Molecular Determinants for Ligand Binding at Serotonin 5-HT_2A and 5-HT_2C GPCRs: Experimental Affinity Results...

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-HT₂ 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-HT₂ GPCRs, 5-HT_2A, and 5-HT_2C homology models were built from the β₂-adrenergic GPCR crystal structure and equilibrated in a lipid phosphatidyl choline bilayer performing molecular dynamics simulations. Ligand docking studies at the 5-HT₂ 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-HT₂ 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.