Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole.
ACS Chem Biol
; 14(8): 1780-1792, 2019 08 16.
Article
em En
| MEDLINE
| ID: mdl-31339684
ABSTRACT
Partial agonists of the dopamine D2 receptor (D2R) 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 D2R-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 D2R agonists.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Antipsicóticos
/
Receptores de Dopamina D2
/
Agonistas de Dopamina
/
Aripiprazol
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article