WO2021052153A1 - 环磷酸腺苷、其衍生物或其前体药物在制备预防和/或治疗抑郁症药物中的用途 - Google Patents

环磷酸腺苷、其衍生物或其前体药物在制备预防和/或治疗抑郁症药物中的用途 Download PDF

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WO2021052153A1
WO2021052153A1 PCT/CN2020/112418 CN2020112418W WO2021052153A1 WO 2021052153 A1 WO2021052153 A1 WO 2021052153A1 CN 2020112418 W CN2020112418 W CN 2020112418W WO 2021052153 A1 WO2021052153 A1 WO 2021052153A1
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depression
camp
adenosine monophosphate
cyclic adenosine
mice
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王广基
阿基业
张悦
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中国药科大学
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid

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  • the present invention relates to the use of drugs, in particular to the use of cyclic adenosine monophosphate, its derivatives or its prodrugs in the preparation of drugs for the prevention and/or treatment of depression.
  • Depression is a complex disease involving multiple mechanisms. It is generally believed to be related to genetic, social and environmental factors, but its specific pathogenesis is still unclear. Clinical studies have shown that long-term pressure stress leads to abnormal immune regulation, especially inflammation and depression are closely related. Pro-inflammatory factors in the circulatory system of depressed patients are significantly increased; at the same time, central microglia are activated and brain inflammation Enhancement, and studies have shown that there is an association between suicidal thoughts and brain inflammation in patients with depression. Animal studies have found that simple peripheral inflammation can cause a series of depression-like behaviors, such as social avoidance, behavioral despair, lack of sugar preference, etc., and antidepressant drugs can significantly improve this phenomenon.
  • peripheral inflammation cause depression in the brain?
  • pressure stress caused increased infiltration of peripheral monocytes into brain tissue, leading to excessive activation of inflammatory signals in the brain and abnormal synaptic function.
  • double-gene editing mice such as Ccr2RFP::Cx3cr1GFP mice
  • visual imaging tools studies have found that the expression of cerebral vascular endothelial adhesion factors increases after pressure stress, recruiting a large number of monocytes to gather and release inflammatory factors , But due to the presence of the blood-brain barrier, peripheral monocytes cannot enter the brain parenchyma.
  • the object of the present invention is to provide the use of cyclic adenosine monophosphate (cAMP), its derivatives or its prodrugs in the preparation of drugs for the prevention and/or treatment of depression.
  • cAMP cyclic adenosine monophosphate
  • the present invention provides the use of cyclic adenosine monophosphate, its derivatives or its prodrugs in the preparation of drugs for the prevention and/or treatment of depression.
  • the structural formula of said cyclic adenosine monophosphate is shown in formula I:
  • the medicine is a preparation prepared from cAMP as an active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients.
  • the pharmaceutical dosage forms include tablets, capsules, patches, ointments, powders, oral liquids, suspensions, syrups, granules, dripping pills, orally disintegrating tablets or sustained-release tablets.
  • the pharmaceutical dosage form is an injection preparation.
  • the depression includes unipolar depression, bipolar depression, psychiatric depression, reactive depression, secondary depression, seasonal depression, postpartum depression or menopausal depression.
  • the prodrug is meglumine cyclic adenosine monophosphate.
  • the present invention also provides the use of cyclic adenosine monophosphate, its derivatives or its prodrugs in the prevention and/or treatment of depression.
  • the administration mode for the prevention and/or treatment of depression includes injection administration or oral administration.
  • cyclic adenosine monophosphate cyclic adenosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • Meglumine cyclic adenosine monophosphate is the meglumine salt form of cyclic adenosine monophosphate to increase the transmembrane ability of cyclic adenosine monophosphate.
  • mice meglumine cyclic adenosine monophosphate and exogenous supplementation of cAMP, the destruction of the blood-brain barrier in the nucleus accumbens brain area of mice can be reversed, and depression-like behaviors of mice can be significantly improved.
  • the present invention evaluates the antidepressant effects of cAMP given by intraperitoneal injection and intracerebral nucleus accumbens injection by establishing a chronic social frustration stress (CSDS) model for C57BL/6J mice.
  • CSDS chronic social frustration stress
  • intraperitoneal injection of cAMP can reduce the incidence of depression and sensitivity after social frustration, significantly improve the blood-brain barrier damage, and reduce the immobility time in tail suspension and forced swimming tests.
  • a single injection of cAMP into the nucleus accumbens in the brain can gradually improve the social avoidance behavior of mice within a week, and reduce the immobility time of tail suspension and the immobility time in the forced swimming test.
  • supplementing cAMP has the effect of preventing and treating depression, and it is expected to be used in the treatment of clinical depression after research.
  • Figure 1 shows the antidepressant effect of intraperitoneal injection of cAMP, in which,
  • CTRL represents the normal control group
  • CSDS represents the social frustration model group
  • CSDS+M-cAMP represents the social frustration model combined with the M-cAMP administration group, analyzed by one-wayANOVA, * ***p ⁇ 0.0001vs CTRL, ns has no significant difference;
  • CTRL represents the normal control group
  • CSDS represents the social frustration model group
  • CSDS+M-cAMP represents the social frustration model combined with the M-cAMP administration group, using one-wayANOVA analysis, *p ⁇ 0.05, **p ⁇ 0.01, * ***p ⁇ 0.0001vs CTRL, ns has no significant difference;
  • Figure 2 shows the antidepressant effect of cAMP injected into the nucleus accumbens brain area in the brain, where,
  • A A statistical graph of the social coefficient of each group of mice at different times after injection
  • CTRL represents the normal control group
  • SS represents the depression-sensitive group
  • SS+M-cAMP represents the depression-sensitive compound nucleus accumbens M-cAMP administration group
  • Example 1 Antidepressant effect of intraperitoneal injection of meglumine cyclic adenosine monophosphate
  • the chronic social frustration model uses CD-1 mice (retired mice, male, 4-6 months old, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., weighing 48 ⁇ 5g) and C57BL/6J mice (male, 7 ⁇ 8 weeks, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., weight 20 ⁇ 2g), under a standard breeding environment (free diet and drinking, alternating day and night, 12 hours each), adaptive breeding for one week.
  • CD-1 mice were screened for 3 consecutive days, and aggressive CD-1 mice were selected for modeling.
  • the CD-1 mice and C57 mice were separated by a perforated transparent plastic partition.
  • C57 mice were placed on the same side of the CD-1 mice to be challenged every day for 10 minutes, and a new one was received every day. After the CD-1 mouse challenge, the C57 mouse was placed on the opposite side, and the CD-1 mouse was continuously exposed to the visual and taste stress for the remaining 24 hours. 10 consecutive days.
  • M-cAMP meglumine cyclic adenosine monophosphate, 10 mg/kg
  • Model evaluation and grouping are as follows: After 10 days of model building, social avoidance experiment was used to detect depression sensitivity of mice. That is, in the open field, the movement trajectory of C57 mice was recorded for 150s in the absence of CD-1 mice and CD-1 mice, and the time when the C57 mice entered the social area was calculated. The ratio of the time that C57 mice enter the social area in the case of CD-1 mice and the time that C57 mice enter the social area in the absence of CD-1 mice is used as the social coefficient. If the social coefficient is less than 1, it is judged as depression In the sensitive group, if the social coefficient is greater than 1, it is judged as the depression tolerance group. The results show that intraperitoneal injection of M-cAMP to supplement cAMP in the body can reduce the incidence of depression sensitivity (A in Figure 1).
  • mice Tail suspension test and forced swimming test were used to evaluate depression-like behaviors.
  • the tail of the mouse (about 2.5 cm from the tip of the tail) was attached to the bracket with tape, and the head of the mouse was about 30 cm from the ground.
  • a video recording of the mouse's activity was started for 6 minutes.
  • Two experimenters performed the calculation of the immobility time within the next 4 minutes in a single-blind situation.
  • the results show that intraperitoneal injection of M-cAMP to supplement cAMP in vivo can significantly reduce the immobility time of C57 mice in the tail suspension experiment (Figure 1 B).
  • Example 2 The antidepressant effect of intracerebral nucleus accumbens injection of meglumine cyclic adenosine monophosphate
  • mice were screened according to the social coefficient and randomly divided into a normal saline group and an intracerebral nucleus accumbens brain area injection M-cAMP group. After the mouse is anesthetized, it is carefully and correctly fixed on the mouse stereotaxic instrument. After the head skin is disinfected, the skull is carefully exposed. The previous bregma is the zero point location. According to the stereotactic coordinates of the mouse brain (front 1.6mm, side 1.4mm, depth 4.4mm), respectively, to the bilateral nucleus accumbens brain area Inject 0.5 ⁇ L of M-cAMP or physiological saline at 0.1 ⁇ L/min.
  • mice After the injection, stay in place for 10 minutes and then slowly remove the microsyringe to prevent liquid from overflowing. Seal the skull with an appropriate amount of bone wax, suture the skin of the head, and observe the feeding. The social avoidance behavior of the mice was evaluated 1, 4, and 7 days after the administration. The tail suspension test and the forced swimming test were used to evaluate the depression-like behavior of the mice on the 8th day and the 9th day, respectively.

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Abstract

本发明公开了环磷酸腺苷(cAMP)、其衍生物或其前体药物在制备预防和/或治疗抑郁症药物中的用途,利用建立的社交挫败应激导致的抑郁小鼠模型,在造模的同时腹腔注射给予cAMP或造模后直接向抑郁小鼠伏隔核脑区定位注射cAMP,可显著改善小鼠的抑郁样行为。本发明公开了cAMP对抑郁症的防治作用,为临床预防和治疗抑郁症提供了一个全新机制的候选药物。

Description

环磷酸腺苷、其衍生物或其前体药物在制备预防和/或治疗抑郁症药物中的用途
本申请要求于2019年09月17日提交中国专利局、申请号为201910879011.4、发明名称为“环磷酸腺苷、其衍生物或其前体药物在制备治疗抑郁症药物中的用途”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物用途,特别涉及环磷酸腺苷、其衍生物或其前体药物在制备预防和/或治疗抑郁症药物中的用途。
背景技术
全球约有3.5亿人患有抑郁症,每年造成80万人自杀。2017年开始,抑郁症已超越癌症和心脏病,成为致残的头号杀手。然而现有的一线药物——单胺再摄取抑制剂对至少1/3抑郁患者完全无效,且最终导致一半以上的患者复发,甚至带来致患者自杀的副作用。因此,开发真正有效的抗抑郁药物是临床上亟待解决的问题。
抑郁症是一个涉及多机制的复杂病症,一般认为与遗传、社会和环境因素有关,但其具体发病机制尚不明确。临床研究表明,长期压力应激导致免疫调节异常,特别是炎症和抑郁症的发生密切相关,抑郁患者循环系统中促炎性因子明显升高;同时,中枢小胶质细胞被激活,脑部炎症增强,且有研究表明抑郁症患者的自杀念头与大脑炎症之间存在关联。动物研究发现,单纯的外周炎症即可引起一系列抑郁样行为,如社交回避、行为绝望、糖水偏好缺失等,并且抗抑郁药物对此现象有显著的改善作用。
那么,外周的炎症是如何导致脑内的抑郁症呢?此前认为压力应激引起外周单核细胞向脑组织浸润增强,导致脑内炎症信号过度激活和突触功能异常。然而,随着双基因编辑小鼠(如Ccr2RFP::Cx3cr1GFP小鼠)和可视化成像工具等的应用,研究发现压力应激后脑血管内皮粘附因子表达增加,招募大量单核细胞集聚并释放炎症因子,但由于血脑屏障的存在,外周单核细胞并不能进入脑实质。最新的研究表明,压力应激导致伏隔核脑区的紧密连接蛋白Cldn5(血脑屏障关键组成成分)显著降低,外周单核 细胞虽不能进入脑实质,但促炎因子IL-6(~21.45kDa)可大量进入脑实质,且这一现象在抑郁症的其他关键脑区海马区和前额皮质中并未出现,说明仅在伏隔核脑区的血脑屏障发生一定程度的破坏。然而为何会出现伏隔核脑区特异性的病理改变及发生这种变化的分子机制还不清楚。
发明内容
发明目的:本发明目的是提供环磷酸腺苷(cAMP)、其衍生物或其前体药物在制备预防和/或治疗抑郁症药物中的用途。
技术方案:本发明提供环磷酸腺苷、其衍生物或其前体药物在制备预防和/或治疗抑郁症药物中的用途,所述环磷酸腺苷的结构式如式I所示:
Figure PCTCN2020112418-appb-000001
进一步地,所述药物是以cAMP为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
进一步地,所述药物剂型包括片剂、胶囊、贴剂、膏剂、散剂、口服液、混悬剂、糖浆、颗粒、滴丸、口崩片或缓释片。
进一步地,所述药物剂型为注射制剂。
进一步地,所述抑郁症包括单相抑郁症、双相抑郁症、精神性抑郁症、反应性抑郁症、继发性抑郁症、季节性抑郁症、产后抑郁症或更年期抑郁症。
进一步地,所述前体药物为环磷腺苷葡胺。
本发明还提供了环磷酸腺苷、其衍生物或其前体药物在预防和/或治疗抑郁症中的用途。
进一步地,所述预防和/或治疗抑郁症的给药方式包括注射给药或口服给药。
运用代谢组学方法对抑郁症关键脑区进行细致研究发现,相较于海马区和前额皮质,伏隔核脑区的环磷酸腺苷(cAMP)水平在抑郁敏感组中明显下降,且与抑郁严重程度显著相关。环磷腺苷葡胺,是环磷酸腺苷的葡甲胺盐形式,以增加环磷酸腺苷的跨膜能力。通过给予小鼠环磷腺苷葡胺,外源性补充cAMP,可逆转小鼠伏隔核脑区的血脑屏障破坏,并显著改善小鼠抑郁样行为。
有益效果:本发明通过对C57BL/6J小鼠建立慢性社交挫败应激(CSDS)模型,评价了腹腔注射和脑内伏隔核注射给予cAMP的抗抑郁作用。研究发现腹腔注射给予cAMP能降低社交挫败造模后抑郁敏感的发生比例,显著改善血脑屏障损伤,降低悬尾不动时间和强迫游泳试验中的不动时间。脑内伏隔核单次注射给予cAMP可在一周内逐渐改善小鼠社交回避行为,并降低悬尾不动时间和强迫游泳试验中的不动时间。提示补充cAMP具有防治抑郁症的作用,有望经过研究用于临床抑郁症的治疗。
附图说明
图1为腹腔注射cAMP的抗抑郁作用,其中,
A:各组小鼠社交系数统计图:其中,CTRL表示正常对照组,CSDS表示社交挫败模型组,CSDS+M-cAMP表示社交挫败模型复合M-cAMP给药组,采用one-wayANOVA分析,****p<0.0001vs CTRL,n.s.无显著差异;
B:各组小鼠悬尾不动时间统计图;
C:各组小鼠强迫游泳不动时间统计图;
D:各组小鼠伏隔核脑区脑实质中伊文斯兰荧光强度统计图,
其中,CTRL表示正常对照组,CSDS表示社交挫败模型组,CSDS+M-cAMP表示社交挫败模型复合M-cAMP给药组,采用one-wayANOVA分析,*p<0.05,**p<0.01,****p<0.0001vs CTRL,n.s.无显著差异;
图2为脑内伏隔核脑区注射cAMP的抗抑郁作用,其中,
A:注射后不同时间各组小鼠社交系数统计图;
B:各组小鼠悬尾不动时间统计图;
C:各组小鼠强迫游泳不动时间统计图,
其中,CTRL表示正常对照组,SS表示抑郁敏感组,SS+M-cAMP表示抑郁敏感复合伏隔核M-cAMP给药组,采用one-wayANOVA分析,*p<0.05,**p<0.01,***p<0.001,n.s.无显著差异。
具体实施方式
实施例1:腹腔注射环磷腺苷葡胺的抗抑郁作用
慢性社交挫败模型采用CD-1小鼠(退役鼠,雄性,4~6个月,购自北京维通利华实验动物技术有限公司,体重48±5g)和C57BL/6J小鼠(雄性,7~8周,购自北京维通利华实验动物技术有限公司,体重20±2g),在标准饲养环境下(自由饮食与饮水,昼夜交替,各12小时),适应性饲养一周。
动物模型的建立:对CD-1小鼠连续筛选3天,筛选出有攻击性的CD-1小鼠用于造模。将CD-1小鼠和C57小鼠用带孔透明塑料隔板隔开,每天将C57小鼠放置在CD-1小鼠同侧使其接受攻击,每次10分钟,每天接受一只新的CD-1小鼠的攻击,结束后将C57小鼠放在对侧,在剩余24小时内继续在视觉和味觉上接受CD-1小鼠的应激。连续10天。
给药方式:在社交挫败模型过程中,每天造模前2h腹腔注射给予M-cAMP(环磷腺苷葡胺,10mg/kg),补充体内cAMP,对照组给予等体积生理盐水。
模型评价和分组如下:10天造模结束后使用社交回避实验检测小鼠抑郁敏感性。即在旷场中,分别在无CD-1小鼠和有CD-1小鼠的情况下记录C57小鼠的行动轨迹150s,以C57小鼠进入社交区域的时间来计算。有CD-1小鼠的情况下C57小鼠进入社交区域的时间与无CD-1小鼠的情况下C57小鼠进入社交区域的时间的比值作为社交系数,若社交系数小于1则判定为抑郁敏感组,社交系数大于1则判定为抑郁耐受组。结果表明,腹腔注射给予M-cAMP,补充体内cAMP,可降低抑郁敏感发生比例(图1中的A)。
对小鼠抑郁样行为的影响:采用悬尾实验和强迫游泳实验评价抑郁样行为。在悬尾实验中,将小鼠尾部(离尾尖约2.5cm处)用胶带粘于支架,使小鼠头部离地面约30cm,同时开始录像记录小鼠的活动状态,持续6 分钟。由两个实验人员在单盲情况下进行后4分钟内不动时间的计算。结果表明,腹腔注射给予M-cAMP,补充体内cAMP,可显著降低C57小鼠在悬尾实验中的不动时间(图1中的B)。在强迫游泳实验中,将C57小鼠小心放入5L玻璃烧杯(杯中水深约20cm)中,水温24±1℃。录像记录小鼠的活动状态,实验过程持续6分钟。实验结束后由2个实验人员在单盲情况下计算后4分钟的不动时间。其不动状态的评判标准为小鼠停止挣扎或显漂浮状态,四肢不动状态或仅有很小的四肢运动使头部悬浮于水面。不同小鼠间将烧杯内换入新水。结果表明,腹腔注射给予cAMP可显著降低C57小鼠在强迫游泳实验中的不动时间(图1中的C)。
对伏隔核脑区血脑屏障通透性的影响:对C57小鼠尾静脉注射2%的伊文斯兰(0.12mL/20g),循环16小时后,心脏灌流,取伏隔核匀浆提取后检测伊文斯兰的荧光强度(Ex=633nm;Em=670nm)。结果表明,腹腔注射给予M-cAMP,补充体内cAMP,可显著抑制伊文斯兰向伏隔核脑区的脑实质中渗漏(图1中的D)。
实施例2:脑内伏隔核注射环磷腺苷葡胺的抗抑郁作用
实验动物及模型的建立和分组同实施例1,造模结束后根据社交系数筛选抑郁敏感小鼠随机分为给生理盐水组和脑内伏隔核脑区注射M-cAMP组。小鼠麻醉后小心并正确固定于小鼠立体定位仪上。头部皮肤消毒后,小心暴露出颅骨,以前卤点(bregma)为零点定位,按小鼠脑立体定位坐标(前1.6mm,侧1.4mm,深4.4mm)分别向双侧伏隔核脑区注射0.5μL M-cAMP或生理盐水,0.1μL/min,注射结束后在原位停留10min后将微量注射器缓慢移出,防止有液体溢出。用适量骨蜡封闭颅骨,缝合头部皮肤,观察饲养。于给药后的1,4,7天评价小鼠社交回避行为,在第8天和第9天分别采用悬尾实验和强迫游泳试验评价小鼠抑郁样行为。
结果表明,伏隔核脑区注射M-cAMP,补充体内cAMP,可在一周内逐渐改善小鼠的社交回避行为,小鼠给予M-cAMP后后社交系数与生理盐水组有显著差异(图2中的A)。在悬尾实验中,伏隔核脑区注射M-cAMP后可显著降低小鼠不动时间(图2中的B),在强迫游泳实验中给予M-cAMP后显著降低小鼠的不动时间(图2中的C)。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。

Claims (8)

  1. 环磷酸腺苷、其衍生物或其前体药物在制备预防和/或治疗抑郁症药物中的用途,所述环磷酸腺苷的结构式如式I所示:
    Figure PCTCN2020112418-appb-100001
  2. 根据权利要求1所述的用途,其特征在于:所述药物是以cAMP、cAMP衍生物或cAMP前体药物为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
  3. 根据权利要求2所述的用途,其特征在于:所述药物的剂型包括片剂、胶囊、贴剂、膏剂、散剂、口服液、混悬剂、糖浆、颗粒、滴丸、口崩片或缓释片。
  4. 根据权利要求2所述的用途,其特征在于:所述药物的剂型为注射制剂。
  5. 根据权利要求1所述的用途,其特征在于:所述抑郁症包括单相抑郁症、双相抑郁症、精神性抑郁症、反应性抑郁症、继发性抑郁症、季节性抑郁症、产后抑郁症或更年期抑郁症。
  6. 根据权利要求1所述的用途,其特征在于:所述前体药物为环磷腺苷葡胺。
  7. 环磷酸腺苷、其衍生物或其前体药物在预防和/或治疗抑郁症中的用途。
  8. 根据权利要求7所述的用途,其特征在于,所述预防和/或治疗抑郁症的给药方式包括注射给药或口服给药。
PCT/CN2020/112418 2019-09-17 2020-08-31 环磷酸腺苷、其衍生物或其前体药物在制备预防和/或治疗抑郁症药物中的用途 WO2021052153A1 (zh)

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