Off-target activity of NBOMes and NBOMe analogs at the µ opioid receptor.

Some psychedelic substances that carry the N-benzyl phenethylamine (NBOMe) structure can activate the µ opioid receptor (MOR), an off-target effect confirmed by two different assays. This activation was blocked by the opioid antagonist naloxone, indicating these NBOMes bind to the same opioid binding pocket as conventional opioids. Molecular docking showed plausible interactions of 25I-NBOMe with MOR similar to those of opioids. However, MOR activation occurred only at high concentrations, making relevant opioid toxicity in vivo unlikely at physiologically relevant levels. Small modifications to the NBOMe structure could yield more potent MOR agonists with dual MOR/5-HT2A activation potential.

Study at a glance

Abstract

New psychoactive substances (NPS) are introduced on the illicit drug market at a rapid pace. Their molecular targets are often inadequately elucidated, which contributes to the delayed characterization of their pharmacological effects. Inspired by earlier findings, this study set out to investigate the µ opioid receptor (MOR) activation potential of a large set of psychedelics, substances which typically activate the serotonin (5-HT2A) receptor as their target receptor. We observed that some substances carrying the N-benzyl phenethylamine (NBOMe) structure activated MOR, as confirmed by both the NanoBiT® βarr2 recruitment assay and the G protein-based AequoScreen® Ca2+ release assay. The use of two orthogonal systems proved beneficial as some aspecific, receptor independent effects were found for various analogs when using the Ca2+ release assay. The specific 'off-target' effects at MOR could be blocked by the opioid antagonist naloxone, suggesting that these NBOMes occupy the same common opioid binding pocket as conventional opioids. This was corroborated by molecular docking, which revealed the plausibility of multiple interactions of 25I-NBOMe with MOR, similar to those observed for opioids. Additionally, structure-activity relationship findings seen in vitro were rationalized in silico for two 25I-NBOMe isomers. Overall, as MOR activity of these psychedelics was only noticed at high concentrations, we consider it unlikely that for the tested compounds there will be a relevant opioid toxicity in vivo at physiologically relevant concentrations. However, small modifications to the original NBOMe structure may result in a panel of more efficacious and potent MOR agonists, potentially exhibiting a dual MOR/5-HT2A activation potential.