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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.

4-{2-[(2-hydroxybenzyl)amino]ethyl}-2,5-dimethoxybenzo­nitrile (25CN-NBOH) was first reported as a potent and highly selective serotonin 2A receptor (5-HT2AR) agonist in 2014. The compound has since found extensive use as a pharmacological tool in a variety of in vivo and in vitro studies. In the present study, we present an improved and scalable synthesis of 25CN-NBOH making this compound readily available to the scientific community.

The 2,5-dimethoxyphenethylamine (2, 5-PEA) scaffold is recognized as a motif conferring potent agonist activity at the seroto-nin 2A receptor (5-HT2AR). The 2,5-dimethoxy motif is present in several classical phenethylamine psychedelics such as mesca-line, TMA-2, DOM, DOI, DOB, 2C-B and 2C-I, and it has previously been suggested that this structural motif is essential for 5-HT2AR activation. In the present study we present data that challenges this assumption. The 2- and 5-desmethoxy derivatives of 2C-B and DOB were synthesized and their pharmacological profiles evaluated in vitro at 5-HT2AR and 5-HT2CR in binding and functional assays and in vivo by assessing their induction of Head Twitch Response in mice. Elimination of either the 2- or 5-methoxy leads to a modest drop in binding affinity and functional potency at 5-HT2AR and 5-HT2CR, which was more pro-nounced upon removal of the 5-methoxy. However, this trend was not mirrored in vivo, as removal of either methoxy group resulted in significant reduction in the compounds ability to induce the Head Twitch Response in mice. Thus, the 2,5-dimethoxyphenethylamine motif appears to be important for in vivo potency of phenethylamine 5-HT2AR agonists, but this does not correlate to the relative affinity and potency of the ligands at the recombinant 5-HT2AR.