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Investigation of the 2,5-Dimethoxy Motif in Phenethylamine Serotonin 2A Receptor Agonists
- Source :
- ACS Chemical Neuroscience. 11:1238-1244
- Publication Year :
- 2020
- Publisher :
- American Chemical Society (ACS), 2020.
-
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.
- Subjects :
- Agonist
Phenethylamine
Physiology
medicine.drug_class
Cognitive Neuroscience
Pharmacology
Trimethoxyamphetamine
Biochemistry
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
In vivo
Phenethylamines
Receptor, Serotonin, 5-HT2C
medicine
Animals
Potency
Structure–activity relationship
Receptor, Serotonin, 5-HT2A
Structural motif
030304 developmental biology
0303 health sciences
Dose-Response Relationship, Drug
Chemistry
Cell Biology
General Medicine
In vitro
Head Movements
Hallucinogens
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 19487193
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- ACS Chemical Neuroscience
- Accession number :
- edsair.doi.dedup.....bffaf702f32611a729f0bad048af65de