多巴胺D3受体的选择性激活和去甲肾上腺素转运体封锁增强持续关注。

文章的细节

引用

复制到剪贴板

马歇尔CA Brodnik ZD,莫滕森OV Reith MEA, Shumsky JS,沃特豪斯BD,西班牙RA, Kortagere年代

多巴胺D3受体的选择性激活和去甲肾上腺素转运体封锁增强持续关注。

神经药理学。2019年4月;148:178 - 188。doi: 10.1016 / j.neuropharm.2019.01.003。Epub 2019年1月8日。

PubMed ID

30633928 (在PubMed

]

文摘

儿茶酚胺发射器多巴胺(DA)、去甲肾上腺素(NE)控制活动和前额叶皮层(PFC)电路PFC-mediated执行功能。因此,药物影响儿茶酚胺神经传递发挥突出对认知的影响。许多这样的代理在临床上用于治疗注意力障碍。例如,哌醋甲酯块DA、NE再吸收,主要选择治疗注意缺陷多动障碍(ADHD)。最近,我们设计了SK609 - DA D3受体的选择性小分子受体激动剂(D3R)。在这项研究中,我们进一步特征SK609选择性地抑制NE的再摄取的能力由NE转运蛋白(净)。我们的研究结果表明SK609选择性地抑制与Ki净值约500海里,表现得像一个净衬底。系统性的SK609剂量(4毫克/公斤;i.p)。在天真的老鼠产生NE、DA增加300%和160%,分别在PFC。以微量透析可把时程延长基于这些神经化学结果,SK609 PFC-dependent测试,视觉引导持续注意任务的老鼠。 SK609 improved performance in a dose-dependent manner with a classical inverted-U dose response function with a peak effect at 4mg/kg. SK609's peak effect was blocked by a pre-treatment with either the D2/D3R antagonist raclopride (0.05mg/kg; i.p) or the alpha-1 adrenergic receptor antagonist prazosin (0.25mg/kg; i.p), confirming a role for both DA and NE in promoting sustained attention. Additionally, SK609 improved sustained attention more prominently among low-performing animals. Doses of SK609 (2, 4, and 8mg/kg) associated with cognitive enhancement did not produce an increase in spontaneous locomotor activity, suggesting a lack of side effects mediated by DA transporter (DAT) activity. These results demonstrate that the novel catecholaminergic modulator SK609 has the potential to treat sustained attention deficits without affecting DAT activity, distinguishing it from amphetamines and methylphenidate.

beplay体育安全吗DrugBank数据引用了这篇文章

药物

以1

哌醋甲酯