Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115, USA.
Biomolecules. 2021 Apr 13;11(4):570. doi: 10.3390/biom11040570.
The dopamine D2/D3 receptor (DR/DR) agonists are used as therapeutics for Parkinson's disease (PD) and other motor disorders. Selective targeting of DR over DR is attractive because of DR's restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the DR and DR poses a challenge in the development of DR selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent DR-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both DR and DR using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved DR potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant DR over DR selectivity, and G protein bias at DR. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at DR and support further evaluation of functionally biased DR agonists for their therapeutic potential.
多巴胺 D2/D3 受体 (DR/DR) 激动剂被用作治疗帕金森病 (PD) 和其他运动障碍的药物。DR 选择性靶向 DR 是有吸引力的，因为 DR 的组织分布受限，潜在的副作用更少，并且具有潜在的神经保护作用。然而，DR 和 DR 之间的高序列同源性给 DR 选择性激动剂的开发带来了挑战。为了解决配体选择性问题，先前基于一种有效的 DR 优先激动剂 PF592,379 作为主要药效团 (PP) 设计并合成了双药效团配体。该 PP 通过化学性质不同的连接子连接到各种次要药效团 (SP) 上。在这里，我们使用 BRET 基功能测定法在 DR 和 DR 上对其中一些新型双药效团配体进行了表征。双药效团配体在效力和功效方面表现出不同的差异。此外，PP 的手性对于赋予 DR 更高的效力、选择性和 G 蛋白信号转导偏向性至关重要。特别是，化合物 AB04-88 在 DR 上表现出显著的 DR 选择性和 DR 上的 G 蛋白偏向性。这种偏向性在 8 到 46 分钟的不同时间点都观察到了一致的结果。总之，这些功能研究得出的构效关系揭示了 DR 独特的药理学，并支持进一步评估功能偏向性 DR 激动剂的治疗潜力。
