Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists

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N-benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting sub-nanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1 to 40-fold) for the 5-HT2A receptor in the binding assays although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.
Original languageEnglish
JournalA C S Chemical Neuroscience
Issue number3
Pages (from-to)243-249
Number of pages8
Publication statusPublished - 7 Jan 2014

ID: 103038300