N -Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT 2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues

Summary

A series of N-benzylated-5-methoxytryptamine analogues and N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) were synthesized and tested. Most compounds showed highest affinity for the 5-HT2 family of serotonin receptors. Substitution at the para position of the benzyl group reduced affinity, while ortho or meta substitution enhanced it. Large lipophilic groups improved affinity but often reduced functional activity. Functional potency was measured at human 5-HT2A, 5-HT2B, and 5-HT2C receptors and rat 5-HT2A and 5-HT2C receptors using intracellular calcium mobilization. Several tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM) but were mostly partial agonists. In mouse head twitch tests, many compounds induced the behavior, which correlated significantly with functional potency at the rat 5-HT2A receptor.

Study at a glance

Abstract

A series of N-benzylated-5-methoxytryptamine analogues was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at serotonin receptors showed that most of the compounds had the highest affinity at the 5-HT2 family receptors. Substitution at the para position of the benzyl group resulted in reduced affinity, whereas substitution in either the ortho or the meta position enhanced affinity. In general, introduction of a large lipophilic group improved affinity, whereas functional activity often followed the opposite trend. Tests of the compounds for functional activity utilized intracellular Ca2+ mobilization. Function was measured at the human 5-HT2A, 5-HT2B, and 5-HT2C receptors, as well as at the rat 5-HT2A and 5-HT2C receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM), but most were partial agonists. Tests in the mouse head twitch assay revealed that many of the compounds induced the head twitch and that there was a significant correlation between this behavior and functional potency at the rat 5-HT2A receptor.