Investigation of the 2,5-Dimethoxy Motif in Phenethylamine Serotonin 2A Receptor Agonists.
Emil Märcher-Rørsted, Adam L. Halberstadt, Adam K. Klein, Muhammad Chatha, Simon Jademyr, Anders A. Jensen, Jesper L. Kristensen
ACS Chemical Neuroscience May 6, 2020 DOI: 10.1021/acschemneuro.0c00129 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | 2C-B DOB |
| Topics | Serotonin |
| Keywords | Phenethylamine Agonists Serotonin 2a receptor Structure−activity relationship Structure-activity relationship In vivo pharmacology |
| Citations | 20 |
| Key findings | The 2,5-dimethoxy motif is important for in vivo potency of phenethylamine 5-HT2AR agonists but does not correlate with in vitro affinity or potency at the recombinant receptor. |
Abstract
The 2,5-dimethoxyphenethylamine (2,5-PEA) scaffold is recognized as a motif conferring potent agonist activity at the serotonin 2A receptor (5-HT2AR). The 2,5-dimethoxy motif is present in several classical phenethylamine psychedelics such as 2,4,5- trimethoxyamphetamine (TMA-2), 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5- dimethoxy-4-bromoamphetamine (DOB), 2,5-dimethoxy-4-bromophenethylamine (2C-B), and 2,5-dimethoxy-4-iodophenethylamine (2C-I), and it has previously been suggested that this structural motif is essential for 5-HT2AR activation. In the present study, we present data that challenges this assumption. The 2- and 5-desmethoxy derivatives of 2C-B and DOB were synthesized, and their pharmacological profiles were evaluated in vitro at 5-HT2AR and 5-HT2CR in binding and functional assays and in vivo by assessing their induction of the head-twitch response in mice. Elimination of either the 2- or 5-methoxy group leads to a modest drop in binding affinity and functional potency at 5-HT2AR and 5-HT2CR, which was more pronounced upon removal of the 2-methoxy group. However, this trend was not mirrored in vivo, as removal of either methoxy group resulted in significant reduction in the ability of the compounds to induce the head-twitch response in mice. Thus, the 2,5-dimethoxyphenethylamine motif appears to be important for in vivo potency of phenethylamine 5-HT2AR agonists, but this does not correlate to the relative affinity and potency of the ligands at the recombinant 5-HT2AR.