دورية أكاديمية
Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole
| العنوان: | Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole |
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| المؤلفون: | 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 |
| بيانات النشر: | American Chemical Society |
| سنة النشر: | 2019 |
| المجموعة: | University of Nottingham: Repository@Nottingham |
| مصطلحات موضوعية: | Molecular Medicine, Biochemistry, General Medicine |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 1554-8929 |
| العلاقة: | https://nottingham-repository.worktribe.com/output/2355472Test; ACS Chemical Biology; Volume 14; Issue 8; Pagination 1780-1792; https://nottingham-repository.worktribe.com/file/2355472/1/Molecular%20determinants%20of%20the%20intrinsic%20efficacy%20of%20the%20antipsychotic%20aripiprazoleTest |
| DOI: | 10.1021/acschembio.9b00342 |
| الإتاحة: | https://doi.org/10.1021/acschembio.9b00342Test https://nottingham-repository.worktribe.com/file/2355472/1/Molecular%20determinants%20of%20the%20intrinsic%20efficacy%20of%20the%20antipsychotic%20aripiprazoleTest https://nottingham-repository.worktribe.com/output/2355472Test |
| حقوق: | openAccess |
| رقم الانضمام: | edsbas.EBAF63E0 |
| قاعدة البيانات: | BASE |
| تدمد: | 15548929 |
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| DOI: | 10.1021/acschembio.9b00342 |