Breathing brief, moderate bouts of low oxygen trigger (low oxygen therapy, LOT) spinal plasticity (the ability of the nervous system to strengthen neural pathways based on new experiences), and improve walking after spinal cord injury (SCI). The greatest improvements in walking ability occur when LOT is administered prior to skill-based walking practice (WALK). However, the enduring benefits of LOT on walking recovery may be undermined by the accumulation of LOT-induced increase in extracellular adenosine. The goal of the study is to understand the extent to which istradefylline (adenosine 2a receptor antagonist) may limit the competing mechanisms of adenosine on LOT-induced walking recovery following SCI.

开始日期2027-09-01

申办/合作机构

The Spaulding Rehabilitation Hospital Corp.

NCT07704385

/ Not yet recruiting临床1/2期IIT

Enhancing Rehabilitation in Aging Study (ERAS)

Acute Intermittent Hypoxia (AIH) is a rehab approach attributed to serotonin. AIH signaling also occurs via adenosine, and the pathways inhibit each other. Increased neural adenosine in aging may stymie AIH plasticity. The hypothesis is pre-treatment with adenosine 2A receptor inhibition (A2AI) enhances AIH effects on motor plasticity in unaffected adults. AIH exposures will be paired with A2AI or placebo, with a 4-week washout. Primary outcome measures include inspiratory and grip strength.

开始日期2026-10-01

申办/合作机构

University of Florida

JPRN-jRCTs051250026

/ Recruiting临床2期

Clinical trial on the efficacy and safety of istradefylline as an adjunctive therapy for obsessive-compulsive disorder

开始日期2025-05-19

申办/合作机构-

100 项与伊曲茶碱相关的临床结果

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100 项与伊曲茶碱相关的转化医学

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100 项与伊曲茶碱相关的专利（医药）

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项与伊曲茶碱相关的文献（医药）

2026-10-01·NEUROPHARMACOLOGY

The adenosine A2A receptor antagonist KW6002 mitigates aldosterone-induced central serous chorioretinopathy in mice

Article

作者: Yang, Jiasheng ; Xu, Kailang ; Tang, Wei-Hang ; Liu, Qiaoli ; Yu, Zijun ; Li, Jiaqi ; Chen, Jiang-Fan ; Que, Jia-Nan ; Qu, Jia

PURPOSE:

Central serous chorioretinopathy (CSC), a prevalent disease characterized by choroidal vascular abnormalities, has extremely limited treatment options. This study investigates the effects of the selective adenosine A_2A receptor (A_2AR) antagonist KW6002 on choroidal vascular hyperpermeability and the blood-retinal barrier (BRB), and explores its therapeutic potential in experimental CSC.

METHODS:

We examined A_2AR expression in the retinal pigment epithelium (RPE)-choroid-sclera complex using quantitative real-time PCR (qPCR) and Western blotting (WB) in mice with an established aldosterone-induced acute CSC model. Before modeling and after model establishment, mice were administered 5 mg/kg KW6002 or a vehicle control via intraperitoneal injection. The retinal and choroidal thickness was assessed by optical coherence tomography (OCT) and hematoxylin-eosin (H&E) staining. We observed Müller cells activation, retinal microglia infiltration, and proinflammatory cytokine expression via immunofluorescence and qPCR. Next, we employed the effects of the A_2AR antagonist KW6002 and genetic A_2AR knockout (A_2AR-KO) on BRB integrity using immunofluorescence and WB. Finally, to clarify how A_2AR knockout confers therapeutic benefits in CSC, we assessed activation of the TNF-α/NF-κB-MMP-2/9 signaling pathway.

RESULTS:

We found that A_2AR signaling was significantly upregulated in the RPE-choroid-sclera complex in CSC models, and both A_2AR antagonist KW6002 and A_2AR-KO significantly inhibited the aldosterone-induced central retinal and choroidal pathologic thickening. Moreover, the KW6002 intervention decreased the activation of Müller cells and the proliferation of microglia, inhibited the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), and ameliorated the retinal damage caused by aldosterone; in contrast, A_2AR-KO resulted in significant upregulation of key tight junction proteins (ZO-1, Claudin-1, and Claudin-5). In summary, these results suggest that the protective effects may be correlated with the suppression of the TNF-α/NF-κB-MMP-2/9 signaling axis.

CONCLUSIONS:

Our findings show that the A_2AR antagonist KW6002 or A_2AR-KO offers a protective effect in experimental CSC, reduces inflammation, and maintains the integrity of the BRB, which may be associated with the inhibition of the TNF-α/NF-κB-MMP-2/9 pathway. These findings present a new method for preventing and treating CSC, which will guide our future clinical strategy development.

2026-06-01·Purinergic Signalling

Purinergic modulation in Parkinson’s disease: the dual role of istradefylline in motor and cognitive outcomes

Review

作者: Rejili, Mokhtar ; Shokr, Mustafa M ; Al-Gareeb, Ali I ; Al-Kuraishy, Hayder M ; Jabir, Majid S ; Albuhadily, Ali K ; Batiha, Gaber El-Saber

Istradefylline, a selective adenosine 2A receptor (A2AR) antagonist, was approved in 2019 as an adjuvant treatment to reduce "OFF" periods in Parkinson's disease (PD) patients. This comprehensive review evaluates its dual impact on PD, contrasting established therapeutic benefits in motor symptom management with emerging concerns regarding cognitive safety. Istradefylline enhances dopaminergic transmission in the substantia nigra pars compacta (SNpc), significantly reducing L-DOPA-induced akinesia. Beyond motor control, it exhibits neuroprotective potential by mitigating neuroinflammation, oxidative stress, and alpha-synuclein-induced neurotoxicity. However, preclinical evidence suggests a concerning paradox: istradefylline may exacerbate cognitive decline by promoting amyloid-beta (Aβ) accumulation through the overactivity of γ-secretase and the disruption of brain-derived neurotrophic factor (BDNF) signaling pathways. Furthermore, its inhibitory effect on D-aspartate protein may trigger mitochondrial dysfunction and endoplasmic reticulum stress, potentially accelerating neurodegeneration in the SNpc. While istradefylline remains a valuable non-dopaminergic strategy for stabilizing motor fluctuations, its influence on long-term cognitive function necessitates careful clinical consideration. Understanding the molecular mechanisms behind these opposing effects is essential for optimizing its use and minimizing neurocognitive risks in PD patients. Future longitudinal trials are vital to clarify its long-term safety profile and disease-modifying potential.

2026-06-01·TISSUE & CELL

Adenosine A₂A receptor as a dual-acting molecular switch: Glial morphological changes and neurovascular tissue remodeling in neuroinflammation and neurodegeneration

Review

作者: Khalifa, Heba S ; Ali, Mohamed A M ; Elnaghy, Fatma ; Sameh, Ahmed ; Elmorsy, Elsayed A ; El-Moaty, Heba Ibrahim Abd ; Ibrahim, Essam H ; Hasan, Waseem Ali ; Hamad, Rabab S ; Morsy, Kareem ; AlShehri, Mohammed A ; El-Kott, Attalla F ; Gaafar, Ahmed ; Saber, Sameh ; Farrag, Alshaimaa A ; Alsoqih, Norah Suliman ; Negm, Sally ; Eissa, Hanan

Neuroinflammation appears in a variety of neurological disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The adenosine A₂A receptor (A₂AR), a Gs protein-coupled receptor that affects cAMP signaling and downstream kinases like PKA, CREB, and NF-κB, is one of the primary regulators of this process. Context-dependent effects of A₂AR activation include lowering acute inflammation and promoting neuronal survival when stimulated moderately, but increasing glial activation and cytokine production when overexpressed over an extended period of time. In microglia and astrocytes, A₂AR signaling regulates inflammatory pathways mediated by NF-κB and MAPK, affecting oxidative stress, blood-brain barrier (BBB) stability, and excitotoxicity. Acute or transient (short-term) A₂AR activation, on the other hand, increases the production of anti-inflammatory cytokines like IL-10 and enhances neurotrophic support through BDNF. A₂AR antagonists, including istradefylline and SCH58261, may reduce microglial triggering and have neuroprotective benefits, according to clinical and experimental data. The context-dependent activity of the receptor is shown by the fact that total receptor blockage interferes with adaptive immune control. Therefore, the therapeutic challenge is to carefully modify A₂AR signaling in particular cell populations, specifically targeting astrocytic or microglial receptors while maintaining the peripheral immunoregulatory activities. The dual regulatory role of A₂AR in neuroinflammation is summarized in this review along with its molecular mechanisms, disease-specific actions, and therapeutic significance. Developing next-generation neuroprotective strategies that reduce A₂AR signaling's pro-inflammatory and neurotoxic effects while preserving its beneficial homeostatic effects will require an understanding of the temporal and cell-specific dynamics of this signaling.

项与伊曲茶碱相关的新闻（医药）

2026-07-05

·AI的铭熠

药学基础研究第6期（总第26期）：British Journal of Pharmacology

来源：British Journal of Pharmacology 药学基础研究第6期（总第26期） —————————————————————————————— 本期聚焦《British Journal of Pharmacology》2026年6月发表的5篇药理学基础研究重要论文，涵盖慢性疼痛靶点Cav3.2 T型钙通道、MASH中NO-cGMP-cGKI信号轴、海马神经发生的腺苷-大麻素受体交叉对话、阿片成瘾的犬尿氨酸通路干预以及DMD肌营养不良的STAT1抑制等前沿方向。这些研究展示了从离子通道、GPCR异源二聚体到转录因子调控的多层次药理学创新，为多种难治性疾病提供了新的治疗思路。 —————————————————————————————— 本期目录 / Table of Contents 1. Cav3.2 T-type calcium channels in chronic pain: Structural insights, pharmacological advances and challenges in subtype selectivity ▍Cav3.2 T型钙通道在慢性疼痛中的作用：结构洞察、药理学进展与亚型选择性挑战 Br J Pharmacol 丨 2026-06-16 丨 Review 2. Pharmacological activation of NO-cGMP signalling attenuates metabolic dysfunction-associated steatohepatitis ▍药理学激活NO-cGMP信号通路减轻代谢功能障碍相关脂肪性肝炎 Br J Pharmacol 丨 2026-06-25 丨 Article 3. Cannabinoid and adenosine A2A receptor crosstalk regulates postnatal and adult hippocampal neurogenesis ▍大麻素与腺苷A2A受体交叉对话调控海马神经发生及受体异源二聚化机制 Br J Pharmacol 丨 2026-06-22 丨 Article 4. Inhibition of kynurenine 3-monooxygenase (KMO) reduces fentanyl and sucrose intake and relapse-like behaviour in rats ▍抑制犬尿氨酸3-单加氧酶减少大鼠芬太尼和蔗糖摄入及复吸样行为 Br J Pharmacol 丨 2026-06-23 丨 Article 5. Leflunomide-inhibited STAT1 activity ameliorates intramuscular M1 macrophage infiltration and promotes muscle regeneration in Duchenne muscular dystrophy ▍来氟米特抑制STAT1活性减轻M1巨噬细胞浸润并促进Duchenne肌营养不良症肌肉再生 Br J Pharmacol 丨 2026-06-26 丨 Article —————————————————————————————— ▎综述·Reviews Cav3.2 T-type calcium channels in chronic pain: Structural insights, pharmacological advances and challenges in subtype selectivity Br J Pharmacol 丨 2026-06-16 丨 Review ▍Cav3.2 T型钙通道在慢性疼痛中的作用：结构洞察、药理学进展与亚型选择性挑战研究背景慢性疼痛的临床管理长期依赖阿片类、抗炎药及抗惊厥药等传统药物，普遍存在疗效不足和显著副作用。T型钙通道在外周及中枢疼痛通路中发挥关键作用，尤其是Cav3.2亚型在神经病理性疼痛和炎性疼痛的发生发展中高度上调，已成为极具前景但尚未经临床验证的镇痛靶点。然而靶向Cav3.2的药物开发面临亚型选择性不足、中枢神经系统及心血管系统副作用等重大转化瓶颈，候选药物ABT-639的反复临床失败更凸显了临床前潜力与临床疗效之间的鸿沟。核心发现 • Cav3.2 T型钙通道在DRG和脊髓背角神经元中表达与功能显著上调，是神经病理性疼痛和炎性疼痛的关键驱动靶点 • ABT-639等候选药物屡次在临床试验中失败，深刻揭示了临床前模型向人类疼痛转化中的方法学局限 • 亚型选择性不足是该通道靶向药物开发的核心障碍，Cav3.1/Cav3.3的广泛生理功能使得非选择性阻断引发不可接受的心血管及中枢副作用 • 该综述提出基于冷冻电镜结构生物学的新一代精准药物设计策略，以变构调控和状态依赖性阻断为主要方向领域意义该综述系统整合了Cav3.2冷冻电镜结构生物学的最新进展、关键临床试验失败的教训以及新兴药理学策略，为从靶点结构到亚型选择性药物的完整转化路径提供了路线图。其提出的变构位点靶向和状态依赖性阻断策略有望突破现有镇痛药物研发的瓶颈，对新型非阿片类镇痛药的开发具有重要的方向性指导意义。英文摘要 (Abstract) The clinical management of chronic pain has long relied on conventional medications, including opioids, anti-inflammatory drugs and anticonvulsants, which are universally associated with inadequate efficacy and prominent adverse effects. This highlights an urgent need for novel therapeutic strategies targeting the underlying mechanisms of pain. Recent studies have demonstrated that T-type calcium channels play a pivotal role in the pathogenesis and progression of neuropathic and inflammatory pain, with their expression and function being significantly up-regulated in neurons of the dorsal root ganglion (DRG) and spinal dorsal horn neurons, emerging as a highly promising yet clinically unvalidated analgesic target. However, the development of blockers directly targeting the Cav3.2 subtype is still confronted with major translational challenges, such as low subtype selectivity, as well as adverse effects in the central nervous system and cardiovascular system. Repeated clinical setbacks of candidate drugs like ABT-639 have highlighted the gap between preclinical potential and clinical efficacy, and to date, no ideal clinical candidate has been identified. This review integrates structural biology insights, lessons from clinical failures and pharmacological advances to guide the research and development of safe, highly selective Cav3.2-targeted analgesic agents. DOI: 10.1111/bph.70537 —————————————————————————————— ▎基础研究·Basic Research Pharmacological activation of NO-cGMP signalling attenuates metabolic dysfunction-associated steatohepatitis Br J Pharmacol 丨 2026-06-25 丨 Article ▍药理学激活NO-cGMP信号通路减轻代谢功能障碍相关脂肪性肝炎研究背景代谢功能障碍相关脂肪性肝炎（MASH）是全球日益严重的慢性肝病，其核心病理环节是肝星状细胞（HSC）活化分化为α-SMA阳性肌成纤维细胞，导致胶原沉积和促炎因子释放。静息态HSC表达完整的NO-cGMP信号轴，但该通路在MASH进展中的具体作用及作为治疗靶点的潜力尚不清楚。氧化应激可导致NO-GC对NO的敏感性降低，这可能是MASH中cGMP信号受损的关键机制。核心发现 • 利用转基因cGMP传感器小鼠首次在活体HSC中实时监测到NO诱导的cGMP信号，证实HSC中NO-GC/cGKI通路功能完整 • HSC特异性cGKI敲除小鼠表现出肌成纤维细胞标志物上调，HSC活化增强，MASH易感性显著增加 • BAY-543（靶向氧化态/NO不敏感NO-GC的激活剂）治疗显著减轻MASH小鼠的HSC活化、炎症、胶原沉积、大泡性脂肪变性和纤维化 • 人纤维化肝脏组织中cGKI表达上调，验证了该通路在人类MASH中的临床相关性领域意义该研究首次将NO-cGMP-cGKI信号轴确立为HSC的功能性通路标志物和关键调控节点，为MASH提供了基于NO-GC激活剂的全新治疗策略。BAY-543通过靶向氧化态NO-GC恢复cGMP信号，尤其适用于氧化应激导致NO-GC失敏的MASH晚期患者，具有明确的临床转化前景，填补了MASH靶向治疗的重要空白。英文摘要 (Abstract) Background and purpose: Metabolic dysfunction-associated steatohepatitis (MASH) is linked to activation of hepatic stellate cells (HSCs) to α-smooth muscle actin-positive myofibroblasts that produce collagen and proinflammatory cytokines. Quiescent HSCs express the NO-cGMP signalling axis. Modulating this pathway could alter HSC activation and fibrosis during MASH progression. Experimental approach: Using transgenic cGMP sensor mice, we monitored NO-induced cGMP in living HSCs. The relevance of this pathway was analyzed using HSC-specific mouse models, ApoE-deficient mice on high-fat diet as a MASH model, human liver sections, and published scRNA-seq datasets. For pharmacological activation, BAY-543, an activator of NO-sensitive guanylyl cyclase (NO-GC), was used. Key results: HSCs in primary culture and liver tissue generated NO-induced cGMP and expressed NO-GC and cGMP-dependent protein kinase type I (cGKI). HSC-specific cGKI knockout livers showed enhanced myofibroblast marker expression. MASH mice developed steatosis, fibrosis, and inflammation, and showed high HSC expression of NO-GC and cGKI. Treatment of MASH mice with BAY-543 significantly attenuated HSC activation, inflammation, collagen deposition, macro-steatosis, fibrosis, and serum liver enzymes. Conclusion: The NO-cGMP-cGKI axis serves as both a functional pathway marker and regulator of HSCs. Pharmacological elevation of cGMP with an NO-GC activator represents a promising therapeutic strategy for MASH. DOI: 10.1111/bph.70523 —————————————————————————————— Cannabinoid and adenosine A2A receptor crosstalk regulates postnatal and adult hippocampal neurogenesis Br J Pharmacol 丨 2026-06-22 丨 Article ▍大麻素与腺苷A2A受体交叉对话调控海马神经发生及受体异源二聚化机制研究背景成年海马神经发生是受大麻素受体（CB1/CB2）和腺苷A2A受体精密调控的过程，两者均可调节神经祖细胞活性。尽管已有证据提示这两大神经调节系统之间存在相互作用，但它们在调控神经发生中交叉对话的机制和程度尚不清楚。揭示大麻素-腺苷系统在神经祖细胞动力学中的功能性相互作用机制，对开发促进神经再生的治疗策略具有重要价值。核心发现 • 非选择性大麻素受体激动剂WIN55212-2可增加体内海马细胞增殖和未成熟神经元形成，此效应可被选择性A2A受体拮抗剂istradefylline完全消除 • 体外实验中CB2或A2A受体激活均促进海马神经祖细胞自我更新性分裂，且A2A拮抗抑制CB2介导的效应，CB1/CB2拮抗也阻断A2A介导的效应 • 受体结合实验首次证实小鼠海马中A2A和CB1受体形成异源二聚体，提示功能性相互作用可能涉及直接受体-受体对话 • CB1/CB2激动剂的促神经发生效应均依赖A2A受体活性，而A2A介导的神经元分化效应也依赖CB1/CB2受体活性领域意义该研究首次证实A2A-CB1受体异源二聚化为海马神经祖细胞动力学调控的分子基础，揭示了腺苷能与大麻素系统在神经发生中的双向相互依赖性。这一发现为靶向GPCR异源二聚体的促神经发生药物开发开辟了新方向，对神经退行性疾病的修复治疗具有重要启示意义。英文摘要 Background and purpose: Adult neurogenesis is a tightly regulated process affected by both cannabinoid receptors (CB1 and CB2) and adenosine A2A receptors, both of which modulate neural progenitor cell activity. While emerging evidence suggests an interaction between these neuromodulatory systems, the extent and mechanism of their interplay in regulating neurogenesis remain unclear. Experimental approach: Using a combination of in vivo and in vitro approaches together with pharmacological and receptor binding assays, we investigated the crosstalk between A2A and CB receptors in regulating hippocampal neurogenesis. Key results: In vivo administration of WIN55212-2, a non-selective cannabinoid receptor agonist, increased hippocampal cell proliferation and immature neuron formation, an effect abolished by istradefylline, a selective A2A receptor antagonist. In vitro, activation of CB2 or A2A receptors promoted self-renewing divisions of hippocampal-derived neural progenitor cells. Co-activation of CB1 or CB2 receptors with A2A receptors promoted a significant increase in cell proliferation. Notably, receptor-binding assays showed that A2A and CB1 receptors form heteromers in the mouse hippocampus. Conclusions and implications: These findings suggest a crosstalk between the adenosinergic and cannabinergic systems responsible for regulating hippocampal progenitor dynamics. The identification of CB1-A2A receptor heteromerization provides new insights into the molecular basis of neurogenic modulation and highlights a promising avenue for the development of novel proneurogenic therapeutic strategies. DOI: 10.1111/bph.70466 —————————————————————————————— Inhibition of kynurenine 3-monooxygenase (KMO) reduces fentanyl and sucrose intake and relapse-like behaviour in rats Br J Pharmacol 丨 2026-06-23 丨 Article ▍抑制犬尿氨酸3-单加氧酶减少大鼠芬太尼和蔗糖摄入及复吸样行为研究背景阿片类药物使用障碍，尤其是涉及芬太尼的滥用，因复吸率极高且现有药物治疗效果有限而面临重大公共卫生挑战。犬尿氨酸通路通过调节谷氨酸能和多巴胺能神经传递，已成为成瘾治疗的潜在靶点。犬尿氨酸3-单加氧酶（KMO）是该通路的关键分支酶，其抑制剂Ro 61-8048已在多种药物成瘾临床前模型中显示减少滥用的效果，但其在芬太尼成瘾及复吸中的作用和机制尚待阐明。核心发现 • KMO抑制剂Ro 61-8048在芬太尼自我给药的获取、维持、消退和复吸所有阶段均显著减少芬太尼摄入和有效杠杆反应 • Ro 61-8048的抗成瘾效应伴有犬尿喹啉酸（KYNA）水平升高和犬尿氨酸通路代谢物谱改变，但其效应超出了单纯的KYNA生成转变 • α7nAChR正性变构调节剂PNU-120596未能阻断Ro 61-8048的效应，证实其抗成瘾机制不依赖于α7nAChR • Ro 61-8048亦减少蔗糖自我给药但不产生厌恶行为或影响运动协调，提示KMO抑制调节药物和自然奖赏的强化强度而非引起普遍行为抑制领域意义该研究首次系统证明了KMO药理学抑制在芬太尼成瘾全过程中的有效性，且揭示其抗成瘾机制独立于α7nAChR，为KMO作为阿片类药物使用障碍的新型治疗靶点提供了强有力的临床前证据。通过药理学手段升高KYNA水平可补充现有治疗方案，具有明确的转化医学潜力。英文摘要 Background and purpose: Opioid use disorder, particularly involving fentanyl, poses major challenges due to high relapse rates and limited effectiveness of pharmacotherapies. The kynurenine pathway has emerged as a target for addiction treatment through its modulation of glutamatergic and dopaminergic neurotransmission. This study investigates the effects of kynurenine 3-monooxygenase (KMO) inhibition on fentanyl self-administration in rats. Experimental approach: Adult male rats received the KMO inhibitor Ro 61-8048 during fentanyl self-administration. Responding was assessed across acquisition, maintenance, extinction and reinstatement. The involvement of α7nAChR was investigated using the positive allosteric modulator PNU-120596. Sucrose self-administration, locomotor activity and rotarod performance were also evaluated. Kynurenine pathway metabolites were quantified in plasma and nucleus accumbens using UPLC-MS/MS. Key results: Ro 61-8048 reduced fentanyl intake and active lever responding across all addiction phases, associated with increased kynurenic acid levels and altered metabolite profiles. PNU-120596 did not prevent Ro 61-8048 effects, indicating an α7nAChR-independent mechanism. Although Ro 61-8048 reduced sucrose self-administration and spontaneous locomotor activity, it did not affect rotarod performance, suggesting KMO inhibition modulates reinforcing strength rather than inducing general behavioural suppression. Conclusions: KMO inhibition robustly attenuates fentanyl-directed behaviour and affects kynurenine pathway metabolism beyond a shift towards KYNA production, supporting KMO inhibition as a potential therapeutic strategy for opioid use disorder. DOI: 10.1111/bph.70549 —————————————————————————————— Leflunomide-inhibited STAT1 activity ameliorates intramuscular M1 macrophage infiltration and promotes muscle regeneration in Duchenne muscular dystrophy Br J Pharmacol 丨 2026-06-26 丨 Article ▍来氟米特抑制STAT1活性减轻M1巨噬细胞浸润并促进Duchenne肌营养不良症肌肉再生研究背景 Duchenne肌营养不良症（DMD）是由dystrophin基因突变引起的X连锁隐性遗传性致死性肌病，目前尚无治愈手段。慢性炎症和M1型巨噬细胞浸润是DMD骨骼肌病理进展的关键驱动因素。STAT1是调控巨噬细胞M1极化的核心转录因子，但STAT1/M1轴在DMD骨骼肌病理中的作用以及靶向该通路的治疗潜力尚未被系统评估。核心发现 • DMD患者和mdx小鼠骨骼肌中STAT1和磷酸化STAT1水平显著上调，与M1巨噬细胞浸润程度呈正相关 • 来氟米特的活性代谢产物A771726通过抑制磷酸化STAT1和STAT1蛋白水平，显著抑制LPS/IFN-γ诱导的M1巨噬细胞极化 • STAT1特异性激活剂RO8191促进巨噬细胞向M1型极化，该效应可被A771726部分拮抗 • 来氟米特4周治疗显著减轻mdx小鼠骨骼肌炎症浸润，降低血清CK和LDH水平，并促进肌球蛋白重链和MyoD表达所标志的肌肉再生领域意义该研究首次揭示了STAT1/M1巨噬细胞轴在DMD骨骼肌病理中的关键致病作用，并证实已上市药物来氟米特可通过抑制STAT1活性实现减轻炎症浸润和促进肌肉再生的双重治疗效果。这一发现为DMD提供了基于老药新用的精准药理治疗策略，具有快速临床转化的优势。英文摘要 Background and purpose: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by dystrophin gene mutations. This study investigated the therapeutic effects of leflunomide, a STAT1 inhibitor, on dystrophic muscles. Experimental approach: The characterization of M1 macrophage polarization and the level of STAT1/p-STAT1 were measured in DMD patients. LPS/IFN-γ and RO8191 were selected to stimulate STAT1 for evaluating the inhibitory effect of A771726 on M1 polarization and STAT1. Conditionally co-cultured M1 RAW264.7 cells and differentiated C2C12 myoblasts were used to explore the differentiation of A771726 to myopathy in inflammatory environments. After 4-week treatment with leflunomide, the protein levels of STAT1 and p-STAT1 were evaluated in mdx mice. CD86 and CD68 were selected for evaluating inflammation events. Muscle function and myofibre damage were examined by behavioural experiments and serum CK and LDH levels, respectively. Key results: STAT1 was remarkably upregulated in mdx mice and DMD patients compared with control groups. A771726 restrained LPS/IFN-γ-induced M1 macrophage polarization via inhibiting p-STAT1 and STAT1. Specific activation of STAT1 by RO8191 promoted macrophage polarization towards M1 type, which was partially counteracted by A771726. Leflunomide inhibited inflammation infiltration mediated by M1 macrophage and exerted promising therapeutic effect on muscle repair in mdx mice. Conclusions: Leflunomide relieved M1 macrophage infiltration and improved muscle regeneration by downregulating STAT1 and p-STAT1. STAT1 may emerge as a promising target for the therapy of DMD. DOI: 10.1111/bph.70518 —————————————————————————————— ▎参考文献·References [1] Cav3.2 T-type calcium channels in chronic pain: Structural insights, pharmacological advances and challenges in subtype selectivity. Br J Pharmacol. 2026 (2026-06-16). DOI: 10.1111/bph.70537. https://doi.org/10.1111/bph.70537 [2] Pharmacological activation of NO-cGMP signalling attenuates metabolic dysfunction-associated steatohepatitis. Br J Pharmacol. 2026 (2026-06-25). DOI: 10.1111/bph.70523. https://doi.org/10.1111/bph.70523 [3] Cannabinoid and adenosine A2A receptor crosstalk regulates postnatal and adult hippocampal neurogenesis. Br J Pharmacol. 2026 (2026-06-22). DOI: 10.1111/bph.70466. https://doi.org/10.1111/bph.70466 [4] Inhibition of kynurenine 3-monooxygenase (KMO) reduces fentanyl and sucrose intake and relapse-like behaviour in rats. Br J Pharmacol. 2026 (2026-06-23). DOI: 10.1111/bph.70549. https://doi.org/10.1111/bph.70549 [5] Leflunomide-inhibited STAT1 activity ameliorates intramuscular M1 macrophage infiltration and promotes muscle regeneration in Duchenne muscular dystrophy. Br J Pharmacol. 2026 (2026-06-26). DOI: 10.1111/bph.70518. https://doi.org/10.1111/bph.70518 —————————————————————————————— 药学基础研究丨每周一推送丨顶刊文献导读关注我们，追踪全球药学前沿药学基础研究第6期丨总第26期丨 2026-07

临床1期

2026-07-01

·DrugAI

J. Med. Chem. | AI强化学习驱动的从头药物设计: A2A腺苷受体拮抗剂案例研究

文献来源:Persico, M.; Micoli, A.; Salmaso, V.; Cianciulli, A.; Moro, S.; Spalluto, G.; Buccioni, M.; Marucci, G.; Volpini, R.; Pozzan, A.; Micheli, F.; Federico, S. Applying Deep-Learning-Driven De Novo Design to Hit Identification: A Case Study on A2A Adenosine Receptor Antagonists.J. Med. Chem. 2026.DOI: 10.1021/acs.jmedchem.6c00231通讯作者单位:Aptuit(Evotec子公司,意大利维罗纳);的里雅斯特大学化学与药学系;帕多瓦大学分子建模研究组(MMS)导读本文是一篇方法学透明度较高的AI从头药物设计实证研究。研究团队使用 AstraZeneca 开发、Evotec 定制化改造的生成式工具 REINVENT 3.2,以 A2A 腺苷受体(A2A AR) 为模型靶点,构建了融合"配体活性预测—对接—血脑屏障渗透性"三组分的多参数优化(MPO)评分函数,驱动强化学习循环生成新分子。全文围绕两个核心变量展开系统性的对照实验: 1. 评分函数的参数化方式(各组分权重、是否引入结构约束惩罚项); 2. 生成后过滤管线的设计逻辑(过滤顺序、过滤类型、是否引入机器学习排序方法)。在保持生成阶段产出的化学空间基本不变的前提下,仅通过调整过滤策略与评分函数权重,实验命中率从 0% 提升到 100%,活性从"完全无效"提升到"高纳摩尔级"。这一结果为AI驱动的从头设计提供了一个具有方法学参考价值的失败-修正完整案例。 1 研究背景1.1 早期药物发现中AI从头设计的定位早期药物发现(EDD)阶段普遍面临高成本、高失败率、专利空间受限(经典筛选依赖已公开化合物库)等结构性问题。生成式AI(de novo design)被视为缓解这些问题的潜在路径,但其应用仍存在明显短板:对高质量、大规模靶点数据的依赖性强;现有方法普遍是靶点特异性而非通用性的;AI输出仍需研究者验证与解读,尚不能替代人类专业判断。文献中绝大多数AI辅助EDD工作集中于基于配体(ligand-based)的超大库虚拟筛选,而真正在生成阶段就引入基于结构(structure-based)组件(即对接打分作为强化学习目标的一部分)的工作仍相对有限。本研究的核心定位,正是系统评估"在生成阶段嵌入结构信息"这一策略的实际效果与边界条件。1.2 选择A2A腺苷受体作为模型靶点的依据 A2A AR属于G蛋白偶联受体(GPCR)腺苷受体家族成员(与A1、A2B、A3 AR同源),在血管扩张、肿瘤免疫抑制以及神经炎症/神经退行性疾病中均发挥关键作用。其拮抗剂伊曲茶碱(istradefylline)已获批用于帕金森病治疗,该受体在阿尔茨海默病、肌萎缩侧索硬化(ALS)、亨廷顿病中也被广泛认为具有治疗潜力。选择该靶点的关键原因在于其"数据基础设施"的完备性:已发表配体数量大、活性/亲和力数据质量及一致性高,同时已公开了数量可观的共结晶结构(本研究药效团建模时纳入了58个拮抗剂结合状态的A2A AR X射线晶体结构)。这使A2A AR成为评估生成式AI方法学优劣的理想"压力测试"靶点——若方法在数据条件最优的情形下仍频繁失败,则在数据稀缺的"孤儿靶点"上的适用性将面临更严峻的挑战。1.3 与既往工作的方法学差异本研究在引言部分明确将自身与 Thomas 等人 2025 年发表于 Nat. Commun. 的同靶点研究(参考文献17)进行了区分:在 Thomas 等的工作中,基于结构对接是强化学习的主要优化目标,药物相似性质与特定残基相互作用处于次要地位;而本研究采取相反的实验设计——先以三组分等权重的"标准"配置进行第一轮生成与验证,在观察到失败后,有意识地将结构约束(特定残基相互作用)提升为主要驱动力,从而系统性地考察评分函数参数化对最终产出质量的因果性影响。2 计算方法体系2.1 数据整理与数据集构建数据整理通过 KNIME 4.7.2 工作流完成,核心步骤包括:基于 ChemAxon 与 RDKit 的结构标准化(清洗结构、中和电荷、生成最可能互变异构体)→ 数据集精炼(按检测类型聚合、活性值转换为对数尺度、去重时保留最高活性记录)→ 输出 SDF/CSV 格式用于建模。四个腺苷受体亚型的原始数据规模如下: 受体亚型数据点数量数据来源 A2A AR(拮抗剂/部分激动剂/反向激动剂) 9,237 ChEMBL + SciFinder A1 AR(拮抗剂) 5,313 ChEMBL A3 AR(拮抗剂) 5,136 ChEMBL A2B AR(拮抗剂) 4,037 ChEMBL A2A AR模型额外纳入了一个74个化合物的外部验证集(数据采集截止日期之后新发表于ChEMBL的化合物),用于独立评估模型的前瞻预测能力。2.2 配体基础组件:QSAR活性预测模型第一轮建模采用 Evotec 自动化建模管线,系统比较了多种建模配置: • 活性阈值(pKi/pIC50 = 6、7、8三档) • 二分类 vs. 三分类(后者引入"中等活性"不确定区间) • 检测类型组合(结合实验 vs. 功能实验;Ki vs. IC50) 分子描述符采用 MACCS指纹联合 18个理化性质描述符(TPSA、ALogP、分子量、FSP3、重原子数、原子数、氢键供体数、芳香杂环数、杂原子数、可旋转键数、芳香环数、芳香碳环数、脂肪杂环数、脂肪环数、饱和杂环数、饱和环数、脂肪碳环数、饱和碳环数,均由 RDKit v2021.3.5 计算)。随机森林(RF)与支持向量机(SVM)模型均通过 scikit-learn 0.21.3 训练,五折交叉验证后保留性能最优者,超参数通过网格搜索优化。最终生产模型(用于评分函数的离散过滤器)为基于 pKi≥7 阈值的二分类模型:预测为"活性"赋分1,预测为"非活性"赋分0。性能指标: 指标数值阈值低/高活性分子数(参考集) 约2,991 / 2,985(基本均衡) 准确率(Accuracy) 0.87(文中要求 >0.8) Cohen's Kappa 0.73(文中要求 >0.7) 外部验证后,该74个化合物被并入训练集以生成最终生产模型。第二轮建模(用于评分函数重新校准):在第一轮9个化合物全部失活的反馈后,团队采用 Evotec 开发的另一套自动化流程(基于 RDKit 2021.03.1 + pycaret 2.3.10),描述符体系升级为 Morgan指纹(2048位)+ Atom Pair指纹(1024位)+ Topological RDKit指纹(1024位)+ MACCS(167位)+ RDKit分子描述符(208个理化/结构/拓扑性质) 的拼接特征;采用85:15训练-测试集划分(回归任务)或分层划分(分类任务),10折交叉验证优化超参数,最终在全部数据上重新训练。这一调整的核心意图是将"失活三唑"的新数据反馈回模型,引导后续生成偏离已证实的无效化学空间。2.3 结构基础组件:分子对接打分采用 GOLD程序(GoldScore打分函数),对接靶点为A2A AR的拮抗剂结合晶体结构(PDB: 4EIY)。受体结构经 MOE2022 套件预处理:去除融合蛋白apocytochrome b(562)RIL(替代了第三胞内环ICL3),并通过 Loop Modeler 基于知识库方法重建ICL3(Lys209–Gly218);补全缺失原子,N/C端以乙酰基/N-甲基酰胺基团封端;通过 Protonate3D 在生理pH(~7.4)下分配最可能质子化状态,Amber14:EHT力场最小化新增氢原子;保留晶体学钠离子(作为负性别构调节剂)及其溶剂化层的3个水分子。对接搜索空间限定在以Asn253与Phe168质心为中心的11Å球形区域内,每个化合物生成10个对接姿势。为将原始GOLD打分映射至0–1区间,采用了基于三个参照拮抗剂的S型(sigmoid)转换校准: 参照化合物对接打分实测pKi ZM-241385(高活性参照) ≈63 ≈8.8 化合物2(PDB: 5OLZ) ≈55 ≈8.5 咖啡因(低活性参照) ≈38 ≈4.6 据此设定:对接打分 <50 → 评分0;50–65 → 0至1连续映射;>65 → 评分1。该校准策略的合理性建立在"高亲和力配体应获得高对接打分"的假设之上,但也正因为这一映射区间较宽(50–65),为后续失败埋下了隐患——较宽的容许区间意味着大量"塞得进口袋但缺乏关键相互作用"的分子同样可以获得高分。2.4 药代动力学组件:CNS-MPO评分采用 Wager 等提出的中枢神经系统多参数优化评分(CNS-MPO),综合评估6项理化性质以预测血脑屏障(BBB)穿透能力,原始量表为0–6分,>4分被视为最佳候选。评分函数中采用升序S型转换:CNS-MPO <3 → 0;3–4 → 0至1连续映射;>4 → 1。后续过滤阶段还引入了独立的 BBB Score(基于芳香环数、重原子数、MWHBN复合描述符、tPSA、生理pH下pKa等不同理化维度),作为CNS-MPO的交叉验证指标。2.5 REINVENT生成框架与强化学习设置 REINVENT 是基于循环神经网络(RNN)+ 强化学习的生成式分子设计平台,核心特性是在生成过程中持续执行多参数优化(MPO)。本研究采用 Evotec 定制版(基于公开版本 REINVENT 3.2),关键设置包括: • Inception策略:以三个文献已知拮抗剂(ZM-241385、PDB 5OLZ配体、咖啡因)作为初始种子,引导模型早期探索方向; • 多样性过滤器(Diversity Filter):基于相同Murcko骨架、最低相似度阈值0.4,防止生成过程收敛到单一狭窄区域; • 强化学习算法:第一轮采用标准策略,第二轮引入 Augmented Hill Climb(Evotec在原版REINVENT基础上新增的算法,用于加速多参数优化收敛)。2.6 复合评分函数的整合逻辑三个组分(配体活性、结构对接、CNS渗透性)各自归一化至0–1区间后取算术平均,总分>0.6的分子被视为满足设计标准并保留为模型输出。研究团队系统比较了四种评分函数配置(单独QSAR、单独3D/Gold、两者等权重组合、三者等权重组合)在1000轮迭代下的优化轨迹与产出规模,以验证生成模型对各单一组分及组合目标的优化能力。3 第一轮生成:标准等权重评分函数3.1 生成阶段产出统计四种评分函数配置各运行1000轮迭代,以平均分>0.6为采集阈值: 评分函数配置保留分子数仅QSAR活性模型 67,582 仅3D/Gold对接组件 109,054 QSAR + Gold(等权重) 97,826 QSAR + Gold + CNS-MPO(等权重) 91,115四套运行合计365,577 经KNIME后处理(去重、理化性质计算、Tanimoto相似度计算、指纹聚类)后,最终保留 365,321个独立分子,作为后续两套过滤策略共同的起点数据集。3.2 多级后处理过滤管线(标准策略) 过滤步骤筛选标准剩余分子数 1. 预测活性 A2A AR分类模型,预测pKi≥7 (大幅缩减,初步富集) 2. 亚型选择性对A1/A2B/A3分类模型预测pKi≤6(或对应IC50阈值) 24,015 3. 回归模型一致性 Ki回归模型与IC50回归模型预测pKi/pIC50均≥7 22,708 4. CNS渗透性 CNS-MPO评分>4 且 BBB Score>4438 5. 药效团/对接姿势筛选见3.3节多级药效团过滤 34 6. 合成可行性与新颖性评估 SciFinder检索去除冗余骨架 6(初选)+ 3(回溯补选)= 9 值得注意的是,第4步(CNS渗透性过滤)是整条管线中淘汰率最高的环节(从22,708骤降至438),说明在该评分体系下,"活性可预测"与"具备CNS成药性"之间存在显著的化学空间错配——这也从侧面解释了为何最终幸存的分子集中于结构高度同质化的骨架(1,2,4-三唑)。在438个分子中,通过来源追溯发现 185个(约42%) 来自"QSAR + Gold + CNS-MPO"三组分组合运行,即三组分协同优化的策略在通过CNS筛选方面表现相对突出。3.3 基于药效团与对接姿势的结构筛选 438个分子经 OpenEye 套件(Tautomers/Omega/Fixpka工具)处理互变异构体、3D构象与生理pH电离状态后,得到 505个结构,使用GOLD–GoldScore对接于A2A AR(PDB: 4EIY),共生成 5,050个对接姿势(每化合物10个)。基于58个拮抗剂结合状态A2A AR晶体结构构建的共识药效团模型,定义了三级递进过滤标准: 药效团过滤级别关键特征定义通过姿势数对应独立分子数P1 (基础药效团) 芳香/疏水中心(与Phe168 π-π堆积)+ 至少一个氢键供体/受体特征(靠近Asn253) 1,263 — 进一步筛选计算确认与Asn253存在氢键且静电/范德华相互作用能为负 364 112 双齿氢键评估是否形成Asn253双齿氢键(强效拮抗剂的标志性特征) 仅3个化合物(因口袋占据不佳/互变异构体问题被放弃) —P2 (扩展药效团) P1基础上新增疏水/芳香特征(靠近His250) 271 83P3 (色酮类似药效团) 新增氢键受体特征(模拟色酮类配体6ZDR/6ZDV的呋喃氧原子,提示可能的水介导相互作用) 9534 最终34个分子经SciFinder新颖性与合成可行性检索,发现 23/34(约68%)为1,2,4-三唑骨架(3、4、5位取代)——这一高度集中的结构偏好直接反映出REINVENT在当前评分函数引导下的化学空间收敛特征。3.4 化合物4–12的合成与药理学评价初选6个三唑衍生物(化合物4–9)合成后,团队对该骨架在CNS-profile过滤阶段被淘汰的同类物进行回溯分析,基于合成可行性补选3个(化合物10–12),最终共9个化合物进入湿实验验证。化合物结构均为4,5-二芳基(或二吡啶基)-1,2,4-三唑-3-硫醇衍生物,3位通过硫醚键连接吗啡啉乙基、二甲氨基烷基、酰胺类等多样化侧链。全部9个化合物经放射性配体竞争结合实验测定,A2A AR的Ki值均大于30,000 nM,即无活性。化合物评分函数来源组合 hA2A AR Ki (nM) 4 QSAR + Gold + CNS-MPO >30,000 5 QSAR + Gold >30,000 6 QSAR + Gold + CNS-MPO >30,000 7 QSAR + Gold >30,000 8 QSAR + Gold >30,000 9 QSAR + Gold >30,000 10 QSAR + Gold + CNS-MPO >30,000 11(11b,COOH衍生物) QSAR + Gold + CNS-MPO >30,000 12 QSAR + Gold >30,000 研究团队特别指出,失活化合物并非集中来自单一评分函数配置(4个来自三组分组合,5个来自双组分组合),说明失活的根源不在于评分函数权重的具体取值,而在于评分体系本身未能编码某个对活性至关重要的结构特征。3.5 失活归因:结合模式复盘分析以化合物4为代表的对接姿势复盘揭示了关键问题(见原文图3):三唑芳香环与Phe168形成π-π堆积;三唑2位氮原子与Asn253形成单一氢键(而非双齿氢键);5-芳基取代基深入口袋底部,与His250形成T形π-π相互作用;4-芳基取代基朝向TM1-2跨膜区;3位取代基则伸向受体细胞外开口区域。这一结合模式与文献报道的多数强效A2A拮抗剂存在本质差异:后者普遍依赖与Asn253形成的双齿氢键作为高亲和力的结构基础。研究结论明确指向:该相互作用未被纳入对接打分的隐式判据,也未在初次药效团设计中被设为强制性筛选标准(双齿氢键过滤虽被纳入P1后续步骤,但因合格分子过少且存在其他问题而被放弃执行),致使整条"事后过滤"管线无法弥补生成阶段就已缺失的关键化学特征。4 替代过滤策略:贝叶斯优化驱动的二次数据挖掘4.1 过滤逻辑重构为验证失败根源是否在于过滤策略而非生成阶段本身,团队对同一批365,321个分子(与3.1节起点完全相同)应用了顺序与类型均不同的过滤管线: 过滤步骤筛选标准剩余分子数 1. CNS渗透性(优先执行) CNS-MPO评分过滤 44,594 2. 亚型选择性对A1/A2B/A3的选择性评估 7,971 3. 排除已证实失活骨架基于第一轮结果剔除"失活"1,2,4-三唑(剔除215个) (7,756) 4. Golden Triangle规则分子量 vs. 生理pH下cLogD,优化代谢清除与口服吸收的理化空间 4,364 5. 贝叶斯优化(BO)排序见4.2节前100(Table S6) 6. 跨管线结构比较与标准管线438个分子(同样剔除三唑)进行DataWarrior骨架共性分析 13(Figure S5) 4.2 贝叶斯优化方法学贝叶斯优化是一种基于"数据-标签对"训练代理模型(通常为高斯过程模型)的监督学习排序方法,代理模型输出预测均值与标准差,经采集函数转化为对未知点的排序依据。本研究中,Evotec开发的命令行工具采用以下设置: • 模型:贝叶斯优化(BO) • 描述符:CDDD(Continuous and Data-Driven Descriptors,基于化学表示互译学习得到的连续型描述符) • 参考数据集:5,934个已知pKi值的A2A拮抗剂 • 采集函数:Expected Improvement(EI),jitter=0.01 • 优化目标:A2A拮抗剂pKi • 高斯过程引擎:botorch 该方法对4,364个分子进行排序,取前100个用于后续分析(Table S6)。4.3 跨管线比较分析与候选确定将BO排序前100个分子与标准管线产出的438个分子(同样排除三唑骨架)在 DataWarrior 中进行自动SAR分析,识别两个子集间共享的优势核心环系,最终确定13个高优先级分子进入合成评估(Figure S5)。其中,吡唑-嘧啶骨架的化合物13因带有游离氨基(理论上具备形成Asn253双齿氢键的潜力)被特别关注——值得说明的是,该化合物并未通过标准的分子建模过滤管线入选,原因是其预测对接姿势实际上完全未显示与Asn253的氢键相互作用;研究者基于结构推理(而非对接打分本身)判断其具有潜在价值,决定将其纳入合成计划,这体现出人类专家判断在AI输出后处理阶段仍不可替代的现实。4.4 化合物13–15的合成与药理学评价化合物13(5-氨基-N,N-二乙基-1-(5-甲基-4-(噻吩-2-基)嘧啶-2-基)-1H-吡唑-4-甲酰胺)及其两个合成中间体——乙酯化合物14、羧酸化合物15——的完整药理学数据如下: 化合物 Ki hA1 AR (nM) Ki hA2A AR (nM) IC50 hA2B AR (nM) Ki hA3 AR (nM) PAMPA-BBB13 (终产物,二乙基酰胺) 1,5016,071 >30,000 3,944 CNS+14 (乙酯中间体) 1,670691 >30,000 2,901 CNS+15 (羧酸中间体) — >30,000(无活性) — — — 关键发现: 1. 化合物13确证有效(Ki = 6.07 μM),是这一替代策略唯一、也是全文唯一来自全新化学骨架的实验验证命中分子; 2. 合成中间体14的活性反而优于终产物(Ki = 691 nM,纳摩尔级),提示侧链末端的二乙基酰胺基团相对乙酯基团在该位点可能存在不利的立体或电性效应,这是一个具有SAR教学价值的"细微结构改动导致活性悬崖"的实例; 3. 羧酸中间体15完全失活,进一步印证该侧链区域对静电/氢键性质高度敏感; 4. 化合物13与14均经PAMPA-BBB实验确证可穿透血脑屏障,验证了CNS-MPO组分在评分函数与过滤体系中的预测有效性。5 第二轮生成:结构约束驱动的评分函数优化5.1 评分函数修订的理论依据基于3.5节的归因分析,研究假设"与Asn253形成双齿氢键"是A2A拮抗剂活性的必要结构特征(该假设有多篇独立文献支持)。因此第二轮的核心策略是将这一假设从"事后过滤标准"前移为"生成阶段的强化学习优化目标"。5.2 关键参数调整调整项第一轮设置第二轮设置 Asn253双齿氢键未纳入评分函数缺失则施加惩罚分对接打分S型转换区间 50–65收紧至55–65 (提高达标门槛) 结构对接组分权重 1(与其他组分等权)提升至5或10 QSAR/CNS-MPO组分权重 1 维持1 强化学习算法标准策略Augmented Hill Climb (加速MPO收敛) QSAR活性模型训练数据原始数据集纳入第一轮失活三唑数据重新训练 ,主动引导AI规避已证实无效区域研究同时讨论了一种正在兴起的替代范式——基于Pareto多目标优化的评分策略(参考文献82–84),相较于本研究采用的加权均值评分函数,Pareto方法理论上能更好地权衡多目标间的取舍。但本研究有意选择"largely as is"地使用REINVENT原生框架,目的是更纯粹地评估该工具本身在生成与后处理两个阶段的能力边界,而非引入额外的优化范式变量。5.3 生成阶段产出统计分别以权重5、权重10进行两组各1000轮独立迭代: 3D结构组分权重保留分子数(平均分>0.6) 权重 = 5 57,847 权重 = 10 59,562合计117,409 经相同的KNIME精炼流程后,保留 117,386个分子(精炼损耗极小,与第一轮365,577→365,321的比例基本一致)。5.4 第二轮过滤管线第二轮采用了更精简、聚焦的过滤策略(活性—CNS—结构三级核心标准),不再单独设置亚型选择性过滤步骤: 过滤步骤筛选标准剩余数量 1. 预测活性同一QSAR模型,pKi>7 84,049 2. CNS渗透性 CNS-MPO + BBB Score(同第一轮阈值) 387 3. 分子对接 GOLD对接于4EIY 4,530个姿势 4. 药效团P1过滤同3.3节定义 1,370 5. Asn253氢键确认至少一个氢键 562 6. 相互作用能筛选静电/范德华能为负(有利) 486 7. 双齿氢键确认与Asn253形成双齿氢键(核心硬性标准) 22 8. 药效团P2过滤新增His250疏水特征 11(5个独立分子) 9. 互变异构体/立体化学排查排除存在歧义结构4个分子(17–20) 最终4个候选分子(17–20)的对接姿势均确认能与Asn253形成双齿氢键(由游离氨基与环内氮原子协同实现,涉及氨基嘧啶、氨基吡啶、氨基噻唑等骨架),中心芳香核与Phe168形成π-π堆积,芳基取代基靠近His250——即生成阶段的结构约束已在最终候选层面得到完整体现。基于合成可行性考量,最终选择2-氨基嘧啶(17)与2-氨基吡啶(18)进行合成,并额外合成了与17结构相近、但未完全通过药效团过滤的类似物化合物16,作为构效关系(SAR)比较的参照分子。5.5 化合物16–18的合成与药理学评价化合物 Ki hA1 AR (nM) Ki hA2A AR (nM) IC50 hA2B AR (nM) Ki hA3 AR (nM) PAMPA-BBB16 (3-腈基苯基-呋喃基氨基嘧啶) 133179 >30,000 4,225 CNS+17 (2-甲氧基苯基-甲基吡啶基氨基嘧啶) 1,225525 >30,000 11,490 CNS+18 (双噻吩基氨基烟酸酯) 539521 >30,000 818 CNS+ 三个化合物全部确证有效,A2A AR亲和力落在179–525 nM区间(高纳摩尔至数百纳摩尔级),全部经PAMPA-BBB实验确证可穿透血脑屏障——实验成功率达到100%,且最佳活性(化合物16,Ki=179 nM)相较第一轮替代策略的最佳结果(6.07 μM)提升约34倍。5.6 选择性谱型与化学新颖性分析需要客观指出的局限性:三个化合物对hA1 AR与hA3 AR的选择性均不理想(尤其对hA1 AR),仅对hA2B AR表现出良好的选择性。研究坦诚说明,这一结果在预期之内,因为第二轮评分函数本身未设置亚型选择性过滤步骤——这是为聚焦验证"结构约束效果"而做出的实验设计简化,并非方法学缺陷,但也提示后续工作若以成药性为目标,仍需重新引入选择性优化组件。化学新颖性方面,2-氨基嘧啶骨架的发现具有一定的标志性意义:对起始数据集的回溯分析显示,共106个分子含有2-氨基嘧啶核心,但绝大多数为四取代而非本研究的三取代模式;仅2个分子与生成结果高度相似(文献报道为A1拮抗剂)。值得关注的是,etrumadenant——一种目前处于II期临床(用于转移性结直肠癌)的双重A2A/A2B拮抗剂,其核心骨架同样为联芳基2-氨基嘧啶——并未出现在训练数据集中,但REINVENT在几乎没有直接先例的条件下生成了结构高度相关的化合物,这是本研究中AI生成能力的一个积极信号。6 三轮实验综合数据汇总为便于横向比较,下表汇总全部实验验证化合物的关键数据: 来源化合物核心骨架类型 Ki/IC50 hA2A AR 选择性表现 BBB预测化学新颖性 Run1标准管线 4–12(9个) 1,2,4-三唑全部>30,000 nM — — — Run1替代管线(BO) 13 吡唑-嘧啶 6,071 nM 中等(vs A1/A3) CNS+全新骨架 Run1替代管线(中间体) 14 吡唑-嘧啶(乙酯) 691 nM 中等 CNS+ 全新骨架 Run2优化模型 16 氨基嘧啶 179 nM 差(vs A1/A3) CNS+ 已知骨架邻近区 Run2优化模型 17 氨基嘧啶 525 nM 差(vs A1/A3) CNS+ 已知骨架邻近区 Run2优化模型 18 氨基烟酸酯(双噻吩) 521 nM 中等(vs A3较好) CNS+ 已知骨架邻近区7 综合讨论7.1 三轮实验定量对比指标 Run1(标准评分) Run1(替代过滤) Run2(优化模型) Asn253双齿氢键约束未启用未启用强制启用合成化合物数 9(4–12) 1(13) 3(16–18) 实验确证活性化合物数 0 1 3 实验成功率 0% 100% 100% 最佳活性无活性 6.07 μM 179 nM7.2 Tanimoto相似度分析与"新颖性—命中率"权衡通过Tanimoto相似度分析(原文Table S9)发现一个具有方法学意义的趋势:第一轮生成的化合物(包括失活三唑与有效化合物13)对所有参照数据库的相似度均低于0.61,即化学空间新颖性较高;而第二轮生成的化合物相似度评分明显更高,提示引入强结构约束后,生成模型更倾向于收敛到化学已知、结构成熟的母核区域。这一发现揭示了AI从头设计中一个值得长期关注的内在张力:结构约束越精确(越接近已知有效相互作用模式),实验命中率越高,但生成结果的化学新颖性也越容易随之下降。在全部实验验证的命中化合物中,仅化合物13代表真正意义上的全新化学型(novel chemotype);第二轮的16–18虽然活性更优、实验成功率更高,但更接近已被探索过的化学motif。7.3 评分函数设计的核心作用:不止是技术细节本研究最具普适价值的方法学结论是:评分函数的参数化方式与生成后过滤管线的设计逻辑,对最终实验结果具有决定性影响,且二者的影响可以相互独立。证据链如下: • 同一批365,321个生成分子,经标准过滤管线得到全部失活的9个化合物;经替代过滤管线(贝叶斯优化排序+跨数据集结构比较)却能挖掘出有效命中化合物13。这说明生成阶段本身已经产出了部分潜在有效分子,但标准的"基于对接姿势的药效团过滤"未能识别出它们——换言之,过滤管线的设计缺陷,而非生成模型能力不足,是Run1标准策略失败的直接原因之一。 • 当把"双齿氢键"这一已知关键判据直接前移至生成阶段的强化学习目标(而非仅作为下游过滤条件)后,Run2的实验成功率从0%跃升至100%,印证了**"硬知识应尽早注入生成循环,而非留待后处理"**这一设计原则的有效性。7.4 局限性:数据丰富靶点与"孤儿靶点"的适用性差异研究明确指出,本方法体系高度依赖A2A AR本身的"数据丰厚性"——大量已知配体、丰富的共结晶结构、明确的关键残基相互作用文献支持,这些都是构建有效QSAR模型、校准对接打分、定义可靠药效团约束的前提条件。对于结构信息匮乏、配体数据稀少的"孤儿靶点",当前方法体系中的多数组件(尤其是QSAR分类模型与基于已知关键相互作用的药效团约束)将难以构建或缺乏可靠性——而这类靶点恰恰是计算驱动从头设计最需要发挥价值、也最难以落地的应用场景,构成了该方法学路径当前最主要的现实瓶颈。7.5 对方法学实践的启示综合全文,可以提炼出若干对从事AI辅助药物设计的研究者具有直接参考价值的实践建议: 1. 评分函数中各组分的权重不应默认等权处理,而应基于对靶点结构生物学认知(如已知的关键残基相互作用)进行有依据的差异化设置; 2. 结构约束(如特定残基的氢键模式)应尽可能编码为强化学习阶段的显式优化目标或惩罚项,而非仅作为生成后的过滤标准——后者只能从已生成的有限候选中"挑剩下的",无法引导生成模型主动探索符合约束的化学空间; 3. 生成结果的后处理过滤策略本身应被视为一个独立的、可系统优化的实验变量——同一份生成产出,不同的过滤逻辑可能导致截然不同的结论,因此在评估生成模型"是否失败"之前,应首先排除过滤管线设计本身的问题; 4. 机器学习排序方法(如贝叶斯优化)可作为传统基于规则/药效团过滤的有效补充,尤其适合在传统方法因结构特征定义过严而漏判潜在候选时发挥作用; 5. 应为"新颖性—命中率"权衡设定明确的项目优先级:若以快速验证可成药性为目标,适度收紧结构约束是合理选择;若以专利布局或全新化学型探索为目标,则需要在评分函数设计中保留更大的化学空间自由度,并接受相应的实验失败率。总结本研究通过两轮REINVENT生成实验与两套差异化的过滤策略,系统性地证明了AI从头药物设计中评分函数参数化与后处理过滤管线设计对最终实验结果具有决定性的、且相互独立的影响。标准等权重评分函数搭配基于药效团的过滤策略导致9个合成化合物全部失活;通过贝叶斯优化重构过滤逻辑后,从同一批生成分子中挖掘出1个微摩尔级全新骨架命中化合物(13);将失败归因(Asn253双齿氢键缺失)直接编码为第二轮评分函数的结构约束后,3个合成化合物实现100%的实验命中率,活性提升至高纳摩尔级,且均预测可穿透血脑屏障。这一系列结果共同表明,成功的生成式从头设计高度依赖于将靶点特异性的结构知识系统性地整合进强化学习的优化目标,而非仅仅依赖更大规模的生成产出或更复杂的下游过滤。同时,该方法体系对数据丰富靶点的适用性已得到较充分验证,但对结构与配体数据匮乏的靶点的可推广性,仍是该领域亟待解决的核心挑战之一。

2026-06-26

·BioSpace

New Autism Research to be Presented at European Purine Scientific Meeting

CALGARY, Alberta, June 26, 2026 (GLOBE NEWSWIRE) -- Marvel Biosciences Corp. (TSXV: MRVL | OTC: MBCOF ), and its wholly owned subsidiary, Marvel Biotechnology Inc. (collectively “Marvel” or the “Company” ), a drug discovery company developing novel therapeutics for autism spectrum disorder and related conditions, is pleased to announce one of their collaborators from the iBraiN Institute in Tours France, Dr. Jérôme Becker, will give an oral presentation at the 3 rd European Purine Meeting, taking place in Bordeaux, France, from July 1 to 3, 2026. Marvel is also proud to support the meeting as a conference gold sponsor. Dr. Becker’s presentation, “Adenosine A2A Receptors as a Therapeutic Target in Autism Spectrum Disorders”, will be given next Friday. The presentation will highlight the pivotal role that Adenosine A2a receptors (A2ARs) play in the neural reward circuits involved in social interaction and communication. Research shows that A2AR antagonism consistently improves social interaction across multiple preclinical models displaying autism-like phenotypes, suggesting that drugs that target the A2AR are a very promising therapeutic target to alleviate social deficits associated with autism spectrum disorders. Marvel and Dr. Becker and Dr. Julie Le Merrer’s research team at the iBraiN institute have collaborated for the past three years to advance the scientific understanding of A2AR biology and evaluate the therapeutic potential of MB-204, Marvel's lead A2AR antagonist, in multiple preclinical models of autism (e.g., Oprm1 , Mecp2 , Shank3 – data forthcoming). "Dr. Becker is a world-class researcher whose work has been instrumental in advancing the understanding of adenosine A2A receptors in autism," said Rod Matheson, Chief Executive Officer of Marvel Biosciences. "Over the past three years, our collaboration has generated compelling preclinical data demonstrating the potential of MB-204 across multiple validated models of autism. Marvel Biosciences is proud to support the European Purine Meeting, and we hope this will raise greater awareness of this field of research in autism. " The Company is also pleased to share its recent interview with Radius Research, featuring Chief Executive Officer, Rod Matheson, and Chief Science Officer, Mark Williams. The interview shares insight into Marvel's patented lead asset, MB-204, the Company's development roadmap, upcoming milestones, and the opportunities ahead as Marvel advances toward Phase 1 clinical studies. Link to interview: About Marvel Biosciences Corp. Marvel Biosciences Corp., through its wholly owned subsidiary Marvel Biotechnology Inc., is a Calgary-based biotechnology company developing new treatments for neurological diseases and neurodevelopmental disorders. Our lead drug candidate, MB-204, is a novel fluorinated derivative version of Istradefylline, an approved Parkinson’s drug and the only adenosine A2A receptor blocker currently on the market. Research shows that blocking the A2A receptor may help treat conditions such as autism, depression, and Alzheimer’s disease. Marvel is also exploring MB-204’s potential in rare disorders like Rett syndrome and Fragile X syndrome, aiming to bring new options to patients with few effective treatments. Contact Information: Marvel Biosciences Corp. J. Roderick (Rod) Matheson, Chief Executive Officer Email: rod@marvelbiosciences.com Dr. Mark Williams, President and Chief Science Officer Email: mark@marvelbiosciences.com Tel: 403 770 2469 Website: | Twitter/X | LinkedIn Neither the TSX Venture Exchange nor its Regulation Services Provider (as that term is deﬁned in the policies of the TSXV) accepts responsibility for the adequacy or accuracy of this press release. All information contained in this news release with respect to the Company and its subsidiary,(collectively, the "Parties") were supplied by Marvel, respectively, for inclusion herein and each parties' directors and oﬃcers have relied on each other for any information concerning such Party. This news release may contain forward-looking statements and other statements that are not historical facts. Forward-looking statements are often identiﬁed by terms such as "will", "may", "should", "anticipate", "expects" and similar expressions. All statements other than statements of historical fact, included in this release, including, without limitation, statements regarding the future plans and objectives of the Company are forward-looking statements that involve risks and uncertainties. There can be no assurance that such statements will prove to be accurate and actual results and future events could diﬀer materially from those anticipated in such statements. Important factors that could cause actual results to diﬀer materially from the expectations of the Company and include other risks detailed from time to time in the ﬁlings made by the Company under securities regulations. The reader is cautioned that assumptions used in the preparation of any forward-looking information may prove to be incorrect. Events or circumstances may cause actual results to diﬀer materially from those predicted, as a result of numerous known and unknown risks, uncertainties, and other factors, many of which are beyond the control of the Company. As a result, the Company cannot guarantee that the above events on the terms will occur and within the time disclosed herein or at all. The reader is cautioned not to place undue reliance on any forward-looking information. Such information, although considered reasonable by management at the time of preparation, may prove to be incorrect and actual results may diﬀer materially from those anticipated. Forward-looking statements contained in this news release are expressly qualiﬁed by this cautionary statement. The forward-looking statements contained in this news release are made as of the date of this news release and the Company will update or revise publicly any of the included forward-looking statements as expressly required by Canadian securities law.

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KEGG	Wiki	ATC	Drug Bank
D04641	伊曲茶碱	N04B	DB11757

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帕金森病	日本	Kyowa Kirin Co., Ltd.	2013-03-25

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适应症	最高研发状态	国家/地区	公司	日期
原发性帕金森病	临床3期	中国	石药集团中奇制药技术（石家庄）有限公司	2019-02-28
轻度认知障碍	临床2期	美国	Kyowa Kirin, Inc.	2022-07-18
不宁腿综合征	临床2期	美国	Kyowa Kirin, Inc.	2005-07-01
药物滥用	临床1期	美国	Kyowa Kirin Co., Ltd.	2016-01-01
恶病质	临床1期	美国	Piston Bio LLC	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


MDS2024	N/A	帕金森病	2,045	Istradefylline 40 mg	顧膚醖齋範築觸觸淵繭(襯醖簾鬱窪衊繭網積壓) = 範醖醖膚鹹願獵夢簾構製鹽衊選襯築壓餘積淵 (艱積窪憲夢淵願淵築壓, 90 ~ 365) 更多	积极	2024-09-27
				Istradefylline 40 mg (Medicare replacement)	顧膚醖齋範築觸觸淵繭(襯醖簾鬱窪衊繭網積壓) = 範鑰醖網廠艱選鹹襯選製鹽衊選襯築壓餘積淵 (艱積窪憲夢淵願淵築壓, 90 ~ 365) 更多
P5-3.017 (AAN2024)	N/A	帕金森病	-	Istradefylline 40mg	蓋顧鬱繭繭齋鹽選遞鏇(願簾鏇觸壓鹹齋蓋糧鹽) = The odds of hallucinations were significantly higher for amantadine vs. istradefylline at 40 and 20mg 鑰淵夢糧遞範壓網選醖 (艱襯醖醖簾鬱觸餘衊積 ) 更多	积极	2024-04-09
				Istradefylline 20mg
MDS2023	临床3期	-	214	Istradefylline	醖衊淵淵網壓夢鹽醖選(鬱積簾糧蓋積醖顧窪築) = 艱憲願網繭簾糧憲顧窪淵夢網鏇廠繭鬱獵壓願 (憲觸鑰糧襯窪壓艱餘鹹 )	积极	2023-08-27
				No Istradefylline	醖衊淵淵網壓夢鹽醖選(鬱積簾糧蓋積醖顧窪築) = 鬱築選憲簾淵艱鏇襯繭淵夢網鏇廠繭鬱獵壓願 (憲觸鑰糧襯窪壓艱餘鹹 )
AAN2022	N/A	帕金森病	-	Istradefylline 20 mg	醖蓋糧範遞醖膚築選憲(鬱顧壓觸艱餘醖壓衊遞) = 衊繭鬱築範鑰築廠觸餘鬱鏇積淵糧鬱糧壓鹹餘 (襯壓淵選廠憲憲築鏇繭 ) 更多	积极	2022-05-03
				Istradefylline 40 mg	醖醖襯窪築鬱構艱範網(壓鬱廠夢選製製齋簾壓) = 獵鹽鏇鬱選醖壓窪繭繭遞製糧餘鑰顧壓願願膚 (構艱膚築積襯襯遞觸鹹 )
NCT01968031 (KW-6002, CTgov)	临床3期	帕金森病	613	Placebo (Placebo)	網遞夢鬱齋窪壓鏇齋衊(鹽淵醖願壓鏇艱淵壓獵) = 壓窪願製廠糧顧範遞壓鬱憲鬱糧醖願範襯製鑰 (糧簾築遞構襯憲網遞積, 夢廠齋襯獵製壓艱製醖 ~ 衊醖網鹹選廠網夢選鑰) 更多	-	2020-11-20
				Placebo+Istradefylline 20 mg (Istradefylline 20 mg/Day)	網遞夢鬱齋窪壓鏇齋衊(鹽淵醖願壓鏇艱淵壓獵) = 鹹鏇願鹹糧鹹觸窪衊膚鬱憲鬱糧醖願範襯製鑰 (糧簾築遞構襯憲網遞積, 壓膚鏇觸遞淵積廠鹽鏇 ~ 顧鑰觸獵願憲網餘鑰憲) 更多
pooled analysis of four pivotal randomized controlled trials of istradefylline (ANA2020)	临床3期	帕金森病	1,143	Istradefylline 20mg/day	鑰積構蓋製窪膚鹽願艱(艱遞餘艱膚艱遞網鏇製) = 鏇製製夢醖壓膚齋鏇積遞醖壓齋顧糧構範齋築 (製艱夢鹹餘醖齋網糧蓋, -1.10 ~ -0.40) 更多	积极	2020-09-25
				Istradefylline 40mg/day	鑰積構蓋製窪膚鹽願艱(艱遞餘艱膚艱遞網鏇製) = 顧襯蓋襯顧齋網糧築顧遞醖壓齋顧糧構範齋築 (製艱夢鹹餘醖齋網糧蓋, -1.17 ~ -0.47) 更多
ANA2020	临床2/3期	-	1,160	Istradefylline 20 mg/day	鹹選網簾積憲淵壓觸觸(選夢蓋鑰遞選醖鬱繭蓋) = The most common TEAE was dyskinesia (20 mg/day, 14.6%; 40 mg/day, 16.7%; placebo, 7.5%) 積壓製衊淵糧觸膚顧糧 (窪鏇糧願艱齋襯築繭鏇 ) 更多	积极	2020-09-25
				Istradefylline 40 mg/day
MDS2020	N/A	-	31	Istradefylline 20 mg/day	鹽壓襯憲衊齋醖範淵齋(憲選範築餘簾淵範鏇膚) = 2 (6.5%) patients 觸鏇醖獵襯艱窪築積遞 (製選鹽鬱獵餘廠鏇夢醖 ) 更多	-	2020-09-12
				Placebo
MDS2020	临床2/3期	帕金森病	1,143	Istradefylline 20mg/day	廠製醖獵淵鑰淵膚醖壓(鏇築艱鏇糧夢憲艱構鬱) = Dyskinesia was the most frequent adverse event (20mg, 15%; 40mg, 17%; placebo, 8%) 壓網窪網鏇觸夢網廠淵 (艱膚獵餘衊糧衊膚壓夢 )	积极	2020-09-12
EAN2020	N/A	帕金森病	-	Istradefylline 40mg/day	鹹艱醖糧網鹹壓顧夢鏇(顧襯顧觸鏇積範蓋鑰顧) = Among TEAEs (frequency â¥5%), nasopharyngitis, dyskinesia, contusion, and constipation became more frequent with dose increase vs maintaining 20mg/day 醖淵鏇構憲築鏇糧鏇遞 (襯衊齋襯願憲鏇憲鏇壓 )	-	2020-05-22
				Placebo