Abstract
Ligands that activate the serotonin 5-HT(2C) G protein-coupled receptor (GPCR) may be therapeutic for psychoses, addiction, and other neuropsychiatric disorders. Ligands that are antagonists at the closely related 5-HT(2A) GPCR also may treat neuropsychiatric disorders; in contrast, 5-HT(2A) activation may cause hallucinations. 5-HT(2C)-specific agonist drug design is challenging because 5-HT(2) GPCRs share 80% transmembrane (TM) homology, same second messenger signaling, and no crystal structures are reported. To help delineate molecular determinants underlying differential binding and activation of 5-HT(2) GPCRs, 5-HT(2A), and 5-HT(2C) homology models were built from the β(2)-adrenergic GPCR crystal structure and equilibrated in a lipid phosphatidyl choline bilayer performing molecular dynamics simulations. Ligand docking studies at the 5-HT(2) receptor models were conducted with the (2R, 4S)- and (2S, 4R)-enantiomers of the novel 5-HT(2C) agonist/5-HT(2A/2B) antagonist trans-4-phenyl-N,N-dimethyl-2-aminotetralin (PAT) and its 4'-chlorophenyl congners. Results indicate PAT-5-HT(2) molecular interactions especially in TM domain V are important for the (2R, 4S) enantiomer, whereas, TM domain VI and VII interactions are more important for the (2S, 4R) enantiomer.