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分子与结构视角下神经退行性疾病中的腺苷 A 受体:高效治疗方法的重要靶点。

Molecular and Structural Insight into Adenosine A Receptor in Neurodegenerative Disorders: A Significant Target for Efficient Treatment Approach.

机构信息

Department of Pharmaceutical Technology, School of Pharmacy, Techno India University, Kolkata, 700091, India.

Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata, 124 B.L. Saha Road, Kolkata, West Bengal, 700053, India.

出版信息

Mol Neurobiol. 2023 Oct;60(10):5987-6000. doi: 10.1007/s12035-023-03441-5. Epub 2023 Jun 30.

Abstract

All biological tissues and bodily fluids include the autacoid adenosine. The P1 class of purinergic receptors includes adenosine receptors. Four distinct G-protein-coupled receptors on the cellular membrane mediate the effects of adenosine, whose cytoplasmic content is regulated by producing/degrading enzymes and nucleoside transporters. A receptor has received a great deal of attention in recent years because it has a wide range of potential therapeutic uses. A and, more significantly, A receptors regulate numerous physiological mechanisms in the central nervous system (CNS). The inferior targetability of A receptors towards adenosine points that they might portray a promising medicinal target since they are triggered only under pharmacological circumstances (when adenosine levels rise up to micromolar concentrations). The accessibility of specific ligands for A receptors would permit the exploration of such a theory. A receptors mediate both potentially neurotoxic and neuroprotective actions. Hence, it is debatable to what extent they play a role in neurodegenerative illnesses. However, A receptor blockers have demonstrated clear antiparkinsonian consequences, and a significant attraction exists in the role of A receptors in other neurodegenerative disorders. Amyloid peptide extracellular accumulation and tau hyperphosphorylation are the pathogenic components of AD that lead to neuronal cell death, cognitive impairment, and memory loss. Interestingly, in vitro and in vivo research has shown that A adenosine receptor antagonists may block each of these clinical symptoms, offering a crucial new approach to combat a condition for which, regrettably, only symptomatic medications are currently available. At least two requirements must be met to determine whether such receptors are a target for diseases of the CNS: a complete understanding of the mechanisms governing A-dependent processes and the availability of ligands that can distinguish between the various receptor populations. This review concisely summarises the biological effects mediated by A adenosine receptors in neurodegenerative disorders and discusses the chemical characteristics of A adenosine receptor antagonists undergoing clinical trials. Selective A receptor blocker against neurodegenerative disorders.

摘要

所有生物组织和体液都包含自体活性物质腺苷。嘌呤能受体 P1 类包括腺苷受体。细胞膜上的四个不同的 G 蛋白偶联受体介导腺苷的作用,其细胞内含量受产生/降解酶和核苷转运体的调节。近年来,一种受体受到了广泛关注,因为它具有广泛的潜在治疗用途。A 受体和更重要的 A 受体调节中枢神经系统 (CNS) 中的许多生理机制。A 受体对腺苷的靶向性较低表明,它们可能是一个有前途的药物靶点,因为只有在药理学情况下(当腺苷水平上升到微摩尔浓度时)才会触发它们。针对 A 受体的特异性配体的可及性将允许探索这样的理论。A 受体介导潜在的神经毒性和神经保护作用。因此,它们在神经退行性疾病中扮演什么角色存在争议。然而,A 受体阻滞剂已证明具有明显的抗帕金森作用,并且 A 受体在其他神经退行性疾病中的作用存在很大吸引力。淀粉样肽细胞外积累和 tau 过度磷酸化是导致神经元细胞死亡、认知障碍和记忆丧失的 AD 的致病成分。有趣的是,体外和体内研究表明,A 腺苷受体拮抗剂可能阻断这些临床症状中的每一种,为对抗这种疾病提供了一种重要的新方法,遗憾的是,目前仅提供对症药物。要确定这些受体是否是中枢神经系统疾病的靶点,必须满足至少两个要求:完全了解调节 A 依赖性过程的机制和可用的配体,这些配体可以区分各种受体群体。本综述简要总结了 A 腺苷受体在神经退行性疾病中的生物学作用,并讨论了正在进行临床试验的 A 腺苷受体拮抗剂的化学特性。针对神经退行性疾病的选择性 A 受体阻滞剂。

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