TY - JOUR

T1 - Introducing Conformational Restraints on 25CN-NBOH

T2 - A Selective 5-HT2A Receptor Agonist

AU - Marcher-Rørsted, Emil

AU - Nykodemová, Jitka

AU - Harpsøe, Kasper

AU - Jensen, Anders A.

AU - Kristensen, Jesper L.

N1 - Funding Information: Generous support from the Lundbeck Foundation (Grant R208-2015-3140) is gratefully acknowledged. Publisher Copyright: © 2023 American Chemical Society.

PY - 2023

Y1 - 2023

N2 - The N-benzylphenethylamines (NBOMes) are a class of ligands from which compounds with impressive selectivity for the serotonin 2A receptor (5-HT2AR) over the closely related serotonin 2C receptor (5-HT2CR) 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.

AB - The N-benzylphenethylamines (NBOMes) are a class of ligands from which compounds with impressive selectivity for the serotonin 2A receptor (5-HT2AR) over the closely related serotonin 2C receptor (5-HT2CR) 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.

KW - 5-HTR

KW - binding mode

KW - psychedelics

KW - serotonin 2A receptor

U2 - 10.1021/acsmedchemlett.3c00014

DO - 10.1021/acsmedchemlett.3c00014

M3 - Journal article

C2 - 36923922

VL - 14

SP - 319

EP - 325

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 3

ER -