Identification of psychedelic new psychoactive substances (NPS) showing biased agonism at the 5-HT2AR through simultaneous use of β-arrestin 2 and miniGαq bioassays.
Eline Pottie, P. Dedecker, Christophe P Stove
Biochemical Pharmacology September 27, 2020 DOI: 10.1016/j.bcp.2020.114251 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study (bioassay development and testing) Peer reviewed |
|---|---|
| Topics | Serotonin |
| Key findings | Several phenylalkylamine psychedelics (25H-NBF, 25H-NBMD, 25H-NBOH, 25H-NBOMe, and 25I-NBF) show statistically significant biased agonism, preferentially recruiting β-arrestin 2 over miniGαq compared to LSD. |
Abstract
Psychedelic new psychoactive substances (NPS), compounds exerting their main pharmacological effects through the activation of the serotonin 2A receptor (5-HT2AR), continuously comprise a substantial portion of the reported NPS. However, these substances and their exact mechanism of action, differentiating them from non-psychedelic 5-HT2AR agonists, require further characterization. One potentially relevant phenomenon is the occurrence of biased agonism, in which (a) certain signaling pathway(s) is preferentially activated over the other(s). To this end, a new bioassay was developed, monitoring the recruitment of an engineered miniGαq protein to the activated 5-HT2AR. The setup was designed to be analogous to that of a previously developed bioassay monitoring β-arrestin 2 recruitment through the NanoBiT system, enabling estimation of the potential preference of a substance to trigger recruitment of one protein over the other. This approach yielded several statistically significantly biased agonists within the group of phenylalkylamine psychedelics, more specifically the N-benzyl substituted 25H analogues 25H-NBF, 25H-NBMD, 25H-NBOH and 25H-NBOMe. All four compounds show a statistically significant preference towards the recruitment of β-arrestin 2 over miniGαq, as compared to the reference psychedelic substance LSD. We identified markedly different responses for Bromo-DragonFLY in the two bioassays, suggesting biased agonism, though the calculated bias factor equalled out to approximately 0. This demonstrates that the accurate assessment of biased agonism requires both the consideration of the observed trends in addition to the numerical value of the bias factor. A second panel of structural (I-substituted) analogues of the former group of phenylalkylamines showed a similar trend in the ranking order of the bias factors, resulting in one additional compound (25I-NBF) being statistically significantly biased.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 33
- The promises and perils of psychedelic pharmacology for psychiatry. Nature Reviews Drug Discovery June 1, 2022
- Structure–Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice ACS Pharmacology & Translational Science November 2, 2022
- 5-HT2A receptors: Pharmacology and functional selectivity. Pharmacological Reviews April 23, 2025
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
- Molecular insights into psychedelic drug action Journal of Neurochemistry November 19, 2021
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