N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues.
ACS chemical neuroscience July 15, 2015 David E Nichols, M Flori Sassano, Adam L Halberstadt et al. 81 citations
A series of N-benzylated-5-methoxytryptamine analogues and a parallel series of N-benzylated 2C-I analogues were synthesized and tested. Most compounds showed highest affinity for 5-HT2 family receptors. Para substitution on the benzyl group reduced affinity, while ortho or meta substitution enhanced it. Large lipophilic groups improved affinity but often reduced functional activity. Functional testing at human and rat 5-HT2A, 5-HT2B, and 5-HT2C receptors revealed no general correlation between affinity and function. Several tryptamine congeners were potent functional agonists (EC50 values from 7.6 to 63 nM) but mostly partial agonists. In the mouse head twitch assay, many compounds induced head twitches, and this behavior correlated significantly with functional potency at the rat 5-HT2A receptor.