Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites

J Med Chem. 1997 Feb 28;40(5):639-46. doi: 10.1021/jm960360q.

Abstract

The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.

MeSH terms

  • Aminoquinolines / chemical synthesis*
  • Aminoquinolines / metabolism
  • Aminoquinolines / pharmacology
  • Animals
  • Dopamine Agonists / chemical synthesis*
  • Dopamine Agonists / metabolism
  • Dopamine Agonists / pharmacology
  • Imidazoles / chemical synthesis*
  • Imidazoles / metabolism
  • Imidazoles / pharmacology
  • Magnetic Resonance Spectroscopy
  • Male
  • Mass Spectrometry
  • Methylamines / chemical synthesis
  • Methylamines / pharmacology
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine / metabolism
  • Receptors, Serotonin / metabolism
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / metabolism
  • Serotonin Receptor Agonists / pharmacology
  • Stereoisomerism

Substances

  • 5,6-dihydro-N,N-dimethyl-4H-imidazo(4,5-ij)quinolin-5-amine
  • Aminoquinolines
  • Dopamine Agonists
  • Imidazoles
  • Methylamines
  • Receptors, Dopamine
  • Receptors, Serotonin
  • Serotonin Receptor Agonists