Differential phospholipase C activation by phenylalkylamine serotonin 5‐HT2Areceptor agonists

Phenylisopropylamine hallucinogens (such as DOI) produce a stronger activation of the serotonin 5-HT2A receptor than their phenethylamine counterparts (such as mescaline), as measured by the receptor's ability to trigger phosphatidyl inositol hydrolysis in cells. Among phenylisopropylamines, those with the (R) configuration at the alpha carbon are more potent than those with the (S) configuration. Computer simulations of how these molecules dock into the receptor reveal different orientations of key binding site residues. The findings support the idea that phenylisopropylamines' greater hallucinogenic potency stems from higher intrinsic activity at the 5-HT2A receptor, though the three-dimensional structure of receptor microdomains also matters.

Study at a glance

Abstract

Experiments compared a series of phenethylamine hallucinogens with their phenylisopropylamine analogues for binding affinity and ability to stimulate serotonin 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol in cells expressing cloned rat and human 5-HT 2A receptors. The (+/-)phenylisopropylamine analogues had significantly higher intrinsic activities for 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol compared to their phenethylamine analogues. With respect to the effects of the stereochemistry of the phenylisopropylamines, those with the (R) absolute configuration at the alpha carbon had higher intrinsic activities for hydrolysis of phosphatidyl inositol in a cell line expressing the human 5-HT 2A receptor compared to those with the (S) absolute configuration. In virtual docking studies comparing the (R)- and (S)-phenylisopropylamines with their phenethylamine analogues, there were distinct differences in the orientations of key ligand binding domain residues that have been identified as important by previous mutagenesis studies. In conclusion, our data support the hypothesis that phenylisopropylamines have higher hallucinogenic potency than their phenethylamine analogues primarily because they have higher intrinsic activities at 5-HT 2A receptors. Although virtual ligand binding led to significant perturbations of certain key residues, our results emphasize the conclusion reached by others that overall three-dimensional structural microdomains within the receptor must be considered.