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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1780-1792
Number of pages13
JournalACS Chemical Biology
Volume14
Issue number8
DOIs
Publication statusPublished - 16 Aug 2019

Cite this

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. / Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole. In: ACS Chemical Biology. 2019 ; Vol. 14, No. 8. pp. 1780-1792.
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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.",
author = "{Klein Herenbrink}, Carmen and Ravi Verma and Lim, {Herman D.} and Anitha Kopinathan and Alastair Keen and Jeremy Shonberg and Draper-Joyce, {Christopher J.} and Scammells, {Peter J.} and Arthur Christopoulos and Javitch, {Jonathan A.} and Ben Capuano and Lei Shi and Lane, {J. Robert}",
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doi = "10.1021/acschembio.9b00342",
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Klein Herenbrink, C, Verma, R, Lim, HD, Kopinathan, A, Keen, A, Shonberg, J, Draper-Joyce, CJ, Scammells, PJ, Christopoulos, A, Javitch, JA, Capuano, B, Shi, L & Lane, JR 2019, 'Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole', ACS Chemical Biology, vol. 14, no. 8, pp. 1780-1792. https://doi.org/10.1021/acschembio.9b00342

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.

In: ACS Chemical Biology, Vol. 14, No. 8, 16.08.2019, p. 1780-1792.

Research output: Contribution to journalArticleResearchpeer-review

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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

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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.

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