Introducing Conformational Restraints on 25CN-NBOH: A Selective 5-HT2A Receptor Agonist

ACS Medicinal Chemistry Letters
2023.0

Abstract

The <i>N</i>-benzylphenethylamines (NBOMes) are a class of ligands from which compounds with impressive selectivity for the serotonin 2A receptor (5-HT<sub>2A</sub>R) over the closely related serotonin 2C receptor (5-HT<sub>2C</sub>R) have emerged. These include 4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5-dimethoxybenzonitrile (25CN-NBOH, <b>1</b>) and 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine (DMPMBB, <b>2</b>). 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 ((<i>S</i>,<i>S</i>)-<b>3</b>) and three essentially inactive stereoisomers. <i>In silico</i> experiments support that one of the four possible stereoisomers would be active. Further <i>in silico</i> investigations showed that <b>1</b>, <b>2</b>, and (<i>S</i>,<i>S</i>)-<b>3</b> share a common binding mode, further supporting the shared stereochemistry between the active enantiomer ((<i>S</i>,<i>S</i>)-<b>3</b>) and <b>2</b>.

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