Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT(2A) and 5-HT(2B) serotonin receptors

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-HT(2A) (h5-HT(2A)) serotonin receptor agonists. Activation of a related receptor population, h5-HT(2B) 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-HT(2A) and 5-HT(2B) 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-HT(2) receptor affinities are significantly correlated with their h5-HT(2A) (r = 0.942) and h5-HT(2B) (r = 0.916) affinities, ii) as with r5-HT(2) receptor affinity, h5-HT(2A) 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-HT(2B) receptor using the Flp-In T-REx system) assays acted as h5-HT(2B) agonists (4-substituent = H, F, Br, I, OCH(2)CH(3), NO(2), nC(3)H(7), tC(4)H(9)) and two (n-hexyl and benzyl) as antagonists, iv) h5-HT(2B) affinity but not action was correlated with the lipophilicity of the 4-position substituent (r = 0.750; n = 10). The findings suggest that h5-HT(2B) receptor affinity, and its relationship to substituent lipophilicity, might be approximated by rat and h5-HT(2A) affinity but cannot be used as a predictor of h5-HT(2B) 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-HT(2B) receptors should be considered.