N-Benzyl-tryptamine Derivatives as Serotonin 5-HT2A Receptor (5-HT2AR) Agonists: Focus on Different In Vitro 5-HT2AR Activity Profiles.
Eline Pottie, Emma Vertriest, Darío Martínez-afani, Breno A. Soares, Bruce K. Cassels, Christophe P Stove
ACS Chemical Neuroscience March 20, 2026 DOI: 10.1021/acschemneuro.5c00352 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Qualitative Peer reviewed |
|---|---|
| Measures | NanoBiT β-arrestin 2 recruitment assay, NanoBiT miniGαq recruitment assay |
| Topics | Serotonin |
| Key findings | N-benzyl-substituted (5-MeO-)tryptamines were more active in the β-arrestin 2 recruitment assay than in the miniGαq recruitment assay, demonstrating biased agonism at the 5-HT2AR. The study also identified structure-activity relationships and showed that functional data can differ between assays, affecting translatability. |
Abstract
N-Benzyl-derived phenethylamines are highly active (psychedelic) 5-HT2AR (serotonin 2A receptor) agonists used as biochemical tools and on the drug market. The impact of adding an N-benzyl substituent to the tryptamine core structure has scarcely been studied. A recent systematic exploration of N-benzyl-substituted (5-MeO-)tryptamines revealed a surprisingly low activity in a Ca2+ mobilization assay for certain analogues. Considering the increased number of reports on biased agonism at the 5-HT2AR, with particular examples in the group of phenethylamines containing an N-benzyl substituent, a series of 16 of these (5-MeO-)tryptamine derivatives (14 of which containing an N-benzyl group) was evaluated in two additional assays. Specifically, two highly similar yet complementary NanoBiT assays, monitoring the recruitment of β-arrestin 2 (βarr2) or miniGαq to the 5-HT2AR, were applied. The functional data allowed assessment of the impact of different substituents on the compounds' 5-HT2AR activity: (i) the introduction of an N-benzyl group on the (5-MeO-)tryptamine core; (ii) the substitution of the N-benzyl at different positions; and (iii) the presence of a 5-MeO group on the tryptamine core structure. Interestingly, the N-benzyl-substituted (5-MeO-)tryptamines were more active in βarr2 than in the miniGαq recruitment assay, and biased agonism was assessed by both quantitative and qualitative methods. Aside from the estimation of structure-activity relationships and biased agonism, the current data set allowed for a comparison of the functional data between different assays, hence providing a better understanding of the translatability of results from one assay to the other.
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
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and 28 more in the library