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, Fort Worth, TX 76107, USA.
Molecules. 2021 May 26;26(11):3182. doi: 10.3390/molecules26113182.
phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted -phenylpiperazine analogs were evaluated. Compound was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson's disease.
苯哌嗪类似物可以选择性地与 D3 多巴胺受体亚型结合，而不是与 D2 多巴胺受体亚型结合，尽管这两种 D2 样多巴胺受体亚型表现出相当大的氨基酸序列同源性。这些受体亚型选择性化合物的结合被发现与其以双位方式与 D3 多巴胺受体亚型结合的能力一致。在这项研究中，评估了一系列 3-噻吩基苯基和 4-噻唑基苯基取代的 -苯哌嗪类似物。发现化合物 以纳摩尔亲和力与人 D3 受体结合，具有显著的 D3 与 D2 结合选择性（约 500 倍）。还对化合物 进行了两项体内测定的活性测试：（1）使用 DBA/2J 小鼠进行致幻剂依赖性头部抽搐反应抑制测定，以及（2）使用单侧 6-羟多巴胺损伤（偏侧帕金森病）大鼠进行 L-多巴依赖性异常不自主运动（AIM）抑制测定。发现化合物 在两种测定中均具有活性。这种化合物可以更好地理解双位 D3 多巴胺受体选择性配体如何导致开发治疗帕金森病患者左旋多巴诱导的运动障碍（LID）的药物治疗。
