Monoamine receptor interaction profiles of 4-thio-substituted phenethylamines (2C-T drugs)

Neuropharmacology. 2018 May 15;134(Pt A):141-148. doi: 10.1016/j.neuropharm.2017.07.012. Epub 2017 Jul 15.

Abstract

Background: 4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. Because of their psychedelic effects, 2C-T drugs are sometimes sold as new psychoactive substances (NPSs). The aim of the present study was to characterize the monoamine receptor and transporter interaction profiles of a series of 2C-T drugs.

Methods: We determined the binding affinities of 2C-T drugs at monoamine receptors and transporters in human cells that were transfected with the respective receptors or transporters. We also investigated the functional activation of serotonergic 5-hydroxytryptamine 2A (5-HT2A) and 5-HT2B receptors, activation of human trace amine-associated receptor 1 (TAAR1), and inhibition of monoamine uptake transporters.

Results: 2C-T drugs had high affinity for 5-HT2A and 5-HT2C receptors (1-54 nM and 40-350 nM, respectively). With activation potencies of 1-53 nM and 44-370 nM, the drugs were potent 5-HT2A receptor and 5-HT2B receptor, respectively, partial agonists. An exception to this were the benzylthiophenethylamines, which did not potently activate the 5-HT2B receptor (EC50 > 3000 nM). Furthermore, the compounds bound to serotonergic 5-HT1A and adrenergic receptors. The compounds had high affinity for the rat TAAR1 (5-68 nM) and interacted with the mouse but not human TAAR1. The 2C-T drugs did not potently interact with monoamine transporters (Ki > 4000 nM).

Conclusion: The receptor binding profile of 2C-T drugs predicts psychedelic effects that are mediated by potent 5-HT2 receptor interactions. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Keywords: Affinity; New psychoactive substances; Phenethylamines; Psychedelics; Receptor.

Publication types

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

MeSH terms

  • Animals
  • Biogenic Amines / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Transport Proteins / metabolism
  • Mice
  • Molecular Structure
  • Phenethylamines / chemistry
  • Phenethylamines / pharmacokinetics
  • Phenethylamines / pharmacology*
  • Protein Binding / drug effects
  • Psychotropic Drugs / chemistry
  • Psychotropic Drugs / pharmacology*
  • Radioligand Assay
  • Rats
  • Receptors, Biogenic Amine / metabolism*
  • Transfection

Substances

  • Biogenic Amines
  • Membrane Transport Proteins
  • Phenethylamines
  • Psychotropic Drugs
  • Receptors, Biogenic Amine
  • 2,5-dimethoxy-4-methylthiophenethylamine