TY - JOUR
T1 - Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole
AU - Klein Herenbrink, Carmen
AU - Verma, Ravi
AU - Lim, Herman D.
AU - Kopinathan, Anitha
AU - Keen, Alastair
AU - Shonberg, Jeremy
AU - Draper-Joyce, Christopher J.
AU - Scammells, Peter J.
AU - Christopoulos, Arthur
AU - Javitch, Jonathan A.
AU - Capuano, Ben
AU - Shi, Lei
AU - Lane, J. Robert
PY - 2019/8/16
Y1 - 2019/8/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070895134&partnerID=8YFLogxK
U2 - 10.1021/acschembio.9b00342
DO - 10.1021/acschembio.9b00342
M3 - Article
C2 - 31339684
AN - SCOPUS:85070895134
SN - 1554-8929
VL - 14
SP - 1780
EP - 1792
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 8
ER -