Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole

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, J. Robert Lane

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16 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1780-1792
Number of pages13
JournalACS Chemical Biology
Issue number8
Publication statusPublished - 16 Aug 2019

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