Monoamine receptor interaction profiles of 4-aryl-substituted 2,5-dimethoxyphenethylamines (2C-BI derivatives)

Many ring-substituted phenethylamines exert psychedelic effects that are thought to be primarily mediated by interactions with serotonergic 5-hydroxytryptamine 2 (5-HT_2A) receptors. The 2,5-dimethoxyphenethylamine (2C derivative) core structure with small lipophilic substituents at the 4-position seems to be particularly favorable for psychedelic effects. In contrast, 2C derivatives with bulky lipophilic substituents at the 4-position of the phenyl ring tend to display antagonist behavior at serotonin 5-HT₂ receptor sites. To gain a better understanding of agonist and antagonist behavior of substituted phenethylamines, binding affinities and functional activation and inhibition of a series of 4'-aryl substituted 2,5-dimethoxyphenethylamine (2C-BI derivatives) at various monoamine receptors were determined. In addition, the interactions of the compounds with monoamine transporters were assessed. Various 2C-BI derivatives potently bound to human serotonergic and adrenergic receptors and to rat and mouse trace amine-associated receptor 1. Additionally, 2C-BI-8 and 2C-BI-12 activated serotonin 5-HT_2A and 5-HT_2B receptors at submicromolar concentrations. 2C-BI-1 and 2C-BI-7 were the only 2C-BI derivatives to activate human trace amine-associated receptor 1. 2C-BI-3 and 2C-BI-4 interacted with monoamine transporters but with low overall potency. In conclusion, the tested 2C-BI derivatives displayed diverse pharmacological profiles. The relatively high affinities of various 2C-BI derivatives at the serotonin 5-HT_2A receptor indicate a high steric tolerance of the binding pocket. Potent partial activation of the serotonin 5-HT_2A receptor by 2C-BI-8 and 2C-BI-12 suggests that these substances may potentially exert psychedelic effects similar to other compounds of the 2C family.