Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists

ACS Chem Neurosci. 2014 Mar 19;5(3):243-9. doi: 10.1021/cn400216u. Epub 2014 Jan 15.


N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding, Competitive
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Inositol Phosphates / metabolism
  • Molecular Structure
  • Phenethylamines / chemical synthesis*
  • Phenethylamines / pharmacokinetics*
  • Radioligand Assay
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / chemical synthesis*
  • Serotonin 5-HT2 Receptor Agonists / pharmacokinetics*


  • Inositol Phosphates
  • Phenethylamines
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists