Abstract
Activation of the serotonin (5‐hydroxytryptamine, 5‐HT) 5HT~2C~ G protein‐coupled receptor (GPCR) is proposed as novel pharmacotherapy for obesity and neuropsychiatric disorders. In contrast, activation of the 5‐HT~2A~ and 5‐HT~2B~ GPCRs is associated with untoward hallucinogenic and cardiopulmonary effects, respectively. There is no crystal structure available to guide design of 5‐HT~2C~ receptor‐specific ligands. For this reason, a homology model of the 5‐HT~2C~ receptor was built based on the crystal structure of the human β~2~ adrenoceptor GPCR to delineate molecular determinants of ligand–receptor interactions for drug design purposes. Computational and experimental studies were carried out to validate the model. Binding of N(CH~3~)~2~‐PAT [(1__R__, 3__S__)‐(–)‐trans‐1‐phenyl‐3‐N,N‐dimethylamino‐1,2,3,4‐tetrahydronaphthalene], a novel 5‐HT~2C~ agonist/5‐HT~2A/2B~ inverse agonist, and its secondary [NH(CH~3~)‐PAT] and primary (NH~2~‐PAT) amine analogs were studied at the 5‐HT~2C~ wild type (WT) and D3.32A, S3.36A, and Y7.43A 5‐HT~2C~ point‐mutated receptors. Reference ligands included the tertiary amines lisuride and mesulergine and the primary amine 5‐HT. Modeling results indicated that 5‐HT~2C~ residues D3.32, S3.36, and Y7.43 play a role in ligand binding. Experimental ligand binding results with WT and point‐mutated receptors confirmed the impact of D3.32, S3.36, and Y7.43 on ligand affinity. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012