On the mechanisms of dopamine receptor agonists in restless legs syndrome.

IF 4.9 2区 医学 Q1 Medicine
Sleep Pub Date : 2025-09-29 DOI:10.1093/sleep/zsaf305
Sergi Ferré, Diego García-Borreguero, Christopher J Earley
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引用次数: 0

Abstract

Several dopaminergic compounds, including the clinically used pramipexole, are labelled as preferential dopamine D3 receptor (D3R) agonists based on their moderately higher affinity for the D3R versus other D2-like receptor subtypes. It is therefore generally believed that D3R is the main target for their initial therapeutic response in restless legs syndrome (RLS). Here, we review the results of recent comprehensive pharmacological studies that demonstrate that in addition to their binding affinities, their functional responses at the different D2-like receptors depend on other pharmacodynamic factors, including intrinsic efficacy, biased agonism, functional efficacy and receptor heteromerization, and pharmacokinetic factors, including brain penetrability. When considering all these factors, the short isoform of the D2 receptor (D2SR) localized in the dopaminergic neurons and D2SRs and D4Rs localized in corticostriatal glutamatergic terminals become preferential targets of low doses of these D2-like receptor agonists. On the other hand, higher doses are necessary to promote activation of postsynaptic striatal D3Rs forming heteromers with D1Rs, which can be associated with the phenomenon of augmentation, the worsening of the RLS symptoms with their chronic use. The putative role of spinal D3Rs, specially with the periodic leg movements of sleep (PLMS) component of RLS, is also discussed. This analysis should provide therapeutic clues for a better targeting of the dopamine receptor subtypes involved in the therapeutic and not in the secondary effects of D2-like receptor agonists in RLS.

多巴胺受体激动剂治疗不宁腿综合征的机制探讨。
几种多巴胺能化合物,包括临床使用的普拉克索,被标记为优先多巴胺D3受体(D3R)激动剂,基于它们对D3R相对于其他d2样受体亚型具有较高的亲和力。因此,一般认为D3R是他们在不宁腿综合征(RLS)的初始治疗反应的主要靶点。在这里,我们回顾了最近的综合药理学研究结果,这些研究表明,除了它们的结合亲和力外,它们对不同d2样受体的功能反应还取决于其他药效学因素,包括内在功效、偏向激动作用、功能功效和受体异质化,以及药代动力学因素,包括脑穿透性。考虑到所有这些因素,定位于多巴胺能神经元的D2受体短异构体(D2SR)和定位于皮质纹状体谷氨酸末端的D2SR和D4Rs成为低剂量D2样受体激动剂的优先靶点。另一方面,需要更高的剂量来促进突触后纹状体D3Rs与D1Rs形成异构体的激活,这可能与慢性使用RLS症状增强和恶化的现象有关。本文还讨论了脊髓D3Rs的作用,特别是与RLS的周期性睡眠腿部运动(PLMS)组成部分。该分析将为更好地靶向多巴胺受体亚型提供治疗线索,这些亚型参与了d2样受体激动剂在RLS中的治疗作用,而不是继发性作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Sleep
Sleep Medicine-Neurology (clinical)
CiteScore
8.70
自引率
10.70%
发文量
0
期刊介绍: SLEEP® publishes findings from studies conducted at any level of analysis, including: Genes Molecules Cells Physiology Neural systems and circuits Behavior and cognition Self-report SLEEP® publishes articles that use a wide variety of scientific approaches and address a broad range of topics. These may include, but are not limited to: Basic and neuroscience studies of sleep and circadian mechanisms In vitro and animal models of sleep, circadian rhythms, and human disorders Pre-clinical human investigations, including the measurement and manipulation of sleep and circadian rhythms Studies in clinical or population samples. These may address factors influencing sleep and circadian rhythms (e.g., development and aging, and social and environmental influences) and relationships between sleep, circadian rhythms, health, and disease Clinical trials, epidemiology studies, implementation, and dissemination research.
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