Synthesis and pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin and its enantiomers in comparison with the two antidepressants mianserin and mirtazapine

J Med Chem. 2002 Jul 18;45(15):3280-5. doi: 10.1021/jm010566d.

Abstract

The synthesis and resolution of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin (6-methoxymianserin, 6) are described. Furthermore, the in vitro and in vivo effects of 6 and its enantiomers are presented. 6 displayed high affinity for the 5-HT2A/2C receptors, only moderate affinity for the adrenoceptors, and no affinity for the NA reuptake site. Surprisingly, 6 also showed moderate to high affinity for the dopamine D2 receptor, an effect that resides in the (R)-(-)-enantiomer.

Publication types

  • Comparative Study

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Animals
  • Antidepressive Agents / chemical synthesis*
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology*
  • Binding Sites
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hydroxyindoleacetic Acid / metabolism
  • In Vitro Techniques
  • Male
  • Mianserin / analogs & derivatives*
  • Mianserin / chemical synthesis*
  • Mianserin / chemistry
  • Mianserin / pharmacology*
  • Microdialysis
  • Mirtazapine
  • Norepinephrine / metabolism
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic / metabolism
  • Receptors, Dopamine / metabolism
  • Receptors, Histamine / metabolism
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 6-methoxymianserin
  • Antidepressive Agents
  • Receptors, Adrenergic
  • Receptors, Dopamine
  • Receptors, Histamine
  • Receptors, Serotonin
  • 3,4-Dihydroxyphenylacetic Acid
  • Mianserin
  • Serotonin
  • Hydroxyindoleacetic Acid
  • Mirtazapine
  • Norepinephrine