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

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

Citation

Klein Herenbrink, C., Verma, R., Lim, H. D., Kopinathan, A., Keen, A., Shonberg, J., Draper-Joyce, C. J., Scammells, P. J., Christopoulos, A., Javitch, J. A., Capuano, B., Shi, L., & Lane, J. R. (2019). Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole. ACS Chemical Biology, 14(8), 1780-1792. https://doi.org/10.1021/acschembio.9b00342

• 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
• DOI: https://doi.org/10.1021/acschembio.9b00342
• Keywords: Molecular Medicine; Biochemistry; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/2355472
• Publisher URL: https://pubs.acs.org/doi/10.1021/acschembio.9b00342
• Contract Date: Jul 30, 2019