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

The -benzylphenethylamines (NBOMes) are a class of ligands from which compounds with impressive selectivity for the serotonin 2A receptor (5-HTR) over the closely related serotonin 2C receptor (5-HTR) have emerged. These include 4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5-dimethoxybenzonitrile (25CN-NBOH, ) and 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine (DMPMBB, ). 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 ((,)-) and three essentially inactive stereoisomers. experiments support that one of the four possible stereoisomers would be active. Further investigations showed that , , and (,)- share a common binding mode, further supporting the shared stereochemistry between the active enantiomer ((,)-) and .