Piperazine-based P2X4 receptor antagonists

IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL
Katharina Sophie Erlitz, Alena I. Siutkina, Ann-Kathrin Prinz, Oliver Koch, Dmitrii V. Kalinin, Anna Junker
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Abstract

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.

Abstract Image

哌嗪类P2X4受体拮抗剂。
P2X4受体(P2X4R)是一种由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着关键作用,使其成为一个有希望的治疗靶点。在本研究中,我们以帕罗西汀的结构框架为基础,探索了哌嗪类P2X4R拮抗剂的设计和合成。我们合成了超过35个化合物来研究Ca 2 + -通量法中P2X4R拮抗活性的构效关系(sar)。几种化合物在拮抗P2X4R效能方面优于帕罗西汀。对其吸收、分布、代谢和排泄特性的进一步研究表明,亲脂性的增加通常与血浆蛋白的高结合和代谢稳定性的降低有关,特别是在含有萘-2-氧基的化合物中。虽然观察到有希望的SARs,但需要进一步优化以增强拮抗P2X4R受体的活性。这项工作为基于哌嗪的P2X4R拮抗剂的开发提供了重要的见解,并为未来针对P2X4R相关疾病的治疗进展奠定了基础。
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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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