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

[Image: see text] 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 Ca(2+) mobilization. Function was measured at the human 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors, as well as at the rat 5-HT(2A) and 5-HT(2C) receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC(50) 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-HT(2A) receptor.