| Autor: |
Klein Herenbrink C, Verma R; Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse-Intramural Research Program , National Institutes of Health , 333 Cassell Drive , Baltimore , Maryland 21224 , United States., Lim HD, Kopinathan A, Keen A, Shonberg J, Draper-Joyce CJ, Scammells PJ, Christopoulos A, Javitch JA, Capuano B, Shi L; Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse-Intramural Research Program , National Institutes of Health , 333 Cassell Drive , Baltimore , Maryland 21224 , United States., Lane JR; Division of Pharmacology, Physiology and Neuroscience, School of Life Sciences, Queen's Medical Centre , University of Nottingham , Nottingham NG7 2UH , U.K.; Centre of Membrane Protein and Receptors , Universities of Birmingham and Nottingham , Nottingham , United Kingdom. |
| Abstrakt: |
Partial agonists of the dopamine D 2 receptor (D 2 R) have been developed to treat the symptoms of schizophrenia without causing the side effects elicited by antagonists. The receptor-ligand interactions that determine the intrinsic efficacy of such drugs, however, are poorly understood. Aripiprazole has an extended structure comprising a phenylpiperazine primary pharmacophore and a 1,2,3,4-tetrahydroquinolin-2-one secondary pharmacophore. We combined site-directed mutagenesis, analytical pharmacology, ligand fragments, and molecular dynamics simulations to identify the D 2 R-aripiprazole interactions that contribute to affinity and efficacy. We reveal that an interaction between the secondary pharmacophore of aripiprazole and a secondary binding pocket defined by residues at the extracellular portions of transmembrane segments 1, 2, and 7 determines the intrinsic efficacy of aripiprazole. Our findings reveal a hitherto unappreciated mechanism for fine-tuning the intrinsic efficacy of D 2 R agonists. |
