N -Benzyl-Tryptamine Derivatives as Serotonin 5-HT 2 Receptor Ligands: Synthesis and Structure-Affinity/Activity Relationships
Darío Martínez-afani, Breno A. Soares, Jaime Mella-Raipán, José de Brea, María I. Loza, Eline Pottie, Christophe P Stove, Bruce K. Cassels
ACS Omega May 13, 2026 DOI: 10.1021/acsomega.5c13162 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with QSAR analysis Peer reviewed |
|---|---|
| Population | In vitro receptor assays |
| Topics | Serotonin |
| Keywords | Agonist 5-HT Receptor Action physics Pharmacology Biochemistry Stereochemistry |
| Citations | 1 |
| Key findings | Meta-substitution of the benzyl moiety in N-benzyltryptamines enhances serotonin 5-HT2 receptor activity, while para-substitution reduces it due to steric clashes. |
Abstract
High Resolution Image Download MS PowerPoint Slide Serotonin 5-HT 2 receptor ligands have attracted the attention of medicinal chemists for the last half-century, first as hallucinogens and later for their antipsychotic, appetite suppressant, antiaddictive and antidepressant potential. Unlike the very potent N -benzylphenethylamine derivatives that include the abundantly studied NBOMe drugs, N -benzyltryptamines have garnered little attention as potentially psychedelic serotonin 5-HT 2A receptor ligands, and none as possible leads for the development of novel agents for the treatment of cognitive disorders, substance abuse, or depression. Here, we have synthesized two parallel sets of 22 tryptamine and 22 5-methoxytryptamine derivatives bearing different unsubstituted and ortho-, meta-, or para- substituted N- benzyl substituents, and assayed them for their affinities and potencies at the serotonin 5-HT 2A, 5-HT 2B, and 5-HT 2C receptors under identical conditions for each receptor subtype. In this way, we have obtained highly comparable data allowing QSAR analysis to be performed which clearly showed the favorable effects of meta - and the unfavorable effects of para -substitution of the benzyl moiety. Considering the electronic and volumetric properties of the substituents, their effects could be attributed respectively to beneficial van der Waals forces in the meta position and steric clashes of para substituents.
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
Cites 23
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology May 1, 2020
- Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology December 1, 2015
- Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nature Communications December 15, 2023
and 18 more in the library