Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, 5-HT2B and 5-HT2C receptors

Since the classical hallucinogens were initially reported to produce their behavioral effects via a 5-HT₂ agonist mechanism (i.e., the 5-HT₂ hypothesis of hallucinogen action), 5-HT₂ receptors have been demonstrated to represent a family of receptors that consists of three distinct subpopulations: 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. Today, there is greater support for 5-HT_2A than for 5-HT_2C receptor involvement in the behavioral effects evoked by these agents. However, with the recent discovery of 5-HT_2B receptors, a new question arises: do classical hallucinogens bind at 5-HT_2B receptors? In the present study we examined and compared the binding of 17 phenylisopropylamines at human 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. Although there was a notable positive correlation (r>0.9) between the affinities of the agents at all three populations of 5-HT₂ receptors, structural modification resulted only in small differences in 5-HT_2B receptor affinity such that the range of affinities was only about 50-fold. As with 5-HT_2A and 5-HT_2C receptor affinity, there is a significant correlation (r>0.9, n=8) between 5-HT_2B receptor affinity and human hallucinogenic potency. Nevertheless, given that 5-HT_2A and 5-HT_2A/2C antagonists – antagonists with low affinity for 5-HT_2B receptors – have been previously shown to block the stimulus effects of phenylisopropylamine hallucinogens, it is likely that 5-HT_2A receptors play a more prominent role than 5-HT_2B and 5-HT_2C receptors in mediating such effects despite the affinity of these agents for all three 5-HT₂ receptor subpopulations.