دورية أكاديمية
Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand
| العنوان: | Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand |
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| المؤلفون: | Mistry, Shailesh N., Shonberg, Jeremy, Draper-Joyce, Christopher J., Klein Herenbrink, Carmen, Michino, Mayako, Shi, Lei, Christopoulos, Arthur, Capuano, Ben, Scammells, Peter J., Lane, J. Robert |
| بيانات النشر: | American Chemical Society |
| سنة النشر: | 2015 |
| المجموعة: | University of Nottingham: Repository@Nottingham |
| الوصف: | We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 0022-2623 |
| العلاقة: | https://nottingham-repository.worktribe.com/output/759243Test; Journal of Medicinal Chemistry; Volume 58; Issue 17; Pagination 6819-6843; https://nottingham-repository.worktribe.com/file/759243/1/jm-2015-005859.R2%20-%20JMC%2058%2817%29%202015%206819.pdfTest |
| DOI: | 10.1021/acs.jmedchem.5b00585 |
| الإتاحة: | https://doi.org/10.1021/acs.jmedchem.5b00585Test https://nottingham-repository.worktribe.com/file/759243/1/jm-2015-005859.R2%20-%20JMC%2058%2817%29%202015%206819.pdfTest https://nottingham-repository.worktribe.com/output/759243Test |
| حقوق: | openAccess |
| رقم الانضمام: | edsbas.3946A6E6 |
| قاعدة البيانات: | BASE |
| تدمد: | 00222623 |
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| DOI: | 10.1021/acs.jmedchem.5b00585 |