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

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-HT_2A) and 5-HT_2B 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-HT_2A and 5-HT_2C 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-HT_2A receptor and 5-HT_2B receptor, respectively, partial agonists. An exception to this were the benzylthiophenethylamines, which did not potently activate the 5-HT_2B receptor (EC₅₀ > 3000 nM). Furthermore, the compounds bound to serotonergic 5-HT_1A 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 (K_i > 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.