Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT2A and 5-HT2B serotonin receptors.

For a series of 13 compounds related to the psychedelic agent 2,5-DMA, rat brain 5-HT2 receptor affinities correlate strongly with human 5-HT2A (r = 0.942) and 5-HT2B (r = 0.916) affinities. Human 5-HT2A affinity also correlates with the lipophilicity of the 4-position substituent (r = 0.798). In functional assays, eight of ten compounds acted as agonists at the human 5-HT2B receptor, while two acted as antagonists. Human 5-HT2B affinity, but not agonist action, correlates with substituent lipophilicity (r = 0.750). Rat and human 5-HT2A affinity may approximate human 5-HT2B affinity but cannot predict agonist action. Some 2,5-DMA analogs on the clandestine market may pose cardiac valvulopathy risk with chronic use via h5-HT2B activation.

Study at a glance

Abstract

Certain 4-substituted analogs of 1-(2,5-dimethoxyphenyl)isopropylamine (2,5-DMA) are psychoactive classical hallucinogens or serotonergic psychedelic agents that function as human 5-HT2A (h5-HT2A) serotonin receptor agonists. Activation of a related receptor population, h5-HT2B receptors, has been demonstrated to result in adverse effects including cardiac valvulopathy. We previously published on the binding of several such agents at the two receptor subtypes. We hypothesized that, due to their structural similarity, the 5-HT2A and 5-HT2B receptor affinities of these agents might be related, and that QSAR studies might aid future studies. For a series of 13 compounds, it is demonstrated here that i) their published rat brain 5-HT2 receptor affinities are significantly correlated with their h5-HT2A (r = 0.942) and h5-HT2B (r = 0.916) affinities, ii) as with r5-HT2 receptor affinity, h5-HT2A affinity is correlated with the lipophilicity of the 4-position substituent (r = 0.798), iii) that eight of the ten compounds examined in functional (Ca+2 mobilization in stable cell lines generated expressing the human 5-HT2B receptor using the Flp-In T-REx system) assays acted as h5-HT2B agonists (4-substituent = H, F, Br, I, OCH2CH3, NO2, nC3H7, tC4H9) and two (n-hexyl and benzyl) as antagonists, iv) h5-HT2B affinity but not action was correlated with the lipophilicity of the 4-position substituent (r = 0.750; n = 10). The findings suggest that h5-HT2B receptor affinity, and its relationship to substituent lipophilicity, might be approximated by rat and h5-HT2A affinity but cannot be used as a predictor of h5-HT2B agonist action of 2,5-DMA analogs. Furthermore, given that certain 2,5-DMA analogs are on the clandestine market, their potential to produce cardiac side effects following persistent or chronic use via activation of h5-HT2B receptors should be considered.