Adding a benzyl group to the nitrogen atom of phenethylamine psychedelics like 2C-B greatly increases their binding and activity at serotonin 5-HT2A receptors. A library of 48 compounds with varied phenethylamine and N-benzyl structures was tested. Most had high 5-HT2A affinity; compound 8b showed the highest affinity at 0.29 nM, while 1b was the most functionally potent at 0.074 nM. Selectivity over the related 5-HT2C receptor ranged from 1- to 40-fold in binding, though 6b achieved 100-fold selectivity. Functional selectivity was higher, with 1b exceeding 400-fold selectivity for 5-HT2A.
The metabolism of the potent psychedelic compound 25B-NBOMe, an illicit drug linked to several fatalities, was studied in pigs and humans. The primary metabolic pathway is 5'-demethylation, followed by conjugation to glucuronic acid. These findings were confirmed by carbon-11 labeling of 25B-NBOMe in three different positions and in vivo evaluation in both species.
The NBOMe compounds, potent serotonin 5-HT2A receptor agonists used recreationally for their hallucinogenic effects, are metabolized primarily by specific cytochrome P450 enzymes. For 25I-NBOMe, CYP3A4 is the major enzyme involved; for 25I-NBOH, CYP2D6 is the major enzyme. 25I-NBOH also undergoes direct glucuronidation, which may reduce the impact of CYP2D6 genetic variation. The intrinsic clearance values were 70.1 mL/min/kg for 25I-NBOMe and 118.7 mL/min/kg for 25I-NBOH. Users of 25I-NBOMe may face drug-drug interactions if taken with a strong CYP3A4 inhibitor. Metabolites included hydroxylation, O-demethylation, N-dealkylation, and dehydrogenation products.
The toxic hallucinogen 25B-NBOMe is rapidly broken down by human liver enzymes and has low oral bioavailability. New chemical variants were synthesized by modifying the part of the molecule where metabolism normally occurs. While some analogues resisted breakdown longer and still strongly activated 5-HT2 receptors, all had an intrinsic clearance above 1.3 L/kg/h, indicating they would still be extensively metabolized on first pass through the liver.