A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor
A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor
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DOI：
10.1021/acs.jmedchem.7b01565
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发表时间：
2019-01-10
影响因子：
7.3
通讯作者：
Capuano, Ben
中科院分区：
文献类型：
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作者：
Fyfe, Tim J.;Zarzycka, Barbara;Capuano, Ben
最近，一种新的负变构调节剂（NAM）的D-2样多巴胺受体1被确定通过虚拟配体筛选。该配体包含噻吩并[2，3-d]嘧啶骨架，其在已知的多巴胺能配体中不具有特征。在此，我们提供了1的变构作用模式的药理学验证，揭示了它是多巴胺功效的NAM，并确定了这种变构的结构决定因素。我们发现，关键的结构部分是重要的功能亲和力和负协同性，而功能化的噻吩并嘧啶在5-和6-位置的结果在类似物与不同的协同性配置文件。连续的化合物迭代产生了类似物，其功能亲和力提高了10倍，并且与多巴胺亲和力和功效的负协同性增强。此外，我们的研究揭示了一个片段样的核心，保持低μ M的亲和力和强大的负协同性显着提高配体效率。
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, while 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 mu M affinity and robust negative cooperativity with markedly improved ligand efficiency.