Studies of perceptiotropic phenethylamines: Determinants of affinity for the 5-HT(2A) receptor

A series of 1-aryl-2-aminopropanes was synthesized in order to extend the knowledge of the requirements for agonist binding to the serotonin 5-HT$\rm\sb{2A}$ receptor. The aryl substituents employed were bromo- and methylthio-substituted benzodifuranyl and tetrahydrobenzodifuranyl isomers; bromoanthryl; and bromodifluorophenyl groups. Two previously known brominated analogs of mescaline were also synthesized for study. The compounds synthesized, along with a number of related compounds, were subjected to immobilized-artificial-membrane chromatography, an analytical technique that produces data which show a linear correlation with octanol-water partition coefficients for this class of compounds. The chromatographic data were used to demonstrate a linear relationship between hydrophobicity and agonist activity at the 5-HT$\rm\sb{2A}$ receptor. In addition, the chromatographic data, when coupled with receptor binding data, allowed agonists to be distinguished from antagonists, and could also be used to estimate the conformation of a ligand bound to the receptor. A theoretical model based on the thermodynamic contributions of hydrophobic and hydrogen bonding interactions was developed to explain these results