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 hypothesi s of hallucinogen action), 5-HT2 receptors have been demonstrated to repres ent a family of receptors that consists of three distinct subpopulations: 5 -HT2A, 5-HT2B, and 5-HT2C receptors. Today, there is greater support for 5- HT2A than for 5-HT2C receptor involvement in the behavioral effects evoked by these agents. However, with the recent discovery of 5-HT2B receptors, a new question arises: do classical hallucinogens bind at 5-HT2B receptors? I n the present study we examined and compared the binding of 17 phenylisopro pylamines at human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Although there was a notable positive correlation (r>0.9) between the affinities of the agent s at all three populations of 5-HT2 receptors, structural modification resu lted only in small differences in 5-HT2B receptor affinity such that the ra nge of affinities was only about 50-fold. As with 5-HT2A and 5-HT2C recepto r affinity, there is a significant correlation (r>0.9, n=8) between 5-HT2B receptor affinity and human hallucinogenic potency. Nevertheless, given tha t 5-HT2A and 5-HT2A/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-HT2A receptors play a more prominent role than 5-HT2B and 5-HT2C receptors in mediating such e ffects despite the affinity of these agents for all three 5-HT2 receptor su bpopulations.