Introducing Conformational Restraints on 25CN-NBOH: A Selective 5-HT 2A Receptor Agonist.

The N -benzylphenethylamines (NBOMes) are a class of ligands from which compounds with impressive selectivity for the serotonin 2A receptor (5-HT 2A R) over the closely related serotonin 2C receptor (5-HT 2C R) have emerged. These include 4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5-dimethoxybenzonitrile (25CN-NBOH, 1 ) and 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine (DMPMBB, 2 ). The present work entails the synthesis and characterization of ligands wherein the structures of these two molecules have been fused. The desired compounds were accessed by a six-step synthetic procedure followed by the chiral resolution of the resulting racemic mixtures, giving one active (( S , S )- 3 ) and three essentially inactive stereoisomers. In silico experiments support that one of the four possible stereoisomers would be active. Further in silico investigations showed that 1 , 2 , and ( S , S )- 3 share a common binding mode, further supporting the shared stereochemistry between the active enantiomer (( S , S )- 3 ) and 2 .