Lambertucci Catia, Dal Ben Diego, Buccioni Michela, Marucci Gabriella, Thomas Ajiroghene, Volpini Rosaria
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino, 1, I-62032, Camerino, Italy.
Curr Med Chem. 2015;22(7):915-28. doi: 10.2174/0929867321666141215093513.
In this work, we have highlighted data reported in the literature trying to draw a complete picture of the structures and biological activity of agonists and orthosteric antagonists of P2X receptors. Actually, only few P2X receptor agonists have been found and most of them are derived from modification of the natural ligand ATP and they are P2X receptor subtype unselective. In particular, BzATP (9) is one of the most potent P2X receptor agonists with EC50 value in the nanomolar range at some subtypes. Differently from agonists, P2X receptor antagonists belong to different chemical classes such as high molecular weight aryl polysulfonate molecules like suramin and its simplified derivatives and anthraquinone compounds. All these molecules proved to be non selective at P2X receptors, and they are endowed with micromolar activity and not favourable pharmacokinetic properties due to the presence of several charged groups. Also modification of the natural ligand ATP led to the discovery of P2X receptor antagonists like TNP-ATP (29), which, although not selective, showed high potency at P2X1, P2X3 (IC50 of 0.006 µM and 0.001 µM, respectively), and heteromeric P2X2/3 receptors. Also the dinucleotide inosine polyphosphate Ip5I (33) was found to be a potent and selective antagonist at P2X1 vs P2X3 receptors with IC50 = 0.003 µM. A significant improvement has been gained from the interest of pharmaceutical companies that in the last years discovered, through the use of high-throughput screening, potent and selective antagonists endowed with novel structures, some of which are currently in clinical trials for several therapeutic applications.
在这项工作中，我们着重介绍了文献中报道的数据，试图全面描绘P2X受体激动剂和正构拮抗剂的结构及生物活性。实际上，仅发现了少数几种P2X受体激动剂，其中大多数是天然配体ATP修饰而来，且对P2X受体亚型无选择性。特别地，BzATP（9）是最有效的P2X受体激动剂之一，在某些亚型中其EC50值处于纳摩尔范围。与激动剂不同，P2X受体拮抗剂属于不同的化学类别，如高分子量芳基多磺酸盐分子（如苏拉明及其简化衍生物）和蒽醌化合物。所有这些分子在P2X受体上均无选择性，由于存在多个带电基团，它们具有微摩尔活性且药代动力学性质不佳。对天然配体ATP的修饰也促成了P2X受体拮抗剂的发现，如TNP - ATP（29），尽管它无选择性，但对P2X1、P2X3（IC50分别为0.006 μM和0.001 μM）以及异源P2X2/3受体显示出高效力。此外，还发现二核苷酸肌苷多磷酸Ip5I（33）是P2X1与P2X3受体的强效选择性拮抗剂，IC50 = 0.003 μM。制药公司的关注带来了显著进展，在过去几年中，通过高通量筛选发现了具有新结构的强效选择性拮抗剂，其中一些目前正处于多种治疗应用的临床试验阶段。
