N -Benzyl-Tryptamine Derivatives as Serotonin 5-HT 2 Receptor Ligands: Synthesis and Structure-Affinity/Activity Relationships

A set of 22 tryptamine and 22 5-methoxytryptamine derivatives with various N-benzyl substituents were synthesized and tested for affinity and potency at serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. The data enabled QSAR analysis, which showed that meta-substitution on the benzyl ring improves activity, while para-substitution reduces it. These effects are attributed to favorable van der Waals interactions at the meta position and steric hindrance at the para position. The findings suggest that N-benzyltryptamines, previously overlooked as psychedelic ligands, could be leads for treating cognitive disorders, substance abuse, or depression.

Study at a glance

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.