N,N-Dialkylated monophenolic trans-2-phenylcyclopropylamines: novel central 5-hydroxytryptamine receptor agonists

J Med Chem. 1988 Jan;31(1):92-9. doi: 10.1021/jm00396a014.

Abstract

N,N-Dialkylated monophenolic derivatives of trans-2-phenylcyclopropylamine were synthesized and tested for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor stimulating activity by use of a biochemical test method in rats. A hydroxy substituent in the 2- or 3-position of the phenyl ring was required for 5-HT-receptor stimulation. N,N-Diethyl or N,N-di-n-propyl substitution gave the most potent 5-HT-receptor agonists. The 4-hydroxy and 3,4-dihydroxy derivatives of trans-2-phenyl-N,N-di-n-propylcyclopropylamine were inactive at central DA and 5-HT receptors. In contrast, the corresponding 3-hydroxy derivative 18 and some of its derivatives weakly affected both DA and NE synthesis. Two of the most potent 5-HT-receptor agonists, trans-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine (8) and the 3-hydroxy isomer 18 were resolved into the enantiomers. The 1R,2S enantiomers of 8 and 18 displayed 5-HT activity, while the 1S,2R enantiomers were inactive. Compound (1R,2S)-18, but not (1R,2S)-8, weakly affected rat brain DA and NE synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Magnetic Resonance Spectroscopy
  • Male
  • Molecular Conformation
  • Phenols / chemical synthesis
  • Phenols / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Receptors, Serotonin / drug effects*
  • Structure-Activity Relationship
  • Tranylcypromine / analogs & derivatives*
  • Tranylcypromine / chemical synthesis*
  • Tranylcypromine / pharmacology

Substances

  • Phenols
  • Receptors, Serotonin
  • Tranylcypromine