Receptor interaction profiles of novel N-2-methoxybenzyl (NSOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)

Background: N-2-methoxybenzyl-phenethylamines (NBOMe drugs) are newly used psychoactive substances with poorly defined pharmacological properties. The aim of the present study was to characterize the receptor binding profiles of a series of NBOMe drugs compared with their 2,5-dimethoxy-phenethylamine analogs (2C drugs) and lysergic acid diethylamide (LSD) in vitro. Methods: We investigated the binding affinities of 2C drugs (2C-B, 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4, 2C-T-7, and mescaline), their NBOMe analogs, and LSD at monoamine receptors and determined functional 5-hydroxytryptamine-2A (5-HT2A) and 5-HT2B receptor activation. Binding at and the inhibition of monoamine uptake transporters were also determined. Human cells that were transfected with the respective human receptors or transporters were used (with the exception of trace amine-associated receptor-1 [TAAR(1)], in which rat/mouse receptors were used). Results: All of the compounds potently interacted with serotonergic 5-HT2A, 5-HT2B, 5-HT2C receptors and rat TAAR(1) (most K-i and EC50: <1 mu M). The N-2-methoxybenzyl substitution of 2C drugs increased the binding affinity at serotonergic 5-HT2A, 5-HT2C, adrenergic alpha(1), dopaminergic D1-3, and histaminergic H-1 receptors and monoamine transporters but reduced binding to 5-HT1A receptors and TAAR(1). As a result, NBOMe drugs were very potent 5-HT2A receptor agonists (EC50: 0.04-0.5 mu M) with high 5-HT2A/5-HT1A selectivity and affinity for adrenergic alpha(1) receptors (K-i: 0.3-0.9 mu M) and TAAR(1) (Ki: 0.06-2.2 mu M), similar to LSD, but not dopaminergic D1-3 receptors (most K-i: >1 mu M), unlike LSD. Conclusion: The binding profile of NBOMe drugs predicts strong hallucinogenic effects, similar to LSD, but possibly more stimulant properties because of alpha(1) receptor interactions. (C) 2015 Elsevier Ltd. All rights reserved.