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

Serotonin 5-HT2 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-HT2A 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-HT2A, 5-HT2B, and 5-HT2C 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.