Erlitz Katharina Sophie, Siutkina Alena I, Prinz Ann-Kathrin, Koch Oliver, Kalinin Dmitrii V, Junker Anna
European Institute for Molecular Imaging (EIMI), University of Muenster, Muenster, Germany.
Department of Preclinical Imaging and Radiopharmacy, University of Tuebingen, Tuebingen, Germany.
Arch Pharm (Weinheim). 2025 Jan;358(1):e2400860. doi: 10.1002/ardp.202400860.
The P2X4 receptor (P2X4R), a ligand-gated ion channel activated by ATP, plays a critical role in neuroinflammation, chronic pain, and cancer progression, making it a promising therapeutic target. In this study, we explored the design and synthesis of piperazine-based P2X4R antagonists, building on the structural framework of paroxetine. A series of over 35 compounds were synthesized to investigate structure-activity relationships (SARs) in a Ca²⁺-flux assay for P2X4R antagonistic activity. Several compounds outperformed paroxetine in terms of antagonistic P2X4R potency. Further studies on absorption, distribution, metabolism, excretion properties revealed that increased lipophilicity often correlated with high plasma protein binding and decreased metabolic stability, particularly in compounds with a naphthalene-2-yloxy group. Although promising SARs were observed, further optimization is needed to enhance antagonistic P2X4R receptor activity. This work provides important insights into the development of piperazine-based P2X4R antagonists and lays the foundation for future therapeutic advancements targeting P2X4R-related diseases.
P2X4受体（P2X4R）是一种由三磷酸腺苷（ATP）激活的配体门控离子通道，在神经炎症、慢性疼痛和癌症进展中起关键作用，使其成为一个有前景的治疗靶点。在本研究中，我们基于帕罗西汀的结构框架，探索了基于哌嗪的P2X4R拮抗剂的设计与合成。合成了一系列超过35种化合物，以在Ca²⁺通量测定中研究P2X4R拮抗活性的构效关系（SARs）。几种化合物在拮抗P2X4R效力方面优于帕罗西汀。对吸收、分布、代谢、排泄特性的进一步研究表明，亲脂性增加通常与高血浆蛋白结合和代谢稳定性降低相关，特别是在具有萘-2-基氧基的化合物中。尽管观察到了有前景的构效关系，但仍需要进一步优化以增强P2X4R拮抗活性。这项工作为基于哌嗪的P2X4R拮抗剂的开发提供了重要见解，并为未来针对P2X4R相关疾病的治疗进展奠定了基础。
