Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, Burjassot, 46100 Valencia, Spain.
Eur J Med Chem. 2013 Oct;68:150-66. doi: 10.1016/j.ejmech.2013.07.036. Epub 2013 Aug 11.
Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure-activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation.
多巴胺介导的神经递质传递在相关的精神和神经障碍中起着重要作用。如今，人们对开发新的多巴胺受体（DR）作用药物产生了极大的兴趣，这些药物可能成为治疗精神分裂症或帕金森病的新靶点。先前的研究表明，异喹啉类化合物，如四氢异喹啉（THIQs）和四氢原小檗碱（THPBs）可以作为选择性 D2 多巴胺能生物碱，因为它们与多巴胺具有结构相似性。在本研究中，我们合成了 11 种 2,3,9-和 2,3,11-三取代的 THPB 化合物（其中 6 种是首次描述的），并评估了它们潜在的多巴胺能活性。使用大鼠纹状体膜上的结合研究来评估它们对 D1 和 D2 DR 的亲和力和选择性，并建立作为多巴胺能药物的结构-活性关系（SAR）。一般来说，所有带有保护酚羟基的测试 THPB 对 D1 和 D2 DR 的亲和力都低于具有游离羟基的同源物。在先前评估 1-苄基-THIQs（BTHIQs）多巴胺能亲和力的研究中，A 环中存在 Cl 导致对 D2 DR 的亲和力和选择性增加。这与当前的研究形成对比，因为在 THPB 的 A 环中存在氯原子会导致对 D1 DR 的亲和力增加，但对 D2 DR 的选择性显著降低。THPB 中 9 位的 OH 基团（9f）比 11 位的 OH 基团（9e）对 DR 的亲和力更高（对 D2 DR 的亲和力高 250 倍）。在新鲜分离的人中性粒细胞中，没有一种化合物表现出任何细胞毒性。对三种代表性的 THPB 进行了分子建模研究。MD 模拟与 DFT 计算的结合从结构和能量的角度提供了配体结合相互作用的清晰图像。因此，化合物 9d（2,3,9-三羟基-THPB）可能作为 D2 DR 激动剂发挥作用，因为丝氨酸残基簇对于激动剂结合和受体激活至关重要。
