The P2X7 receptor (P2X7R) stands out among the purinergic receptors due to its strong involvement in the regulation of tumor growth and metastasis formation as well as in innate immune responses and afferent signal transmission. Numerous studies have pointed out the beneficial effects of P2X7R antagonism for the treatment of a variety of cancer types, inflammatory diseases, and chronic pain. Herein we describe the development of novel P2X7R antagonists, incorporating piperazine squaric diamides as a central element. Besides improving the antagonists’ potency from pIC₅₀ values of 5.7–7.6, ADME properties (logD_7.4 value, plasma protein binding, in vitro metabolic stability) of the generated compounds were investigated and optimized to provide novel P2X7R antagonists with drug-like properties. Furthermore, docking studies revealed the antagonists binding to the allosteric binding pocket in two distinct binding poses, depending on the substitution of the central piperazine moiety.

P2X7 受体 (P2X7R) 在嘌呤能受体中脱颖而出，因为它强烈参与调节肿瘤生长和转移形成以及先天免疫反应和传入信号传递。大量研究指出了 P2X7R 拮抗剂对治疗多种癌症、炎症性疾病和慢性疼痛的有益作用。在这里，我们描述了新型 P2X7R 拮抗剂的发展，将哌嗪方二酰胺作为中心元素。_{除了从 5.7-7.6 的 pIC 50}值提高拮抗剂的效力外，ADME 特性（logD _7.4值，血浆蛋白结合，体外研究和优化生成的化合物的代谢稳定性，以提供具有药物样特性的新型 P2X7R 拮抗剂。此外，对接研究揭示了拮抗剂以两种不同的结合姿势与变构结合袋结合，这取决于中心哌嗪部分的取代。