1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes as 5-HT(2A) partial agonists

J Med Chem. 2000 Aug 10;43(16):3074-84. doi: 10.1021/jm9906062.


Phenylalkylamines such as 1-(4-bromo-2, 5-dimethoxyphenyl)-2-aminopropane (DOB; 1a) and its corresponding iodo derivative DOI (2) are commonly used 5-HT(2) serotonin agonists. Previous studies have established that the 2,5-dimethoxy substitution pattern found in these compounds is optimal for high affinity at 5-HT(2A) receptors and that substituents at the 4-position can modulate affinity over a wide range. We have previously shown, however, that when the 4-position is substituted with a 3-phenylpropyl substituent (i.e., 3), the compound binds with an affinity comparable to that of 1a but that it possesses 5-HT(2A) antagonist character. The present study examined the structure-affinity relationships of 3, and the results were very much unexpected. That is, the 2,5-dimethoxy substitution pattern of 3 is not required for high affinity. Either of the two methoxy groups can be removed without untoward effect on affinity, and relocation of the methoxy substituents actually enhances affinity by as much as an order of magnitude. None of the compounds displayed more than 20-fold selectivity for 5-HT(2A) over 5-HT(2C) receptors. In addition, several were demonstrated to act as 5-HT(2A) partial agonists. As such, the results of this study suggest that the structure-affinity relationships of phenylalkylamines as 5-HT(2A) ligands now be reinvestigated in greater detail.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Line
  • Inositol Phosphates / metabolism
  • Ligands
  • Mice
  • Propylamines / chemical synthesis*
  • Propylamines / chemistry
  • Propylamines / metabolism
  • Radioligand Assay
  • Rats
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / metabolism
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / metabolism
  • Structure-Activity Relationship


  • Inositol Phosphates
  • Ligands
  • Propylamines
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists