A thieno[2,3-d]pyrimidine scaffold is a novel negative allosteric modulator of the dopamine D2 receptor
| العنوان: | A thieno[2,3-d]pyrimidine scaffold is a novel negative allosteric modulator of the dopamine D2 receptor |
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| المؤلفون: | Herman D. Lim, Peter J. Scammells, Ben Capuano, Shailesh N. Mistry, J. Robert Lane, Vsevolod Katrich, Barbara Zarzycka, Tim J. Fyfe, Barrie Kellam |
| بيانات النشر: | American Chemical Society, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0303 health sciences, Allosteric modulator, genetic structures, Chemistry, Ligand, Stereochemistry, Allosteric regulation, Dopaminergic, Cooperative binding, Cooperativity, 01 natural sciences, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, 03 medical and health sciences, Dopamine receptor, Dopamine receptor D2, Drug Discovery, Molecular Medicine, 030304 developmental biology |
| الوصف: | Recently, a novel negative allosteric modulator (NAM) of the D 2-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3-d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, whilst functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low ?M affinity and robust negative cooperativity with markedly improved ligand efficiency. |
| وصف الملف: | application/pdf; |
| اللغة: | English |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::86dcdb887ac601e3b4d609d2f2c6cb86 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....86dcdb887ac601e3b4d609d2f2c6cb86 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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