Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists.
ACS chemical neuroscience – March 19, 2014
Source: PubMed
Summary
A specific chemical change dramatically enhances how compounds engage brain receptors. Scientists varied N-benzyl phenethylamines to understand their binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. From 48 new compounds, many showed exceptional 5-HT2A receptor affinity (0.29 nM) and potent functional activity (0.074 nM). Crucially, some compounds achieved remarkable selectivity, one showing over 400-fold preference for the 5-HT2A receptor. These positive results highlight successful strategies for developing potent, selective receptor-targeting compounds.
Abstract
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 subnanomolar 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.