Translocation of the 5-alkoxy substituent of 2,5-dialkoxyarylalkylamines to the 6-position: effects on 5-HT(2A/2C) receptor affinity

Bioorg Med Chem Lett. 2002 Aug 5;12(15):1997-9. doi: 10.1016/s0960-894x(02)00306-2.


Positional modification of 2,5-dimethoxyamphetamine analogues has been studied. Specifically, the 5-alkoxy substituent was translocated to the 6-position of the phenyl nucleus. Methoxy groups were also constrained by incorporation into appended dihydrofuran and furan rings. 2,6-Dimethoxy-4-methylamphetamine had an approximately 3-fold lower affinity for the 5-HT(2A) receptor compared to the parent 2,5-dimethoxy-4-methylamphetamine (DOM). The rigid compound based on the 2,3,5,6-tetrahydrobenzo[1,2-b;5,4-b']difuran nucleus and the aromatic analogue containing the benzo[1,2-b;5,4-b']difuran nucleus possessed an approximate 7- and 27-fold increase in affinity, respectively, compared to 2,6-dimethoxy-4-methylamphetamine, the non-rigid, positional isomer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamines / chemistry*
  • Amphetamines / pharmacology*
  • Animals
  • Cells, Cultured / metabolism
  • Prefrontal Cortex / metabolism
  • Protein Binding
  • Radioligand Assay
  • Rats
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin / metabolism*
  • Recombinant Proteins / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship


  • Amphetamines
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin
  • Recombinant Proteins