Hallucinogens and serotonergic mechanisms

Classical hallucinogens possess 5-HT2 agonist activity; certain structurally related agents are antagonists, but there is no evidence that the antagonists are hallucinogenic. Both the discriminative stimulus and human hallucinogenic potencies of the agonists are significantly correlated with 5-HT2 receptor affinity when [3H]-ketanserin is used as radioligand (Glennon et al., 1984). These agents appear to bind with higher affinity when [3H]DOB, an agent that apparently labels the agonist high-affinity state of 5-HT2 receptors, is used as radioligand (Sadzot et al., 1989). For a series of DOB-related agents, 5-HT2(KET) affinity can be modeled by the lipophilicity of the 4-position substituent; lipophilicity alone does not completely account for the affinity of 5-HT2 agonists. Using [3H]DOB as radioligand to minimize differences observed between agonists and antagonists, 5-HT2 affinity is related both to the lipophilicity and electron withdrawing nature of the 4-position substituents. The difference between 5-HT2(KET) and 5-HT2(DOB) binding may be related to the intrinsic activity of DOB-related agents. Serotonin, with an intrinsic activity of 1.0, is not hallucinogenic whereas hallucinogens may be hallucinogenic because they are high-affinity 5-HT2 partial agonists.