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Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole

Klein Herenbrink, Carmen; Verma, Ravi; Lim, Herman D.; Kopinathan, Anitha; Keen, Alastair; Shonberg, Jeremy; Draper-Joyce, Christopher J.; Scammells, Peter J.; Christopoulos, Arthur; Javitch, Jonathan A.; Capuano, Ben; Shi, Lei; Lane, J. Robert


Carmen Klein Herenbrink

Ravi Verma

Herman D. Lim

Anitha Kopinathan

Alastair Keen

Jeremy Shonberg

Christopher J. Draper-Joyce

Peter J. Scammells

Arthur Christopoulos

Jonathan A. Javitch

Ben Capuano

Lei Shi

Associate Professor


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 determine the intrinsic efficacy of aripiprazole. Our findings reveal a hitherto unappreciated mechanism through which to fine-tune the intrinsic efficacy of D2R agonists.


Klein Herenbrink, C., Verma, R., Lim, H. D., Kopinathan, A., Keen, A., Shonberg, J., …Lane, J. R. (2019). Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole. ACS Chemical Biology, 14(8), 1780-1792.

Journal Article Type Article
Acceptance Date Jul 24, 2019
Online Publication Date Jul 24, 2019
Publication Date Aug 16, 2019
Deposit Date Jul 30, 2019
Publicly Available Date Jul 25, 2020
Journal ACS Chemical Biology
Print ISSN 1554-8929
Electronic ISSN 1554-8937
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 14
Issue 8
Pages 1780-1792
Keywords Molecular Medicine; Biochemistry; General Medicine
Public URL
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Molecular determinants of the intrinsic efficacy of the antipsychotic aripiprazole (1.1 Mb)

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