Serotonergic psychedelics like LSD, mescaline, and psilocin produce their subjective effects by activating the serotonin 2A receptor (5-HT2AR). Some structurally similar ergolines, such as lisuride, do not evoke psychedelic effects. In cell-based assays, the known psychedelic AL-LAD activated 5-HT2AR with higher intrinsic efficacy (137–167%) than LSD, while the non-psychedelic lisuride showed markedly decreased efficacy (49%) in one pathway and no activation in another. The results suggest that ergoline compounds may require a threshold level of 5-HT2AR activation across two signaling pathways to produce psychedelic effects, a hypothesis that needs further investigation.
Five positional isomers of the psychedelic compound 25H-NBOMe, each differing in the placement of two methoxy groups on the phenyl ring of the phenethylamine moiety, were tested in split-nanoluciferase assays to measure their ability to recruit cytosolic proteins to the serotonin 2A receptor. Molecular docking simulations estimated which receptor residues interact with each isomer's methoxy groups. This is the first comparative evaluation of how the positioning of methoxy groups in the phenethylamine moiety of NBOMes affects functional activity at the receptor.
Psychedelic new psychoactive substances (NPS) that activate the serotonin 2A receptor (5-HT2AR) remain a large share of reported NPS, but their exact mechanisms—especially what distinguishes them from non-psychedelic 5-HT2AR agonists—need more study. A new bioassay was developed to monitor recruitment of an engineered miniGαq protein to the activated 5-HT2AR, designed to parallel an existing assay for β-arrestin 2 recruitment. This allowed estimation of a substance's preference for triggering one protein over the other (biased agonism).