Purpose: While many drugs of abuse have been extensively investigated, hallucinogens, in general, have not been as well characterized with respect to the brain targets that might account for their specific sensory effects. The 5-HT2A receptor has been reported to be a target for some of the better characterized hallucinogens, such as lysergic acid (LSD) and dimethyltryptamine (DMT), but their sensory effects are different, as are those of many other hallucinogenic compounds, suggesting that other receptor targets may be involved. Here a panel of five cloned receptors was screened against the known hallucinogen DMT, two novel hallucinogens with structural similarities to DMT, Diisopropyltryptamine (DiPT) and 4-hydroxy-DiPT (4-OH-DiPT), and two marine natural products intermediates named CJL-4 and CJL-5.
Methods: Stable cells lines were created that express one of a panel of five different cloned receptors. These included three serotonin receptor subtypes, 5-HT1A, 5-HT2A, 5-HT2C, a dopamine receptor and a sigma receptor. Radioligand competition binding assays were utilized to assess the ability of the test compounds to interact with the different receptors. A two-stage displacement, corresponding to moderate and strong interactions, was used as a cut-off for the purpose of profiling.
Results: DMT, DiPT, 4-OH-DiPT, CJL-4 and CJL-5 all had strong interactions with the 5-HT2A receptor. However, the interaction profiles with respect to the other receptors were different for each compound.
Conclusions: DMT, DiPT and 4-OH-DiPT have hallucinogenic activity and bind to the 5-HT2A receptor, a common site of action for hallucinogens. The variability in the profiles of these drugs for the other receptors screened may provide further insight with respect to their reported differences in sensory distortion experiences. The two natural product intermediates CJL-4 and CJL-5 also bound the 5-HT2A receptor suggesting that they have hallucinogenic potential or that they might be able to block hallucinations.