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

TY - JOUR

T1 - Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists

AU - Hansen, Martin

AU - Phonekeo, Karina

AU - Paine, James S

AU - Leth-Petersen, Sebastian

AU - Begtrup, Mikael

AU - Bräuner-Osborne, Hans

AU - Kristensen, Jesper Langgaard

PY - 2014/3/19

Y1 - 2014/3/19

N2 - 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.

AB - 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.

U2 - 10.1021/cn400216u

DO - 10.1021/cn400216u

M3 - Journal article

C2 - 24397362

SN - 1948-7193

VL - 5

SP - 243

EP - 249

JO - A C S Chemical Neuroscience

JF - A C S Chemical Neuroscience

IS - 3

ER -