《生命科学》 2026, 38(10): 1728-1741
P2X受体正向变构调节剂：新兴的治疗机遇与挑战
摘 要：
P2X受体是一类由细胞外ATP激活的配体门控离子通道，在疼痛信号传递、突触传递、免疫炎症反应及骨代谢等多种生理病理过程中发挥关键作用。当前靶向P2X受体的药物研发以拮抗剂为主，用于抑制受体功能亢进，但无法应对遗传、应激或退行性变化导致的受体功能低下。因此，开发增强受体功能的正向变构调节剂（positive allosteric modulators，PAMs）具有重要意义。本文结合P2X受体的生理作用，系统梳理靶向该受体的PAMs研究进展，分析各亚型PAMs的治疗潜力与转化挑战，为该领域后续研究和药物开发提供参考。
通讯作者：于烨 , Email:yuye@cpu.edu.cn 郭常润 , Email:gcr@cpu.edu.cn
Abstract:
P2X receptors constitute a family of ATP-gated ion channels that play pivotal roles in diverse physiological and pathological processes, including nociceptive signaling, neurotransmission, immune-inflammatory responses, cardiovascular regulation, and sensory transduction. Current pharmacological strategies have predominantly focused on antagonists aimed at mitigating receptor hyperfunction; however, these approaches fail to address states of receptor hypofunction arising from genetic alterations, cellular stress, or degenerative processes. Consequently, the development of positive allosteric modulators (PAMs) capable of enhancing receptor function represents a promising yet underexplored strategy to address this unmet therapeutic need. This review systematically delineates the physiological functions of individual P2X receptor subtypes and catalogs known PAMs with their distinct mechanisms and therapeutic implications. For P2X1, expressed in platelets and smooth muscle, PAMs such as MRS2219 and gintonin may offer hemostatic benefits in acute bleeding and potential applications in male infertility, though systemic thrombotic risks necessitate targeted delivery strategies. P2X2 and P2X2/3 heterotrimers, critical for auditory protection and taste sensation, can be modulated by neurosteroids (e.g., DHEA, progesterone) and anthraquinone derivatives, presenting opportunities for treating noise-induced hearing loss and stress-related depression, provided that site-specific delivery to the cochlea or brain regions is achieved. Notably, P2X3 has long been considered devoid of PAM therapeutic value due to its association with pathological sensitization; however, the recent identification of PSFL77 as the first selective intracellular PAM challenges this paradigm and expands mechanistic
understanding. P2X4 represents the most pharmacologically versatile subtype, with ivermectin and various natural products demonstrating potential in alcohol use disorder, Parkinson's disease, infectious diseases, and cardiovascular conditions, though challenges remain in optimizing blood-brain barrier penetration and avoiding pain-related side effects. Finally, P2X7 PAMs, including clemastine, tenidap, and ginsenoside CK offer unique prospects for enhancing macrophage-mediated pathogen clearance and tumor immunotherapy, contingent upon managing species selectivity and inflammatory risks. Furthermore, it critically examines the therapeutic potential and translational challenges associated with subtype-specific PAMs, thereby providing a theoretical framework to guide future investigations and drug discovery endeavors in this
emerging field.
Communication Author：YU Ye , Email:yuye@cpu.edu.cn GUO Chang-Run , Email:gcr@cpu.edu.cn
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