Faculty of Pharmacy, Philadelphia University, PO Box - 1, 19392, Amman, Jordan.
Pratiksha Institute of Pharmaceutical Sciences, Chandrapur Road, Panikhaiti, Guwahati-26, Assam, India.
Curr Pharm Des. 2019;25(25):2697-2715. doi: 10.2174/1381612825666190716100509.
Adenosine is a purine nucleoside, responsible for the regulation of a wide range of physiological and pathophysiological conditions by binding with four G-protein-coupled receptors (GPCRs), namely A1, A2A, A2B and A3 adenosine receptors (ARs). In particular, A1 AR is ubiquitously present, mediating a variety of physiological processes throughout the body, thus represents a promising drug target for the management of various pathological conditions. Agonists of A1 AR are found to be useful for the treatment of atrial arrhythmia, angina, type-2 diabetes, glaucoma, neuropathic pain, epilepsy, depression and Huntington's disease, whereas antagonists are being investigated for the treatment of diuresis, congestive heart failure, asthma, COPD, anxiety and dementia. However, treatment with full A1 AR agonists has been associated with numerous challenges like cardiovascular side effects, off-target activation as well as desensitization of A1 AR leading to tachyphylaxis. In this regard, partial agonists of A1 AR have been found to be beneficial in enhancing insulin sensitivity and subsequently reducing blood glucose level, while avoiding severe CVS side effects and tachyphylaxis. Allosteric enhancer of A1 AR is found to be potent for the treatment of neuropathic pain, culminating the side effects related to off-target tissue activation of A1 AR. This review provides an overview of the medicinal chemistry and therapeutic potential of various agonists/partial agonists, antagonists and allosteric modulators of A1 AR, with a particular emphasis on their current status and future perspectives in clinical settings.
腺苷是一种嘌呤核苷，通过与四个 G 蛋白偶联受体（GPCR）结合，即 A1、A2A、A2B 和 A3 腺苷受体（AR），负责调节广泛的生理和病理生理条件。特别是，A1 AR 广泛存在，介导全身各种生理过程，因此代表了管理各种病理状况的有前途的药物靶标。已经发现 A1 AR 的激动剂可用于治疗心房性心律失常、心绞痛、2 型糖尿病、青光眼、神经病理性疼痛、癫痫、抑郁症和亨廷顿病，而拮抗剂则正在研究用于治疗利尿、充血性心力衰竭、哮喘、COPD、焦虑和痴呆症。然而，使用全 A1 AR 激动剂与许多挑战相关，例如心血管副作用、非靶标激活以及 A1 AR 的脱敏导致快速耐药性。在这方面，已经发现 A1 AR 的部分激动剂有益于增强胰岛素敏感性，从而降低血糖水平，同时避免严重的 CVS 副作用和快速耐药性。A1 AR 的变构增强剂被发现对治疗神经病理性疼痛有效，减少了与 A1 AR 非靶标组织激活相关的副作用。本综述提供了 A1 AR 的各种激动剂/部分激动剂、拮抗剂和变构调节剂的药物化学和治疗潜力的概述，特别强调了它们在临床环境中的当前状况和未来前景。
