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 Peer reviewed DOI: 10.1021/acsomega.5c13162 via OpenAlex
Summary
Serotonin 5-HT 2 receptor ligands have been studied for their potential in treating various disorders, but N-benzyltryptamines have received little attention as psychedelic agents. This study synthesized 44 derivatives (22 tryptamines and 22 5-methoxytryptamines) with different N-benzyl substitutions and assessed their affinities at serotonin receptors. The findings indicate that meta-substitution enhances potency while para-substitution has negative effects due to steric clashes.
Study at a glance
| Sample size | 44 |
|---|---|
| Population | derivatives of tryptamine and 5-methoxytryptamine |
| Key finding | Meta-substitution of the benzyl moiety improves potency at serotonin receptors, whereas para-substitution leads to unfavorable effects. |
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.