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.
A new molecule, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed based on a computer model of the 5-HT(2A) receptor. This compound showed three times higher affinity and potency than mescaline at the receptor, with equal efficacy. In drug discrimination tests, it fully substituted for LSD and was five times more potent than mescaline. Separating the molecule into its mirror-image forms confirmed the computer predictions: the R-(+) isomer had higher affinity and potency than the S-(-) isomer, with efficacy similar to mescaline at the 5-HT(2A) receptor.