5‑HT_2A/5-HT_2C Receptor Pharmacology and Intrinsic Clearance of <i>N</i>‑Benzylphenethylamines Modified at the Primary Site of Metabolism

The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability, and 5-HT_2A/5-HT_2C receptor profile of novel analogues of 25B-NBOMe modified at the primary site of metabolism. Although microsomal stability could be increased while maintaining potent 5-HT₂ receptor agonist properties, all analogues had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism