A subset of hallucinogenic compounds, ‘the psychedelics,’ primarily exert their psychoactive and clinical actions via the serotonin 5-HT2A receptor. Psychedelic drugs include lysergamides (e.g., LSD), tryptamines (e.g., psilocin), and phenethylamines (e.g., mescaline, 2C-B, 2C-I). In vitro 5-HT2A binding affinities of a variety of psychedelics correlate with potency to induce psychedelic effects in humans and this has been further supported by behavioral studies in rodents. The addition of an N-benzyl moieties to phenethylamines to form N-benzyl phenethylamines such as ‘NBOMes’ including N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe), increases the 5-HT2A receptor affinity and hallucinogenic potency. Several selective 5-HT2A ligands have been designed based on this scaffold, though selectivity is still limited. To probe the role of the functional group modifications on both the phenethylamine and N-benzyl rings, 30 analogues of N-benzylphenethylamines have been designed, and synthesized. Syntheses and analytical characterizations including high performance liquid chromatography (HPLC), 1-D and 2-D NMR, and high-resolution mass spectrometry (HRMS) are presented. A three step synthetic route has been optimized to make the desired nitrostyrenes from the respective benzaldehydes via a Henry reaction, followed by reduction of the nitrostyrene to the phenethylamine, and finally reductive amination to give the N-benzyl-phenethylamine. The resulting N-benzyl-phenethylamines are evaluated via competitive radioligand binding assays at 5-HT2A, 5-HT2B and 5-HT2C. Functional assays are also carried out including Ca2+flux assay and a Gq BRET-based assays. Finally, hallucinogen-like activity is assessed using the mouse head twitch response assay, which shows high construct and predictive validity for human psychedelic activity. Binding to the 5-HT2A receptor has been modeled using in silico docking to provide structural insights into the observed activities. Ongoing, structure activity relationship (SAR) studies suggest the importance of key substitutions on both the phenethylamine and N-benzyl aromatic rings.

Design, syntheses, and structure activity relationship characterizations of novel N-benzyl phenethylamines

ACS Spring 2022

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