Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, 21040- 360, Brazil.
Laboratory of Technological Development in Virology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, 21040-360, Brazil.
Curr Drug Targets. 2019;20(9):919-937. doi: 10.2174/1389450120666190213095923.
Extracellular purines and pyrimidines have important physiological functions in mammals. Purines and pyrimidines act on P1 and P2 purinergic receptors, which are widely expressed in the plasma membrane in various cell types. P2 receptors act as important therapeutic targets and are associated with several disorders, such as pain, neurodegeneration, cancer, inflammation, and thrombosis. However, the use of antagonists for P2 receptors in clinical therapy, with the exception of P2Y12, is a great challenge. Currently, many research groups and pharmaceutical companies are working on the development of specific antagonist molecules for each receptor subtype that could be used as new medicines to treat their respective disorders.
The present review compiles some interesting findings on the application of P2 receptor antagonists in different in vitro and in vivo experimental models as well as the progress of advanced clinical trials with these compounds.
Despite all of the exciting results obtained on the bench, few antagonists of P2 receptors advanced to the clinical trials, and once they reach this stage, the effectiveness of the therapy is not guaranteed, as in the example of P2X7 antagonists. Despite this, P2Y12 receptor antagonists have a history of success and have been used in therapy for at least two decades to prevent thrombosis in patients at risk for myocardial infarctions. This breakthrough is the motivation for scientists to develop new drugs with antagonistic activity for the other P2 receptors; thus, in a matter of years, we will have an evolution in the field of purinergic therapy.
细胞外嘌呤和嘧啶在哺乳动物中具有重要的生理功能。嘌呤和嘧啶作用于 P1 和 P2 嘌呤能受体，这些受体广泛表达于各种细胞类型的质膜上。P2 受体作为重要的治疗靶点，与多种疾病相关，如疼痛、神经退行性变、癌症、炎症和血栓形成。然而，除了 P2Y12 之外，在临床治疗中使用 P2 受体拮抗剂是一个巨大的挑战。目前，许多研究小组和制药公司正在致力于开发针对每个受体亚型的特异性拮抗剂分子，这些分子可作为治疗各自疾病的新药。
本综述汇集了一些关于 P2 受体拮抗剂在不同体外和体内实验模型中的应用的有趣发现，以及这些化合物在高级临床试验中的进展。
尽管在实验台上取得了所有令人兴奋的结果，但只有少数 P2 受体拮抗剂进入临床试验，而一旦进入这一阶段，治疗的有效性就不能保证，正如 P2X7 拮抗剂的例子一样。尽管如此，P2Y12 受体拮抗剂已经有了成功的历史，并已在治疗中使用了至少二十年，以预防心肌梗死高危患者的血栓形成。这一突破激励科学家们开发具有拮抗活性的其他 P2 受体的新药；因此，在几年内，我们将在嘌呤能治疗领域取得进展。
