Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
Division of Drug Discovery and Safety, LACDR, Leiden University, the Netherlands.
Biochem Pharmacol. 2021 May;187:114311. doi: 10.1016/j.bcp.2020.114311. Epub 2020 Oct 29.
Prof. Geoffrey Burnstock originated the concept of purinergic signaling. He demonstrated the interactions and biological roles of ionotropic P2X and metabotropic P2Y receptors. This review paper traces the historical origins of many currently used antagonists and agonists for P2 receptors, as well as adenosine receptors, in early attempts to identify ligands for these receptors - prior to the use of chemical libraries for screening. Rather than presenting a general review of current purinergic ligands, we focus on common chemical scaffolds (privileged scaffolds) that can be adapted for multiple receptor targets. By carefully analyzing the structure activity relationships, one can direct the selectivity of these scaffolds toward different receptor subtypes. For example, the weak and non-selective P2 antagonist reactive blue 2 (RB-2) was derivatized using combinatorial synthetic approaches, leading to the identification of selective P2Y, P2Y, P2Y or P2X2 receptor antagonists. A P2X4 antagonist NC-2600 is in a clinical trial, and A adenosine agonists show promise, for chronic pain. P2X7 antagonists have been in clinical trials for depression (JNJ-54175446), inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, inflammatory pain and chronic obstructive pulmonary disease (COPD). P2X3 antagonists are in clinical trials for chronic cough, and an antagonist named after Burnstock, gefapixant, is expected to be the first P2X3 antagonist filed for approval. We are seeing that the vision of Prof. Burnstock to use purinergic signaling modulators, most recently at P2XRs, for treating disease is coming to fruition.
杰弗里·伯斯通教授首创了嘌呤能信号转导的概念。他证实了离子型 P2X 和代谢型 P2Y 受体的相互作用和生物学作用。这篇综述追溯了目前用于 P2 受体以及腺苷受体的许多拮抗剂和激动剂的历史起源，这些拮抗剂和激动剂是在早期尝试鉴定这些受体的配体时使用的，当时还没有使用化学文库进行筛选。我们没有对当前的嘌呤能配体进行全面综述，而是专注于常见的化学支架（优势支架），这些支架可以适应多种受体靶标。通过仔细分析结构-活性关系，可以将这些支架的选择性导向不同的受体亚型。例如，弱且非选择性的 P2 拮抗剂反应蓝 2（RB-2）使用组合合成方法衍生化，从而鉴定出选择性 P2Y、P2Y、P2Y 或 P2X2 受体拮抗剂。一种 P2X4 拮抗剂 NC-2600 正在进行临床试验，A 腺苷激动剂也显示出治疗慢性疼痛的潜力。P2X7 拮抗剂已在抑郁症（JNJ-54175446）、炎症性肠病（IBD）、克罗恩病、类风湿关节炎、炎症性疼痛和慢性阻塞性肺疾病（COPD）的临床试验中进行。P2X3 拮抗剂正在进行慢性咳嗽的临床试验，一种以伯斯通教授命名的拮抗剂 gefapixant 有望成为第一个提交批准的 P2X3 拮抗剂。我们看到，伯斯通教授利用嘌呤能信号转导调节剂，最近是在 P2XR 上，治疗疾病的愿景正在成为现实。
