Sutton Charles, Williams Erin Q, Homsi Hoomam, Beerepoot Pieter, Nazari Reza, Han Dong, Ramsey Amy J, Mash Deborah C, Olson David E, Blough Bruce, Salahpour Ali
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Departments of Neurology and Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, United States.
Front Cell Neurosci. 2022 May 9;16:832536. doi: 10.3389/fncel.2022.832536. eCollection 2022.
Mutations in the dopamine transporter gene (SLC6A3) have been implicated in many human diseases. Among these is the infantile parkinsonism-dystonia known as Dopamine Transporter Deficiency Syndrome (DTDS). Afflicted individuals have minimal to no functional dopamine transporter protein. This is primarily due to retention of misfolded disease-causing dopamine transporter variants. This results in a variety of severe motor symptoms in patients and the disease ultimately leads to death in adolescence or young adulthood. Though no treatment is currently available, pharmacological chaperones targeting the dopamine transporter have been shown to rescue select DTDS disease-causing variants. Previous work has identified two DAT pharmacological chaperones with moderate potency and efficacy: bupropion and ibogaine. In this study, we carried out structure-activity relationships (SARs) for bupropion and ibogaine with the goal of identifying the chemical features required for pharmacological chaperone activity. Our results show that the isoquinuclidine substituent of ibogaine and its analogs is an important feature for pharmacological chaperone efficacy. For bupropion, the secondary amine group is essential for pharmacological chaperone activity. Lastly, we describe additional ibogaine and bupropion analogs with varying chemical modifications and variable pharmacological chaperone efficacies at the dopamine transporter. Our results contribute to the design and refinement of future dopamine transporter pharmacological chaperones with improved efficacies and potencies.
多巴胺转运体基因（SLC6A3）的突变与许多人类疾病有关。其中包括被称为多巴胺转运体缺乏综合征（DTDS）的婴儿帕金森病 - 肌张力障碍。患病个体的功能性多巴胺转运体蛋白极少或没有。这主要是由于错误折叠的致病多巴胺转运体变体的滞留。这导致患者出现各种严重的运动症状，并且该疾病最终会在青春期或青年期导致死亡。尽管目前尚无治疗方法，但针对多巴胺转运体的药理伴侣已被证明可挽救某些导致DTDS的致病变体。先前的研究已经确定了两种具有中等效力和功效的多巴胺转运体药理伴侣：安非他酮和伊博格碱。在本研究中，我们对安非他酮和伊博格碱进行了构效关系（SAR）研究，目的是确定药理伴侣活性所需的化学特征。我们的结果表明，伊博格碱及其类似物的异喹核碱取代基是药理伴侣功效的重要特征。对于安非他酮，仲胺基团对药理伴侣活性至关重要。最后，我们描述了具有不同化学修饰和在多巴胺转运体上具有可变药理伴侣功效的其他伊博格碱和安非他酮类似物。我们的结果有助于设计和优化未来具有更高功效和效力的多巴胺转运体药理伴侣。
