自 Burnstock 确立嘌呤信号传导定义以来的近50年里，腺苷、P2Y 和 P2X 受体调节剂的发现和临床应用已经取得了突飞猛进的进展。虽然针对这些19种受体的选择性配体（激动剂和拮抗剂）的大多数临床试验失败了，但目前仍在重点研发中寻找适用于新疾病和更具选择性或靶向性的化合物，这些化合物具有潜在较小的副作用，如有偏倚的GPCR激动剂。新受体和酶结构的阐明正在引领强有力的选择性激动剂、拮抗剂、变构调节剂和抑制剂的有理设计。 A2A 腺苷受体（AR）拮抗剂被应用于神经退行性疾病和癌症免疫疗法。 A3AR 激动剂有望用于治疗慢性炎症（如牛皮癣）、中风和疼痛，以及癌症。 P2YR 调节剂被认为可用于治疗炎症、代谢性疾病、急性肾损伤、癌症、疼痛和其他疾病，通常具有免疫机制。已广泛使用以抗血凝药品为主的 ADP 活化的 P2Y12R 拮抗剂，但也在考虑将其重用于神经炎症。 P2X3 拮抗剂已进入治疗慢性咳嗽的临床试验。 P2X7 拮抗剂已进入治疗炎症性疾病和抑郁症的临床试验（能穿透血脑屏障的化合物）。因此，嘌呤能信号传导现在被认为是身体内平衡组织和器官在压力下的广泛调节系统，这可以通过药物干预进行治疗。以更先进的药代动力学和药效学方法，包括基于结构的药物设计、前药和有偏向的信号传导，克服了以前许多临床试验的失败。版权所有 © 2023. Elsevier Ltd. 发布。

The discovery and clinical implementation of modulators of adenosine, P2Y and P2X receptors have progressed dramatically in ∼50 years since Burnstock's definition of purinergic signaling. Although most clinical trials of selective ligands (agonists and antagonists) of these nineteen receptors failed, there is a renewed impetus to redirect efforts to new disease conditions and the discovery of more selective or targeted compounds with potentially reduced side effects, such as biased GPCR agonists. The elucidation of new receptor and enzyme structures is steering rational design of potent and selective agonists, antagonists, allosteric modulators and inhibitors. A2A adenosine receptor (AR) antagonists are being applied to neurodegenerative conditions and cancer immunotherapy. A3AR agonists have potential for treating chronic inflammation (e.g. psoriasis), stroke and pain, as well as cancer. P2YR modulators are being considered for treating inflammation, metabolic disorders, acute kidney injury, cancer, pain and other conditions, often with an immune mechanism. ADP-activated P2Y12R antagonists are widely used as antithrombotic drugs, while their repurposing toward neuroinflammation is considered. P2X3 antagonists have been in clinical trials for chronic cough. P2X7 antagonists have been in clinical trials for inflammatory diseases and depression (compounds that penetrate the blood-brain barrier). Thus, purinergic signaling is now recognized as an immense regulatory system in the body for rebalancing tissues and organs under stress, which can be adjusted by drug intervention for therapeutic purposes. The lack of success of many previous clinical trials can be overcome given more advanced pharmacokinetic and pharmacodynamic approaches, including structure-based drug design, prodrugs and biased signaling.Copyright © 2023. Published by Elsevier Ltd.