Neurochemical binding profiles of novel indole and benzofuran MDMA analogues

Naunyn Schmiedebergs Arch Pharmacol. 2017 Jan;390(1):15-24. doi: 10.1007/s00210-016-1297-4. Epub 2016 Sep 20.


3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT2 receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT2a,b,c and NEα2 receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT2a,b,c receptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT2c receptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC50 determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT2a,c receptors as compared to MDMA.

Keywords: 3,4-Methylenedioxy-N-methylamphetamine (MDMA); MDMA analogues; Monoamine receptors; Monoamine transporters; Neurochemical profile.

Publication types

  • Comparative Study

MeSH terms

  • Benzofurans / chemistry
  • Benzofurans / metabolism*
  • Benzofurans / pharmacology
  • Binding Sites
  • Catechol O-Methyltransferase / chemistry
  • Catechol O-Methyltransferase / metabolism
  • Humans
  • Indoles / chemistry
  • Indoles / metabolism*
  • Indoles / pharmacology
  • Monoamine Oxidase / chemistry
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / metabolism
  • Monoamine Oxidase Inhibitors / pharmacology
  • N-Methyl-3,4-methylenedioxyamphetamine / chemistry
  • N-Methyl-3,4-methylenedioxyamphetamine / metabolism*
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology
  • Neurotransmitter Uptake Inhibitors / chemistry
  • Neurotransmitter Uptake Inhibitors / metabolism*
  • Neurotransmitter Uptake Inhibitors / pharmacology
  • Protein Binding
  • Protein Conformation
  • Radioligand Assay
  • Receptors, Serotonin, 5-HT2 / chemistry
  • Receptors, Serotonin, 5-HT2 / drug effects
  • Receptors, Serotonin, 5-HT2 / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / chemistry
  • Serotonin 5-HT2 Receptor Agonists / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / pharmacology
  • Stress Disorders, Post-Traumatic / drug therapy*
  • Stress Disorders, Post-Traumatic / metabolism
  • Structure-Activity Relationship
  • Tyrosine 3-Monooxygenase / chemistry
  • Tyrosine 3-Monooxygenase / metabolism
  • Vesicular Monoamine Transport Proteins / antagonists & inhibitors
  • Vesicular Monoamine Transport Proteins / chemistry
  • Vesicular Monoamine Transport Proteins / metabolism*


  • Benzofurans
  • Indoles
  • Monoamine Oxidase Inhibitors
  • Neurotransmitter Uptake Inhibitors
  • Receptors, Serotonin, 5-HT2
  • Serotonin 5-HT2 Receptor Agonists
  • Vesicular Monoamine Transport Proteins
  • Tyrosine 3-Monooxygenase
  • Monoamine Oxidase
  • Catechol O-Methyltransferase
  • N-Methyl-3,4-methylenedioxyamphetamine