Serotonin 2A receptor binding, functional activity, and in vitro metabolism of two trideuteromethoxy 2C-B isotopologues.
Naunyn-Schmiedeberg's archives of pharmacology June 18, 2026 DOI: 10.1007/s00210-026-05566-5 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Cell lines expressing human 5-HT2A receptors |
| Interventions | 2C-B 2CB-2OCD3 2CB-5OCD3 |
| Topics | Serotonin |
| Keywords | Binding affinity Calcium Deuterium Kinetic isotope effect Psychedelic Β-arrestin 2 |
| Key points | Deuteration of the ring methoxy groups of 2C-B increased affinity at 5-HT2A receptors but did not affect functional activity in calcium release or β-arrestin 2 recruitment assays. |
Abstract
The aim of this study was to investigate the effects of deuterium substitution on the in vitro pharmacology of the psychedelic drug 2-(4-bromo-2,5-dimethoxyphenyl)ethan-1-amine (2C-B). Two deuterated isotopologues of 2C-B, namely 2-(4-bromo-5-methoxy-2-(methoxy-d3)phenyl)ethan-1-amine (2CB-2OCD3) and 2-(4-bromo-2-methoxy-5-(methoxy-d3)phenyl)ethan-1-amine (2CB-5OCD3), were synthesized and tested in cell lines expressing human 5-HT2A receptors for potential isotope effects on 5-HT2A receptor binding and functional activity, and for metabolism by human liver microsomes (HLM). The 2C-B isotopologues and 2C-B exhibited picomolar-to-nanomolar potency in binding to [125I]DOI-labelled 5-HT2A receptors and were equally efficacious to 2C-B in stimulating 5-HT2A-mediated intracellular Ca++ release and β-arrestin 2 engagement. No appreciable metabolism was observed for 2C-B or the deuterated analogues by HLM over the time course of the experiment. Deuteration of the ring methoxys of 2C-B appeared to increase affinity at [125I]DOI-labelled 5-HT2A receptors, likely due to dampened internal vibrational frequencies and rotational motions arising from primary and secondary kinetic isotope effects. Deuteration did not affect the ability of the drugs to stimulate intracellular calcium release or to recruit β-arrestin 2, with all compounds displaying similar low nanomolar potency and efficacy in these assays.