N -Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT 2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues
Simon D. Brandt, Maria F. Sassano, David E. Nichols, Simon Elliott, Landon M. Klein, Adam L. Halberstadt, Wolfgang J Fiedler
UNC Libraries October 29, 2020 DOI: 10.17615/6efy-d986 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Interventions | N-benzylated-5-methoxytryptamine analogues N-benzylated analogues of 2 5-dimethoxy-4-iodophenethylamine (2C-I) |
| Topics | Serotonin |
| Keywords | Phenethylamine 5-HT Receptor 5-ht2 receptor Pharmacology |
| Citations | 4 |
| Key findings | Several N-benzylated-5-methoxytryptamine analogues were very potent functional agonists at serotonin 5-HT2 receptors (EC50 values from 7.6 to 63 nM), and their ability to induce head twitch in mice correlated with functional potency at the rat 5-HT2A receptor. |
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.