Programme for Proteomics, Paracelsus Medical University, 5020 Salzburg, Austria.
Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria.
Biomolecules. 2023 Mar 3;13(3):467. doi: 10.3390/biom13030467.
The worldwide increase in cognitive decline, both in aging and with psychiatric disorders, warrants a search for pharmacological treatment. Although dopaminergic treatment approaches represent a major step forward, current dopamine transporter (DAT) inhibitors are not sufficiently specific as they also target other transporters and receptors, thus showing unwanted side effects. Herein, we describe an enantiomerically pure, highly specific DAT inhibitor, S-CE-123, synthetized in our laboratory. Following binding studies to DAT, NET and SERT, GPCR and kinome screening, pharmacokinetics and a basic neurotoxic screen, S-CE-123 was tested for its potential to enhance and/or rescue cognitive functions in young and in aged rats in the non-invasive reward-motivated paradigm of a hole-board test for spatial learning. In addition, an open field study with young rats was carried out. We demonstrated that S-CE-123 is a low-affinity but highly selective dopamine reuptake inhibitor with good bioavailability. S-CE-123 did not induce hyperlocomotion or anxiogenic or stereotypic behaviour in young rats. Our compound improved the performance of aged but not young rats in a reward-motivated task. The well-described impairment of the dopaminergic system in aging may underlie the age-specific effect. We propose S-CE-123 as a possible candidate for developing a tentative therapeutic strategy for age-related cognitive decline and cognitive dysfunction in psychiatric disorders.
全球范围内认知能力下降的情况，无论是在衰老过程中还是与精神障碍有关，都需要寻找药物治疗方法。尽管多巴胺能治疗方法是一个重大进展，但目前的多巴胺转运体（DAT）抑制剂不够特异，因为它们也针对其他转运体和受体，从而表现出不必要的副作用。在此，我们描述了一种我们实验室合成的对映体纯、高度特异的 DAT 抑制剂 S-CE-123。在对 DAT、NET 和 SERT 进行结合研究、GPCR 和激酶组筛选、药代动力学和基本神经毒性筛选后，我们测试了 S-CE-123 对年轻和老年大鼠在非侵入性奖励驱动的洞板测试中空间学习的认知功能增强和/或挽救的潜力。此外，还对年轻大鼠进行了开阔场研究。我们证明 S-CE-123 是一种低亲和力但高度选择性的多巴胺再摄取抑制剂，具有良好的生物利用度。S-CE-123 不会引起年轻大鼠的过度活跃、焦虑或刻板行为。我们的化合物改善了奖励驱动任务中老年大鼠的表现，但不能改善年轻大鼠的表现。衰老过程中多巴胺能系统的明显损伤可能是年龄特异性效应的基础。我们提出 S-CE-123 可能是开发针对与年龄相关的认知衰退和精神障碍认知功能障碍的治疗策略的候选药物。
