Kim Young-Cho, Alberico Stephanie L, Emmons Eric, Narayanan Nandakumar S
Department of Neurology, University of Iowa, Iowa City, IA 52242, USA.
Department of Neurology, University of Iowa, Iowa City, IA 52242, USA; Aging Mind and Brain Initiative, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Front Biol (Beijing). 2015 Jun;10(3):230-238. doi: 10.1007/s11515-015-1360-4. Epub 2015 May 13.
The neurotransmitter dopamine acts via two major classes of receptors, D1-type and D2-type. D1 receptors are highly expressed in the striatum and can also be found in the cerebral cortex. Here we review the role of D1 dopamine signaling in two major domains: L-DOPA-induced dyskinesias in Parkinson's disease and cognition in neuropsychiatric disorders. While there are many drugs targeting D2-type receptors, there are no drugs that specifically target D1 receptors. It has been difficult to use selective D1-receptor agonists for clinical applications due to issues with bioavailability, binding affinity, pharmacological kinetics, and side effects. We propose potential therapies that selectively modulate D1 dopamine signaling by targeting second messengers downstream of D1 receptors, allosteric modulators, or by making targeted modifications to D1-receptor machinery. The development of therapies specific to D1-receptor signaling could be a new frontier in the treatment of neurological and psychiatric disorders.
神经递质多巴胺通过两大类受体发挥作用，即D1型和D2型受体。D1受体在纹状体中高度表达，在大脑皮层中也可发现。在此，我们综述D1多巴胺信号在两个主要领域的作用：帕金森病中左旋多巴诱发的运动障碍以及神经精神疾病中的认知。虽然有许多针对D2型受体的药物，但尚无特异性靶向D1受体的药物。由于生物利用度、结合亲和力、药理动力学和副作用等问题，选择性D1受体激动剂难以用于临床应用。我们提出了通过靶向D1受体下游的第二信使、变构调节剂或对D1受体机制进行靶向修饰来选择性调节D1多巴胺信号的潜在治疗方法。针对D1受体信号的治疗方法的开发可能成为神经和精神疾病治疗的新前沿。
