / pharmacology*

Substances

  • Indoles
  • Pyridines
  • Receptor, Serotonin, 5-HT2B
  • Receptors, Serotonin
  • Serotonin Antagonists
  • SB 206553