Laboratory of Bioorganic Chemistry, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
ChemMedChem. 2020 Nov 4;15(21):1958-1973. doi: 10.1002/cmdc.202000465. Epub 2020 Sep 18.
The purinergic signaling system includes membrane-bound receptors for extracellular purines and pyrimidines, and enzymes/transporters that regulate receptor activation by endogenous agonists. Receptors include: adenosine (A , A , A and A ) and P2Y (P2Y , P2Y , P2Y , P2Y , P2Y , P2Y , P2Y , and P2Y ) receptors (all GPCRs), as well as P2X receptors (ion channels). Receptor activation, especially accompanying physiological stress or damage, creates a temporal sequence of signaling to counteract this stress and either mobilize (P2Rs) or suppress (ARs) immune responses. Thus, modulation of this large signaling family has broad potential for treating chronic diseases. Experimentally determined structures represent each of the three receptor families. We focus on selective purinergic agonists (A , A ), antagonists (A , P2Y ), and allosteric modulators (P2Y , A ). Examples of applying structure-based design, including the rational modification of known ligands, are presented for antithrombotic P2Y R antagonists and anti-inflammatory P2Y R antagonists and A AR agonists. A AR agonists are a potential, nonaddictive treatment for chronic neuropathic pain.
嘌呤能信号系统包括细胞外嘌呤和嘧啶的膜结合受体，以及调节内源性激动剂激活受体的酶/转运体。受体包括：腺苷（A1、A2A、A2B 和 A3）和 P2Y（P2Y1、P2Y2、P2Y4、P2Y6、P2Y11、P2Y12、P2Y13 和 P2Y14）受体（均为 GPCR），以及 P2X 受体（离子通道）。受体激活，特别是伴随生理应激或损伤时，会产生信号传递的时间序列，以抵消这种应激，并动员（P2Rs）或抑制（ARs）免疫反应。因此，对这个庞大的信号家族进行调节具有治疗慢性疾病的广泛潜力。实验确定的结构代表了这三个受体家族中的每一个。我们专注于选择性嘌呤能激动剂（A1、A2A）、拮抗剂（A2BAR、P2Y12）和变构调节剂（P2Y1、A3AR）。介绍了应用基于结构的设计的示例，包括对已知配体的合理修饰，用于抗血栓形成的 P2Y12R 拮抗剂和抗炎性 P2Y12R 拮抗剂和 A3AR 激动剂。A3AR 激动剂是治疗慢性神经性疼痛的一种潜在、非成瘾性治疗方法。
