Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center-Fort Worth, Texas, TX, 76107, USA.
Eur J Med Chem. 2023 Dec 5;261:115751. doi: 10.1016/j.ejmech.2023.115751. Epub 2023 Sep 9.
The difference in the secondary binding site (SBS) between the dopamine 2 receptor (DR) and dopamine 3 receptor (DR) has been used in the design of compounds displaying selectivity for the DR versus DR. In the current study, a series of bitopic ligands based on Fallypride were prepared with various secondary binding fragments (SBFs) as a means of improving the selectivity of this benzamide analog for DR versus DR. We observed that compounds having a small alkyl group with a heteroatom led to an improvement in DR versus DR selectivity. Increasing the steric bulk in the SBF increase the distance between the pyrrolidine N and Asp110, thereby reducing DR affinity. The best-in-series compound was (2S,4R)-trans-27 which had a modest selectivity for DR versus DR and a high potency in the β-arrestin competition assay which provides a measure of the ability of the compound to compete with endogenous dopamine for binding to the DR. The results of this study identified factors one should consider when designing bitopic ligands based on Fallypride displaying an improved affinity for DR versus DR.
多巴胺 2 受体 (DR) 和多巴胺 3 受体 (DR) 之间的次级结合位点 (SBS) 的差异已被用于设计对 DR 具有选择性的化合物。在当前的研究中，一系列基于 Fallypride 的双位配体，用各种次级结合片段 (SBF) 作为提高苯甲酰胺类似物对 DR 相对于 DR 的选择性的手段。我们观察到，具有杂原子的小烷基取代基的化合物导致对 DR 相对于 DR 的选择性提高。在 SBF 中增加空间位阻会增加吡咯烷氮和 Asp110 之间的距离，从而降低 DR 亲和力。最佳系列化合物是（2S，4R）-反式-27，它对 DR 相对于 DR 具有适度的选择性，并且在β-arrestin 竞争测定中具有高效力，该测定提供了一种衡量化合物与内源性多巴胺竞争结合 DR 的能力的方法。这项研究的结果确定了在设计基于 Fallypride 的双位配体时应考虑的因素，这些配体对 DR 相对于 DR 的亲和力得到了改善。
