CN113164501A - Igf-2受体的激动剂配体治疗安格曼综合征和自闭症的用途 - Google Patents
Igf-2受体的激动剂配体治疗安格曼综合征和自闭症的用途 Download PDFInfo
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Abstract
本发明提供了用于治疗神经发育障碍例如安格曼综合征和自闭症的方法,包括向个体给予包含IGF‑2受体的激动剂配体的组合物。IGF‑2受体的激动剂配体可以是IGF‑2或6‑磷酸甘露糖或其衍生物。还公开了包含6‑磷酸甘露糖衍生物的组合物。
Description
关于联邦资助研究或开发的声明
本发明是基于美国国立卫生研究院(National Institutes of Health)授予的授权号MH065635和MH074736的政府支持下完成的。政府对本发明享有某些权利。
相关申请的交叉引用
本申请要求于2018年8月10日提交的美国临时专利申请62/717,372的优先权,其公开内容通过引用并入本文。
背景技术
安格曼综合征(Angelman Syndrome,AS)是一种神经系统疾病,大约每20,000名新生儿中就有一例。AS的特征或症状包括发育延迟,言语缺失,行走和平衡障碍以及癫痫发作。癫痫发作可能有多种类型,并且通常对许多处方药无响应。AS也与认知受损有关。安格曼综合征的某些特征与自闭症谱系障碍重叠,尽管这两种病症都有其独特的特征。目前,尚无用于AS或自闭症的已知疗法,也没有改善与这些适应症相关的各种症状的可行治疗方法。
发明内容
本公开提供了用于治疗神经发育障碍例如安格曼综合征(AS)和自闭症的方法。该方法包括向需要治疗的对象给予包含对胰岛素样生长因子2(IGF-2或IGF-II)受体具有特异性的IGF-2受体的激动剂配体的组合物。例如,组合物可以包含治疗有效量的IGF-2和/或6-磷酸甘露糖(M6P)或其衍生物,或基本上由其组成。可以使用与IGF-2受体特异性结合的M6P或IGF-2的任何衍生物。M6P的衍生物包括但不限于其中碳1被烷氧基(例如,甲氧基,乙氧基等)或炔烃官能化并且碳6被膦酸酯,乙酯,丙二酸甲酯,膦酸,羧酸盐或丙二酸酯官能化的衍生物。
附图说明
图1:IGF-2逆转了在AS小鼠模型中观察到的大多数行为缺陷。实验时间表显示在图表上方。在所有实验中,在训练或测试前20分钟,小鼠均接受皮下注射载剂或IGF-2(↑)。所有数据均表示为平均值±s.e.m.。N=8-12/组。双向方差分析(ANOVA),然后进行Bonferroni事后检验。*P<0.05,**P<0.01,***P<0.001。(A)在注射载剂或IGF-2的作为对照的正常小鼠(野生型,WT)以及Ube3a-/+小鼠(AS的小鼠模型,也称为小鼠)的训练(测试)24小时后进行测试时,在情境恐惧条件训练中,冲击递送之前(Pre-US)或冲击递送之后(Post-US)僵直时间所占的百分比。(B)训练后4h和24h进行测试,训练前20分钟注射载剂或IGF-2的WT和Ube3a-/+小鼠的新物体识别期间,与熟悉的物体相比,对新物体的探索偏好百分比。(C)在测试(Test)之前,注射载剂或IGF-2的WT和Ube3a-/+小鼠的Y型迷宫中的正确交替百分比(正确%)。(D)在测试前20分钟,然后在3天和7天后再次测试,注射载剂或IGF-2的WT和Ube3a-/+小鼠从旋转杆上跌落的潜伏期。(E)在测试前20分钟,注射载剂物或IGF-2的WT和Ube3a-/+小鼠埋藏珠粒所花费的时间。(F)在测试前20分钟注射载剂或IGF-2后,WT和Ube3a-/+小鼠在开放区域中心所花费的时间。每组从左到右的柱形条分别是:WT载剂,WTIGF-2,Ube3a-/+载剂和Ube3a-/+IGF-2。
图2:与WT同窝仔相比,AS小鼠背侧海马(dHC)的生化标志物特征。从未受过训练(称为原初)的8周龄Ube3a-/+小鼠和WT同窝仔中收集的整个海马蛋白提取物的蛋白质印迹分析。针对在相同印迹上检测到的β-肌动蛋白(用作上样对照),将每个相对值标准化。所有数据均表示为平均值±s.e.m.,并标准化为WT原初小鼠的平均值。N=4/组。独立的t检验。*P<0.05,**P<0.01。
图3:与WT同窝仔相比,AS小鼠内侧前额叶皮层(mPFC)的生化标志物表征。从原初(未受过训练)的8周龄Ube3a-/+小鼠和WT同窝仔的mPFC收集的整个海马蛋白提取物的蛋白质印迹分析。针对在相同印迹上检测到的β-肌动蛋白(用作上样对照),将每个相对值标准化。所有数据均表示为平均值±s.e.m.,并标准化为WT原初小鼠的平均值。N=4/组。独立的t检验。*P<0.05,**P<0.01。
图4:正常(野生型,WT)小鼠中IGF2R.L1(L1)(M6P)对nOR影响的剂量反应曲线。实验时间表显示在图表上方。所有数据均表示为平均值±s.e.m.。N=4/组。单向方差分析(ANOVA),然后进行Bonferroni事后检验。*P<0.05,**P<0.01。在进行nOR训练前20分钟,WT小鼠经皮下注射不同剂量的IGF2R.L1(L1)。图表显示,在训练后4小时和24小时进行的测试中,与熟悉的物体相比,对新物体的探索偏好百分比。
图5:M6P逆转AS小鼠的认知和运动缺陷。实验时间表显示在图表上方。在所有实验中,在训练或测试前20分钟,小鼠接受皮下注射载剂或850μg/Kg的M6P(IGF-2R.L1或L1)(↑)。(A)训练后4h和24h进行测试,训练前20分钟注射载剂或IGF-2R.L1的WT(对照)和Ube3a-/+(AS)小鼠的nOR范例期间,与熟悉的物体相比,对新物体的探索偏好百分比。N=4/组。数据表示为平均值±s.e.m.。双向方差分析(ANOVA),然后进行Bonferroni事后检验。*P<0.05,**P<0.01,***P<0.001。(B)在测试(Test)之前,注射载剂或M6P的WT和AS小鼠在Y型迷宫中的正确交替百分比(正确%)。数据表示平均值(±s.e.m.)。(C)在测试前20分钟,注射载剂或IGF-2R.L1的WT和AS小鼠的后肢扣爪评分。后肢扣爪评分的测量和表示如下:如果后肢始终向外张开,远离腹部,则其得分为0。如果一个后肢朝腹部缩回的时间超过悬吊时间的50%,则将其记为1分。如果两个后肢部分地向腹部缩回的时间超过悬吊时间的50%,则得分为2。如果两个后肢完全缩回并触摸腹部的时间超过悬吊时间的50%,则得分为3。数据以得分表示。B和C:N=8-14/组。双向方差分析(ANOVA),然后进行Tukey事后检验。*P<0.05,**P<0.01,***P<0.001。
图6:PnM6P逆转AS小鼠的记忆力和运动缺陷。实验时间表显示在图表上方。在所有实验中,在训练或测试前20分钟,小鼠接受皮下注射载剂或850μg/Kg的膦酸酯-M6P(PnM6P),称为IGF-2R.L2(或L2)(↑)。(A)训练后4h、24h和5天(5d)进行测试,训练前20分钟注射载剂或L2的WT(对照)和Ube3a-/+(AS)小鼠的nOR范例期间,与熟悉的物体相比,对新物体的探索偏好百分比。N=4/组。数据表示为%平均(±s.e.m.)。(B)在测试前20分钟(测试1),并且在两天后再次测试(测试2),注射载剂或L2的WT(对照)和AS小鼠从旋转杆上跌落的潜伏期。数据以秒为单位表示。(C)在测试前,注射载剂或L2的WT和AS小鼠的后肢扣爪评分。B和C:N=3-4/组。数据以后肢得分表示。双向方差分析(ANOVA),然后进行Bonferroni事后检验。*P<0.05,**P<0.01,***P<0.001。
具体实施方式
本公开提供了用于治疗神经变性疾病,例如安格曼综合征(AS)和自闭症谱系障碍(ASD)的组合物和方法。该组合物和方法涉及IGF-2受体配体。
如本文所用,术语“治疗”是指与正在治疗的特定病症例如安格曼综合征的存在相关的一种或多种症状或特征的减少或延迟。治疗并不意味着完全治愈。例如,本公开中对AS的治疗是指减轻或抑制与AS相关的一种或多种症状。
本文所用的术语“治疗有效量”是足以以单次或多次剂量达到预期治疗目的的量。例如,治疗AS的有效量是足以缓解AS的一种或多种症状的量。通过治疗缓解的症状可能包括:发育标志,言语,智力,运动(行走和平衡)社交行为和癫痫症中的一项或多项。期望或需要的确切量将根据给药方式,患者的具体情况等而变化。受益于本公开,本领域普通技术人员(例如临床医生)可以确定适当的有效量。
在本公开中提供值的范围的情况下,应理解,除非文中另有明确说明,各中间值到该范围上下限之间的下限单位的十分之一,以及在所述范围内的任何其他中间值均包括在本发明范围内。这些较小范围的上限和下限可以独立地包括在本公开内容所涵盖的较小范围中。
如本公开中所使用的,除非文本中另有明确说明,单数形式包括复数形式,反之亦然。
本公开描述了IGF-2受体的激动剂配体对神经发育障碍如安格曼综合征(AS)的作用。在一个方面,本公开提供了一种通过向需要治疗的对象给予包含一种或多种IGF-2受体的激动剂配体的组合物来治疗神经发育障碍例如安格曼综合征或自闭症的方法。在本公开中,术语“个体”和“对象”可以互换使用。对象可以是任何动物对象,例如人,实验动物或任何其他动物。在一个实施方案中,IGF-2受体的激动剂配体对IGF-2受体是特异性的,而不是IGF-2相关的其他受体(例如IGF-1或胰岛素受体)的配体。例如,激动剂配体(在本文中也称为试剂)可以是修饰的甘露糖(例如,M6P),修饰的M6P(例如,M6P的衍生物),IGF-2,或修饰的IGF-2或与IGF-2受体结合并激活其细胞反应的任何化学物质或肽。M6P的膦酸酯和磺酸酯衍生物在本领域中是已知的(授予Ferguson的美国专利6,140,307,其描述通过引用并入本文)。此外,还可以使用具有氨基酸取代(例如人Leu 27)的IGF-2(Armitaj等人,Neuroscience,2010年10月27日;170(3):722-30)。
对M6P的修饰(在本文中也称为M6P衍生物)包括对甘露糖的碳1和/或碳6的修饰。衍生物的实例包括其中碳1被烷氧基(例如,甲氧基,乙氧基等)或炔烃官能化并且碳6被膦酸酯,乙酯,丙二酸甲酯,膦酸,羧酸盐或丙二酸酯官能化的例子。在各种实例中,碳1被烷氧基(例如甲氧基)官能化并且碳6被以下基团官能化:膦酸酯(在本文中称为L2),乙酯(在本文中称为L3),丙二酸甲酯(在本文中称为L4),膦酸(在本文中称为L5),羧酸盐(例如,羧酸的钠盐)(在本文中称为L6),或丙二酸酯(在本文中称为L7),以及碳1被炔烃官能化并且碳6被以下基团官能化:膦酸(称为L8)或膦酸酯(称为L9)。上面列出的M6P及其衍生物的结构如下所示:
激动剂配体可以以类似于IGF-2或M6P的亲和力结合至IGF-2受体。已知IGF-2以约40-60nM的Kd结合其受体(Williams等人,Science,2012年11月30日,338(6111):1209-1213),M6P以约1nM或大约1μM的亲和力结合IGF-2受体(取决于它与两个已知位点结合的亲和力)(Olson等人,J.Biol.,Chem.2004年8月6日;279(32):34000-9.Epub 2004年5月28日)。
通常,用于本公开的IGF-2受体配体的治疗剂量为约1-10,000μg/kg体重。IGF-2的用量可以为约1-500μg/kg体重及其间的所有值和范围。例如,IGF-2的用量可以为1-500μg/kg,1-100μg/kg,1-50μg/kg,10-500μg/kg,10-100μg/kg,10-50μg/kg体重。在一个实施方案中,可以皮下给予10-45μg/kg的IGF-2。在特定的实施方案中,IGF-2的使用浓度可以为10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、200、300、400和500μg/kg体重。
M6P和M6P衍生物的用量可以为约1-2,000μg/kg体重及其间的所有值和范围。例如,M6P的用量可以为1-2,000μg/kg,1-1,500μg/kg,1-1,000μg/kg,1-500μg/kg,1-100μg/kg,10-2,000μg/kg,10-1,500μg/kg,10-1,000μg/kg,10-500μg/kg,10-100μg/kg,50-2,000μg/kg,50-1,500μg/kg,50-1,000μg/kg,50-500μg/kg和50-100μg/kg体重,以及上述范围内的所有值。在一个实施方案中,M6P或衍生物可以以850μg/kg皮下给予。在一个实施方案中,M6P或衍生物的用量可以为100-1,000μg/kg。在特定的实施方案中,M6P的用量可以为50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1,250、1,500、1,750和2,000μg/kg体重。此外,基于本文提供的关于动物的数据,本领域技术人员可以获得M6P和IGF-2的相关人剂量。这种转化的指导是本领域已知的(参见,例如,Nair等人,J.Basic Clin.Pharma.,v 7(2),2016年3月-2016年5月;27-31,通过引用并入本文)。
M6P可以以游离磷酸或其药学上可接受的单盐或二盐的形式存在,例如钠盐,钙盐,镁盐或钡盐。它也可以以可以在体内从中释放M6P的含M6P的化合物的形式提供,也可以以可以在体内从中产生M6P的前体的形式提供。M6P衍生物(在适用的情况下(例如,L3,L7和L8))也可以以游离酸或其盐(例如,其单钠盐或二钠盐)的形式存在。
一方面,本公开提供了一种用于治疗神经发育障碍的方法,所述神经发育障碍的特征在于言语和运动的发育延迟,智力障碍,大约在蹒跚学步的年龄癫痫发作,以及异常行为和/或重复行为,例如拍手。这种神经发育障碍的例子包括安格曼综合征和自闭症谱系障碍。
安格曼综合征是一种神经性疾病,其特征是智力和发育延迟。AS是由E3泛素连接酶Ube3A突变引起的。安格曼综合征的症状可包括:发育延迟,例如在6到12个月内没有爬行或咿呀学语,智力发育减弱,无言语或极少说话,共济失调(无法适当地移动、行走或平衡),僵硬或生涩的运动(例如拍手),活动过度,胳膊和腿发抖,经常微笑和大笑,一阵不适当的笑声,牙齿间距大,快乐、易激动的性格,癫痫发作,伴有减慢和锯齿状的波和尖峰的脑电图异常,通常2至3岁开始并且可能伴有肌阵挛和非典型性缺失的癫痫发作,伴有眼偏斜和呕吐的部分癫痫发作,头背部明显平直的小头症(微短头症(microbrachyoephaly)),斜视(斜视症(strabismus)),舌头受力和吮吸/吞咽障碍,舌头突出,过度咀嚼/嘴巴行为,下肢活动过度深层肌腱反射,伴有内扭转或外翻位脚踝的步态宽阔,对热的敏感性增加,双臂高举地行走,迷恋水或皱纹的物品(例如一些纸张或塑料),年龄较大的儿童肥胖,便秘,下颌突出,头发、皮肤和眼睛的色素沉着(色素过度沉着症(hypopigmentation)),频繁流口水,凸颌(prognathia),婴儿期进食困难和/或截断性肌张力低下,和/或脊柱侧弯。症状通常在出生时并不明显,通常首先表现为发育延迟,例如在6-12月龄之间无法爬行或咿呀学语以及在12月龄之前头部生长延迟。患有安格曼综合征的个体可能还存在睡眠障碍,包括难以启动和维持睡眠,延长的睡眠潜伏期,入睡后长时间的清醒,大量的夜间醒来以及减少的总睡眠时间,遗尿症,磨牙症,睡眠恐惧,梦游症,夜间运动亢进和打鼾。
可以临床上测量AS症状的严重性(Williams等,美国医学遗传学杂志(AmericanJournal of Medical Genetics)2005 140A;413-8,通过引用并入本文),并且还可以对不同症状的严重性进行定量(Lossie等人,医学遗传学杂志(Journal of Medical Genetics)2001,38;834-845,通过引用并入本文;Ohtsuka等人,Brain and Development 2005,27;95-100,通过引用并入本文)。这可能包括语言能力的程度,独立活动的程度,癫痫发作的频率和严重程度,理解语言的能力,运动技能的获得,成长参数。可以对疑似安格曼综合征患者使用对22种不同标准的严重程度进行量化的筛查程序(Lossie等,医学遗传学杂志2001,38)。AS严重程度的其他度量包括心理测量方法,以区分与心理运动发育成就,视觉技能,基于非语言事件的社交互动,表达语言能力,接受语言能力和言语受损有关的发育延迟程度。可以测量步态和运动缺陷的程度,以及注意能力和脑电图异常的程度(Williams等人,美国医学遗传学杂志2005 140A;413-8)。在适当的年龄,也可以使用智力测验,例如考夫曼简要智力测验2(KBIT-2;Kaufman&Kaufman,Circle Pines,MN:American Guidance Services;2004,通过引用并入本文)。上述特征中的一种或多种可以用于评估用本发明的组合物治疗的有效性。
在一个实施方案中,评估治疗效果的评估方案包括:神经学和神经视觉检查以及运动能力评估(例如大运动功能测量量表(Gross Motor Function Measure Scale)),认知评估(例如格里菲思精神发育量表(Griffiths Mental Development Scale)和Uzgiris-Hunt量表以及空间工作记忆测试);适应性评估(例如Vineland适应性行为量表);沟通评估(例如MacArthur-Bates沟通发展清单和儿童语言表达的视频记录),行为方面(例如IPDDAG量表)和神经视觉方面的评估,参见Micheletti等人所述(Ital J Pediatr.2016;42(1):91),通过引用并入本文。
自闭症谱系障碍(ASD)的特征是复杂的发育障碍,会干扰大脑的正常发育,特别是影响社交互动和沟通技巧。它通常出现在生命的头三年。自闭症个体在语言和非语言交流,社交互动以及休闲或娱乐活动方面存在困难。社会交往中的障碍包括难以发起和维持交往,识别和体验情绪的能力受损,以及难以处理和欣赏他人情绪的能力。自闭症个体之间的沟通缺陷有所不同,一些自闭症个体的交流形式严重受限,而一些个体具有明显的语言技能。重复和刻板的行为包括复杂的仪式,难以适应变化以及不寻常的动作,例如拍手。对自闭症的诊断可能有用的一些特征性行为包括:口语的缺乏或延迟,语言或运动习惯的反复使用(拍手或旋转物体),很少或没有眼神接触,对某些物体的持续固定,以及对社交缺乏兴趣。
一旦做出诊断,即可开始给予IGF-2,IGF-2修饰物(例如IGF-2类似物),M6P或其衍生物。可以通过监测AS或ASD的一种或多种症状来确定治疗的频率和持续时间。可以根据需要持续进行治疗,包括几天,几个月或几年。即使症状消失或无法测量,也可以继续治疗。
可以通过与任何合适的药学上可接受的载体、赋形剂和/或稳定剂组合,以药物组合物的形式提供本发明的试剂。药学上可接受的载体、赋形剂和稳定剂的实例可参见《雷明顿:科学与药学实践》(Remington:The Science and Practice of Pharmacy)(2005)第21版,宾夕法尼亚州费城,Lippincott Williams&Wilkins。例如,M6P可用作悬浮液或溶液。合适的载体包括在使用的剂量和浓度下对接受者无毒的赋形剂或稳定剂,包括:缓冲剂,例如乙酸盐,Tris,磷酸盐,柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂,例如十八烷基二甲基苄基氯化铵;氯化六甲铵;苯扎氯铵,苄索氯铵;苯酚,丁醇或苯甲醇;对羟基苯甲酸烷基酯,例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚;氨基酸,例如甘氨酸,谷氨酰胺,天冬酰胺,组氨酸,精氨酸或赖氨酸;单糖,二糖和其他碳水化合物,包括葡萄糖,甘露糖或糊精;螯合剂,如EDTA;渗透压调节剂(tonicifier),例如海藻糖和氯化钠;糖,例如蔗糖,甘露醇,海藻糖或山梨糖醇;表面活性剂,例如聚山梨酯;成盐的抗衡离子,例如钠;和/或非离子表面活性剂,例如吐温或聚乙二醇(PEG)。药物组合物可以包含0.01-99重量/体积%或重量/重量%的活性物质(例如,M6P或其衍生物或IGF-2或其修饰物(例如,IGF-2类似物))。
可以使用本领域已知的任何合适的给药途径给予本发明组合物。例如,可以通过静脉内,肌内,腹膜内,脑脊髓内,皮下,关节内,滑膜内,口服,局部或吸入途径给予组合物。该组合物可以胃肠外或肠内给药。在一个实施方案中,本发明的组合物可以口服给药,例如是片剂,胶囊剂,丸剂,粉末剂,糊剂,颗粒剂,酏剂,溶液剂,混悬剂,分散剂,凝胶剂,糖浆剂或任何其他可摄取形式。M6P和/或其衍生物和/或IGF-2和/或其修饰物(例如IGF-2类似物)可以通过脂质体,微粒,微胶囊递送。组合物可以以单次给药或多次给药的形式引入,或者可以在一段时间内以连续的方式引入。例如,给药可以是预定的给药次数或每日、每周或每月给药,其可以是连续的或间歇性的,如临床需要和/或治疗上所指示的那样。
在一个实施方案中,IGF-2受体配体是唯一的活性成分。活性成分是指它是组合物中特异性结合IGF-2受体的唯一成分。IGF-2受体配体可以是IGF-2,其修饰物(例如,IGF-2类似物),或M6P或其他M6P衍生物。在一个实施方案中,M6P或其衍生物是唯一的活性成分。在一个实施方案中,M6P或其衍生物不连接(例如,不直接或通过接头共价结合)任何其他部分,并且不充当任何其他部分或试剂的载体。在一个实施方案中,M6P衍生物可以是L2,L3,L4,L5,L6,L7,L8或L9。
一方面,本公开提供了M6P衍生物和包含甘露糖衍生物的组合物。M6P的衍生物可以通过在M6P的碳1和/或碳6上进行化学反应来制备。在己糖的碳1和/或碳6上进行化学反应的各种方法是本领域已知的。M6P衍生物的实例包括但不限于:膦酸酯(L2),乙酯(L3),丙二酸甲酯(L4),膦酸(L5),羧酸盐(L6),丙二酸酯(L7),炔烃(L8),和炔烃前药(L9)。在一个实施方案中,本公开提供选自L2,L3,L4,L5,L6,L7,L8和L9的化合物。在一个实施方案中,本公开提供了包含L1,L2,L3,L4,L5,L6,L7,L8和L9中的一个或多个的组合物。
下述实施例作为说明性实施例提供,并不旨在以任何方式进行限制。
实施例1
使用的小鼠模型:通过将携带父本印迹Ube3A(泛素蛋白连接酶E3A)敲除突变的突变雄性小鼠(B6.129S7-Ube3atm1Alb/J)(购自Jackson实验室www.jax.org;库存编号#016590)与C57BL/6J雌性正常小鼠进行繁殖获得小鼠。将雌性杂合小鼠与雄性C57BL/6J小鼠进行繁殖;该杂交的后代是杂合雄性(母体传播),杂合雌性(母体传播),野生型雄性和野生型雌性。这些后代用于行为和生化研究。这些小鼠在本文中称为小鼠,其正常同窝仔称为野生型(WT)小鼠或对照小鼠。
治疗:在开始行为程序前20分钟皮下(s.c.)注射IGF-2或载剂对照溶液。
结果:
IGF-2可逆转AS小鼠中受损的记忆力和运动反应以及重复行为。
作为学习/认知反应的量度(已知会在安格曼综合征(AS)中发生变化),我们测试了不同类型的厌恶和非厌恶性记忆。我们发现AS小鼠在厌恶(关联恐惧条件;CFC)和非厌恶(新物体识别;nOR)形式的长期记忆中均显示出强大的缺陷。具体而言,在CFC范例中,对小鼠进行了训练,使其将腔室(关联环境)与厌恶性足部电击相关联。训练前20分钟注射IGF-2或载剂溶液。一天后(这是用来测量长期记忆的时间),我们将小鼠放回到同一个腔室中,测试了记忆保留,并测量了它们与恐惧相关的(僵直)行为。我们发现,注射了对照溶液(载剂)的WT同窝小鼠(对照)具有很强的记忆力,表现为很强的僵直反应,而注射载剂的AS小鼠表现出明显较少的僵直行为,表明长期记忆保留不足(图1A)。相反,用IGF-2治疗的AS小鼠表现出相似的僵直,因而具有与对照小鼠相似的记忆保留,表明IGF-2完全逆转了AS小鼠的记忆受损。
我们在非厌恶记忆nOR测试中发现了相似的结果。这项任务是一项针对识别记忆的经过验证的测试,它基于啮齿动物自发地倾向于花费比熟悉的物体更多的时间来探索新物体。在一个新的场景中,小鼠被暴露于两个相同的物体,并测量了探索每个物体所花费的时间。随后,在第一次体验后的4小时和24小时,将小鼠放回到相同的场景,但是这次将其中一个物体替换为一个新物体,并测量了探索两个物体所花费的时间。如预期的那样,在训练后4小时进行测试时,对照小鼠花费了显著更多的时间探索新物体,这表明对第一个物体的记忆。相比之下,AS小鼠没有表现出这种偏好,而是花费相同的时间探索两个物体,表明记忆受损(图1B)。IGF-2注射完全逆转了AS小鼠的记忆缺陷,如它们对新物体的明显偏好所显示。此外,尽管在训练后24小时进行测试时,对照组和AS小鼠均表现出明显的记忆保留衰退,但两组接受IGF-2治疗的小鼠均对新物体的偏好显著,表明IGF-2逆转在AS中观察到的长期记忆缺陷的能力持续存在。
为了评估探索策略和工作记忆,我们采用了三臂Y型迷宫的自发交替范例。我们发现,注射载剂的对照小鼠(WT)在三个臂之间交替进行探索,而注射载剂的AS小鼠在探索未探访的臂之前,以重复的方式在最近探访的臂之间进行了更多的交替造访(图1C)。相反,在暴露于Y型迷宫前20分钟用IGF-2处理的AS小鼠具有与对照小鼠相似的探索策略,表明IGF-2可以逆转这些小鼠中出现的重复的僵硬的行为。
AS还与明显的运动受损相关,这同样在AS小鼠中重现。通过将小鼠放在加速旋转杆上(RotaRod测试),可以可靠地评估小鼠的运动协调能力。在此测试中,我们观察到与WT对照小鼠相比,载剂处理的AS小鼠的运动能力明显不足(图1D)。但是,用IGF-2治疗的AS在RotaRod上显示出运动能力的显著改善,实际上,它们的跌落潜伏期恢复到与正常对照小鼠相似的水平。
我们还观察到,在埋珠测试(marble-burying test)中与对照WT同窝仔相比,AS小鼠表现出的行为存在显著差异。将正常小鼠放在有垫草和珠粒的空屋笼中时,通常会表现出适度的埋藏行为。与这些对照小鼠相比,AS小鼠的埋藏水平极低,埋藏花费的时间(图1E)和埋藏的珠粒量显著较少。但是,IGF-2治疗可以恢复AS小鼠的缺陷,然后显示出与正常小鼠相似的埋藏水平。
为了测量IGF-2对焦虑样行为的影响,我们使用了开放视野并测量了中心进入(测量焦虑行为):没有发现IGF-2治疗对AS小鼠的影响,与正常小鼠的行为相比仍然存在变化(图1F)。
在基础条件下海马和内侧前额叶皮层的生化特征表明IGF-2途径、可塑性和代谢标志物异常。我们进行了蛋白质印迹分析,以比较在基础条件下(保留在家笼中)成年AS小鼠和WT同窝仔的两个对学习和记忆及执行功能重要的大脑区域,背侧海马(dHC)和内侧前额叶皮层(mPFC)的蛋白质水平。我们发现在背侧海马(dHC)和内侧前额叶皮层(mPFC)中对葡萄糖代谢,可塑性,抑制性神经元功能和IGF-2通路至关重要的标志物类别发生了显著改变。具体而言,我们评估了AS和WT同窝仔中的全蛋白和突触神经体(突触级分)提取物以比较以下物质的表达水平:i)IGF-2和IGF-2R;ii)mTOR和磷酸化mTOR,ULK-1和磷酸化ULK-1;iii)兴奋性神经元可塑性(Arc/Arg3.1,GluA1,GluA2);iv)抑制性神经元标志物(GAD67);和v)葡萄糖/能量代谢(LDHB,MCT1,MCT4,MCT2,GLUT1,GLUT3,pAMPK)。
迄今为止进行的分析表明,与野生型同窝仔相比,AS小鼠在两个大脑区域的IGF-2/IGF-2R,可塑性和葡萄糖代谢机制都有改变。具体来说,如图2(dHC)和图3(mPFC)所示,AS小鼠的dHC中GAD67明显减少,表明抑制性神经元发生了改变。AS dHC的代谢酶乳酸脱氢酶B(LDHB)也显著减少,GLUT3显著增加,并且总GLUT1、内皮GLUT1和星形胶质GLUT1都有明显增加的趋势,这表明AS小鼠的葡萄糖代谢显著改变。AMPA受体亚基GluA2表现出明显的下降趋势,但未达到显著水平。增加样本数量可能会显示出显著性缺陷。在AS小鼠的dHC中,在基础条件下,IGF-2,IGF-2受体,AMPA受体亚基GluA1,可塑性相关基因Arc/Arg3.1,突触富集蛋白PSD95,pULK和单羧酸盐转运蛋白MCT1,MCT4和MCT2的水平均未改变。
在mPFC中(图3),与正常小鼠相比,在AS小鼠中,IGF-2途径存在更显著的变化,在全蛋白提取物中IGF-2的成熟形式显著增加而pro-IGF-2显著减少,同时,突触神经体级分显示出IGF-2的成熟形式显著减少而pro-IGF-2(未成熟形式)的减少趋势却很强。IGF-2受体水平在AS小鼠的mPFC中不受影响。突触神经体级分还显示,与塑性相关的立即早期基因Arc/Arg 3.1显著降低,GluA2也显著降低,但GluA1没有显著降低。与dHC相似,在AS小鼠的mPFC中发现LDHB的水平显著下降,并且GLUT3呈强烈下降趋势。在mPFC中,神经元抑制标志物GAD67的水平有所降低,但尚未达到统计学上的显著水平。此外,pAMPK,PSD95,pULK单羧酸盐转运蛋白MCT1,MCT4和MCT2的水平在AS小鼠的mPFC中没有改变。
实施例2
该实施例证实了全身给予6-磷酸甘露糖(M6P)可逆转安格曼综合征小鼠模型中的记忆缺陷。我们首先测试了不同的M6P浓度对正常小鼠记忆增强的作用。结果如图4所示。IGF2R.L1是M6P。
此外,我们发现在模拟安格曼综合征的小鼠(Ube3a-/+小鼠,AS小鼠)中全身给予M6P可以逆转其记忆受损(图5)。
具体来说,我们在小鼠中使用了新物体识别(nOR)范例来评估非厌恶性情节记忆。在这项任务中,利用啮齿动物对新事物的天生偏好。在训练期间,允许小鼠探索2个相同的物体。在测试日,将训练物体之一替换为新物体。因为小鼠天生喜欢新事物,所以如果小鼠识别出熟悉的物体,它将在新物体上花费更多的时间。
皮下注射M6P可逆转AS小鼠的记忆受损。如图5A所示,nOR训练后4小时的测试显示,注射了对照溶液(载剂)的对照组(野生型同窝仔,WT)小鼠具有较强的记忆力,而注射载剂的AS小鼠表现出明显的记忆受损,证实了它们已建立的记忆缺陷。训练前进行M6P注射可逆转AS小鼠的记忆缺陷,事实上其记忆保留水平与对照组WT小鼠相似。在训练后24小时进行测试时,WT和AS小鼠均显示出显著的记忆保留,而注射载剂的WT和AS小鼠则发生遗忘(图5A)。
如上所述,AS小鼠在三臂Y型迷宫中以自发交替范例测量时,探索策略/工作记忆存在缺陷。与载剂注射相比,IGF-2R.L1(M6P)注射完全逆转了缺陷(图5B)。
AS还与运动受损相关,这同样在AS小鼠中重现。用于评估运动问题的一项测试是后肢扣爪,这在运动系统受损的小鼠模型中观察到,包括在运动系统的神经变性疾病中。该测试揭示了尾巴悬吊而不是屈曲反应时具有运动缺陷的小鼠的扣爪和蝙蝠状姿势。如图5C中所示,与WT对照小鼠相比,注射载剂的AS小鼠表现出显著的后肢扣爪反应。在AS小鼠中注射IGF-2R.L1可显著减少后肢扣爪,从而逆转它们的缺陷。
实施例3
我们测试了一种修饰的M6P:称为IGF-2R.L2(或L2)的膦酸酯M6P(PnM6P)。如图6所示,在训练后4小时,以850μg/kg注射的L2显著逆转了AS小鼠的nOR缺陷,并显著增强了WT小鼠的nOR记忆力(图6A)。训练后24小时,与注射载剂组相比,注射L2的WT和AS小鼠均显示出显著的记忆力。在训练后5天进行重新测试(5天测试)时,所有组(注射载剂或L2)均未显示出明显的记忆力,尽管WT对照组显示出强烈的记忆增强趋势,如果每组中包括更多数量的对象,这些趋势会变得明显。
如RotaRod测试所示(如第0034段所述),L2还可以逆转AS小鼠的运动缺陷。尽管与WT对照小鼠相比,注射载剂的AS小鼠表现出明显的运动缺陷(图6B),但是注射L2的AS小鼠显著提高了它们在RotaRod上的运动能力,事实上,这些小鼠的跌落潜伏期恢复到与WT对照小鼠相似的水平(图6B)。
L2注射逆转了通过后肢扣爪测量的运动缺陷。尽管与注射载剂的对照小鼠相比,注射载剂的AS小鼠表现出显著更高的后肢扣爪行为得分,但是注射L2的AS小鼠使它们的后肢扣爪行为恢复到对照水平(图6C)。
实施例4
本实施例描述了M6P衍生物的合成和表征。
一般合成方法
除非另有说明,所有反应均在进行磁力搅拌的同时,在氮气或氩气正压下,在火焰干燥或烘箱干燥的玻璃器皿中进行。通过使溶剂通过活性氧化铝柱进入火焰干燥的玻璃器皿,获得无水二氯甲烷(CH2Cl2),乙醚(Et2O),1,4-二噁烷,四氢呋喃(THF),甲苯(PhMe)和N,N-二甲基甲酰胺(DMF)。除非另外说明,否则使用从商业供应商(Acros Organics,AKScientific,Alfa Aesar,Chem-Impex International,Combi-Blocks,Sigma-Aldrich,Strem Chemicals,Synthonix,Tokyo Chemical Industry Co.)获得的其他溶剂和试剂。薄层色谱(TLC)使用预先涂有F254荧光指示剂(Millipore Sigma)的硅胶60玻璃板进行反应监测,通过阻挡紫外线(λ=254nm)可视化,或通过用高锰酸钾(KMnO4)水溶液,酸性钼酸铵铈(IV)(CAM)水溶液,酸性对茴香醛乙醇溶液,或茚三酮丁醇溶液染色,然后用热风枪轻轻加热。使用玻璃柱或Teledyne Isco MPLCRf+,用硅胶(40-63μm,Silicycle或Merck),在氮气压力下于室温进行快速柱色谱。在25℃,在配备有CryoProbeTM的Bruker Avance III HD 400MHz光谱仪上,记录质子核磁共振(1H NMR)谱,表示为百万分之一(ppm,δ量级),相对于四甲基硅烷的低场(TMS,δ=0ppm),内部参比NMR溶剂的残余质子离子(protium)共振(CDCl3:7.26[CHCl3],CD3OD:4.87[MeOH],D2O:3.31[H2O],C6D6:7.16[C6H6],(CD3)2SO:2.50[(CH3)2SO])。在25℃,在配备有CryoProbeTM的Bruker Avance III HD400MHz光谱仪上记录质子解耦的碳-13核磁共振(13C{1H}NMR)谱,表示为百万分之一(ppm,δ量级),相对于四甲基硅烷的低场(TMS,δ=0ppm),内部参比NMR溶剂的C-13共振的中心线(CDCl3:77.36[CHCl3],CD3OD:49.00[MeOH],(CD3)2SO:39.52[(CH3)2SO])。在25℃,在配备有CryoProbeTM的Bruker Avance III HD 400MHz光谱仪上记录质子解耦的磷-31核磁共振(31P{1H}NMR)谱,表示为百万分之一(ppm,δ量级),相对于磷酸的低场(H3PO4,δ=0ppm),外部参比三苯基磷酸酯标准溶液(0.0485M在CDCl3中,δ=-17.7ppm)。报告的数据表示为:化学位移(百万分之一,ppm,δ量级)(积分,多重性,以Hz为单位的偶合常数J,原子分配)。多重性缩写为:s,单峰;d,双重峰;t,三重峰;q,四重峰;quint,五重峰;sext,六重峰;hept,七重峰;br,宽峰;m,多重峰;或其组合。高分辨率质谱(HRMS)使用Agilent 6224精确质量飞行时间(TOF)液相色谱质谱仪(LC/MS)结合常压化学电离(APCI)或电喷雾电离(ESI)方法进行。参比聚苯乙烯标准品,在Thermo Scientific Nicolet 6700 FT-IR光谱仪上记录傅立叶变换红外(FT-IR)光谱。信号以波数(cm-1)表示为吸收频率,描述符缩写为:w,弱;m,中等;s,强,br,宽。在具有反相(RP)Phenomenex半制备柱(00D-4439-E0 Gemini,C18相,粒径3μm,孔径)的Agilent1260Infinity II液相色谱仪上进行高效液相色谱(HPLC)纯化,流速为8mL/分钟,溶剂混合物为在(A)乙腈(HPLC级)和(B)水(HPLC级)中的0.1%甲酸(FA)。在具有Flint Glass Faraday电池调制器、钠灯光源和光电倍增管(PMT)检测器的Jasco P-2000旋光仪上记录旋光度测量值。根据公式[α]=(100·α)/(l·c)计算比旋光度,其中浓度c以g/100mL为单位,光程长度l以分米为单位。计算的比旋光度报告为无单位值,并表示为:[α]D T比旋光度(c浓度,溶剂),其中温度T以℃为单位,D代表钠D-线监测仪的波长(589nm)。
化合物的合成与表征
合成L2
甲基6-O-三苯甲基-α-D-甘露吡喃糖苷(2)
三苯甲基醚2根据改进的公开方法(Traboni等人,ChemistrySelect 2017,2,4906-4911;Tennant-Eyles等人,J.Tetrahedron:Asymmetry 2000,11,231-243)进行制备。向甲基-α-D-甘露吡喃糖苷(5.02g,25.8mmol,1.0当量)和三苯甲基氯(7.91g,28.4mmol,1.1当量)的混合物中加入吡啶(5.2mL,64.6mmol,2.5当量)。将反应混合物加热至100℃,并搅拌30分钟。30分钟后,将所得粘稠的糊状物通过在40℃超声溶解在CH2Cl2中。将溶液用饱和氯化铵水溶液(2×)洗涤,用无水硫酸钠干燥,过滤,并在减压下浓缩。粗残余物通过快速柱色谱法纯化(50%至100%乙酸乙酯/己烷),得到为白色泡沫状的2(11.0g,25.2mmol,98%)。NMR光谱与文献报道的那些相匹配(Traboni等人,ChemistrySelect 2017,2,4906-4911;Tennant-Eyles等人,J.Tetrahedron:Asymmetry 2000,11,231-243)。1H NMR(400MHz,CDCl3)δ7.48-7.28(15H,m),4.72(1H,d,J=1.6Hz),3.92(1H,m),3.82-3.63(3H,m),3.50-3.39(2H,m),3.38(3H,s),2.73(1H,m),2.54(1H,m),2.27(1H,m)。13C NMR(101MHz,CDCl3)δ143.9,128.9,128.3,127.5,100.9,87.7,72.0,70.64,70.59,70.1,65.2,55.3。
甲基2,3,4-三-O-苯甲基-α-D-甘露吡喃糖苷(4)
苯甲基醚3根据改进的公开方法(Hofmann等人,Carbohydr.Res.2015,412,34-42)进行制备。将三苯甲基醚2(2.01g,4.61mmol)溶解在无水DMF(115mL)中,并在0℃,向该溶液分批加入NaH(60%,在矿物油中,14.8g,371mmol,7.2当量)的悬浮液。将反应混合物在0℃下搅拌10分钟,并向该混合物中缓慢加入苯甲基氯(39.1g,309mmol,6.0当量),将悬浮液在0℃下搅拌5分钟,然后温热至室温并搅拌16小时。将反应混合物用水淬灭,并用乙酸乙酯萃取。有机层用无水硫酸钠干燥,并减压浓缩,得到3,为粘稠的黄色油,将其直接用于以下过程。
醇4根据改进的公开方法(Jaramillo等人,J.Org.Chem.1994,59,3135-3141)进行制备。将苯甲基醚3溶解在MeOH-CH2Cl2(2:1,6mL)中,并添加p-TsOH直至pH<4。将反应混合物在室温搅拌20小时,然后用Et3N中和并在减压下浓缩。将残余物溶于CH2Cl2中,并用蒸馏水和盐水洗涤。有机层经无水硫酸钠干燥并在减压下浓缩。粗残余物通过快速柱色谱法(30%至60%乙酸乙酯/己烷)纯化,得到浅黄色浆状的醇4(0.90g,1.94mmol,42%)。NMR光谱与文献报道的那些光谱相匹配(Norberg等人,Carbohydr.Res.2017,452,35-42)。1H NMR(CDCl3,400MHz)δ7.41-7.30(15H,m),4.97(1H,d,J=10.9Hz),4.81(1H,d,J=12.3Hz),4.75-4.65(5H,m),3.99(1H,app.t,J=9.4Hz),3.92(1H,dd,J=9.4,2.9Hz),3.90-3.84(1H,m),3.83-3.76(2H,m),3.68-3.62(1H,m),3.33(3H,s),2.00(1H,app.t,J=6.4Hz)。13C NMR(101MHz,CDCl3)δ138.8,138.7,138.6,128.70,128.68,128.67,128.3,128.1,128.0,127.9,99.6,80.5,75.5,75.2,75.0,73.2,72.5,72.4,62.7,55.1。HRMS(APCI/LC-TOF)m/z:[M+NH4]+C28H32O6计算值482.2537;实测值482.2533。
甲基2,3,4-三-O-苯甲基-6-脱氧-6-二乙氧基氧膦基亚甲基-α-D-甘露吡喃糖苷(7)
醛5根据伯醇氧化的一般方法(Tojo等人,醇氧化为醛和酮的方法:当前常用方法指南(Oxidation of alcohols to aldehydes and ketones:a guide to current commonpractice).Springer Science&Business Media:2006)进行制备。在氮气下在无水DMSO(1.8mL)中制备4的溶液(0.334g,0.72mmol,0.4M)。向该溶液中加入Et3N(1.0mL,7.2mmol,10当量),并将反应混合物在冰水浴中冷却至0℃并搅拌。在0℃下,向该溶液中滴加三氧化硫-吡啶配合物(0.347g,2.2mmol,3.0当量)的DMSO(1mL)溶液。将反应混合物温热至室温,并搅拌20小时。溶液用CH2Cl2稀释并用蒸馏水洗涤,用无水硫酸钠干燥,并在减压下浓缩,得到5,为黄色油。将该油通过二氧化硅短柱过滤,并直接用于以下过程。
膦酸酯7根据改进的公开方法(Vidil等人,Eur.J.Org.Chem.1999,447-450)进行制备。向NaH(60%,在矿物油中,37.8mg,0.945mmol,2.2当量)在无水甲苯(2mL)中的悬浮液滴加亚甲基二膦酸四乙酯(0.27mL,1.08mmol,2.5当量),并在室温下搅拌30分钟。在氮气下将5的无水甲苯溶液(5mL)滴加到该混合物中,并在室温搅拌2小时。反应混合物用CH2Cl2稀释,并用蒸馏水淬灭。有机层用CH2Cl2(3×)萃取,用无水硫酸钠干燥,并在减压下浓缩。粗残余物通过快速柱色谱法纯化(40%至100%乙酸乙酯/己烷),得到7,为无色浆液(162mg,0.272mmol,62%)。NMR谱与文献报道的那些相匹配(Vidil等人,Eur.J.Org.Chem.1999,447-450)。[α]D 20=+40.4(c=1.01,CHCl3)。1H NMR(CDCl3,400MHz)δ7.39-7.27(15H,m),6.96(1H,ddd,J=22.1,17.2,4.3Hz),6.12(1H,ddd,J=21.2,17.5,1.8Hz),4.88和4.59(2H,AMq,J=10.6Hz),4.77和4.70(2H,ABq,J=12.4Hz),4.73(1H,s),4.63(2H,s),4.14-4.03(5H,m),3.90(1H,dd,J=9.3,3.0Hz),3.81-3.77(1H,m),3.72(1H,t,J=9.5Hz),3.29(3H,s),1.31(6H,t,J=7.1Hz)。13C NMR(CDCl3,101MHz)δ148.4(d,J=5.8Hz),138.7,138.5,138.3,128.7,128.4,128.14,128.05,127.9,118.3(d,J=188.2Hz),99.6,80.4,78.5(d,J=1.9Hz),75.7,75.0,73.2,72.7,71.5(d,J=21.5Hz),62.1(dd,J=5.8,1.3Hz),55.3,16.7.31P NMR(162MHz,CDCl3)δ18.3.FT-IR(净,cm-1):ν(C-H)=2982(m),ν(P=O)=1253(s),ν(P-O-C)=1024(s),ν(P-O-C)=969(m)。
甲基2,3,4-三-O-苯甲基-6-脱氧-6-二异丙氧基羰基氧基-甲基-氧膦基亚甲基-α-D-甘露吡喃糖苷(10)
膦酸8根据公开方法(Vidil等人,Eur.J.Org.Chem.1999,447-450)进行制备。在氮气下向7(0.146g,0.245mmol,1当量)的无水CH3CN(5.6mL)溶液中添加吡啶(31μL,0.392mmol,1.6当量)和三甲基甲硅烷基溴化物(0.32mL,2.45mmol,10当量),并在室温下搅拌。2小时后,将反应混合物冷却至0℃,并加入吡啶(51μL,0.634mmol,2.6当量)和H2O(185μL,10.3mmol,42当量),然后温热至室温并搅拌。2小时后,将反应混合物用CH2Cl2和2M HCl(4mL)和H2O(4mL)稀释。有机层用CH2Cl2萃取,经无水硫酸钠干燥,并在减压下浓缩,得到8,为棕色油。粗残余物直接用于以下过程。
膦酸酯10根据改进方法(Graham等人,(2017).国际专利申请公开号WO2017/87256)进行制备。在氮气下8在无水CH3CN中的混合物用DIPEA(0.480mL,2.76mmol,9.9当量),TBAB(93.1mg,0.289mmol,1.0当量)和碳酸氯甲基异丙酯(0.30mL,2.24mmol,8.1当量)处理,然后加热至60℃。搅拌16小时后,将反应混合物在减压下浓缩。粗残余物通过快速柱色谱法纯化(30%至100%乙酸乙酯/己烷),得到10,为无色油(116mg,0.150mmol,54%)。TLC(EtOH/EtOAc/己烷1.5:1.5:7):Rf=0.49。1H NMR(CDCl3,400MHz)δ7.40–7.29(15H,m),7.10(1H,ddd,J=24.5,17.2,3.8Hz),6.40–6.17(1H,m),5.80–5.65(6H,m),4.81–4.59(7H,m),4.22–4.14(1H,m),3.91(1H,dd,J=9.3,3.1Hz),3.83–3.78(1H,m),3.74(1H,t,J=9.5Hz),3.30(3H,s),1.32–1.29(12H,m)。13C NMR(CDCl3,101MHz)δ153.5,138.7,138.5,138.3,128.8,128.7,128.6,128.2,128.1,127.9,99.7,84.5(d,J=5.7Hz),84.4(d,J=6.8Hz),80.5,78.3(d,J=2.1Hz),75.8,75.0,73.5(d,J=3.5Hz),73.3,72.7,71.3(d,J=22.3Hz),55.3.31P NMR(162MHz,CDCl3)δ26.3。
甲基6-脱氧-6-二异丙氧基羰基氧基-甲基-氧膦基甲基-α-D-甘露吡喃糖苷(L2)
合成L2的最后步骤根据公开的氢化方法(Jeanjean等人,Bioorg.Med.Chem.Lett.2008,18,6240-6243)进行。在烘箱干燥的小瓶中,将10(36.0mg,0.047,1当量)干燥并在高真空下脱气。向其中加入10%Pd/C(36.6mg,0.344mmol,7.4当量),并用CH2Cl2(2mL)和EtOH(2mL)冲洗。将反应混合物在表面下用N2鼓泡1分钟。然后将反应混合物在减压下脱气,并用H2(5×)替换环境气体。将反应混合物在H2下剧烈搅拌4小时,之后,将反应混合物在减压下脱气并重新填充N2(5×)。将反应混合物用CH2Cl2(2mL)稀释,并通过湿硅藻土短柱过滤。将过滤的有机层在减压下浓缩,并将粗残余物通过HPLC纯化(40%至85%[H2O+0.1%FA]:[CH3CN+0.1%FA],tR(L2)=7.00分钟),得到L2(10.1mg,0.020mmol,43%),为白色固体。所有13C-31P耦合常数均在标准值范围内(Buchanan等人,Can.J.Chem.1976,54,231-237)。1H NMR(400MHz,CDCl3)δ.68(2H,dd,J=20.5Hz,J=5.3Hz,H8),5.65(2H,dd,J=18.3Hz,J=5.4Hz,H8’),4.93(2H,hept,J=6.3Hz,H10),4.68(1H,s,H1),3.95-3.86(1H,br,H5),3.74(1H,m,H2),3.58(2H,m,H3,H4),3.35(3H,s,OCH3 ),3.22-3.07(1H,m,OH),2.95(2H,m,2×OH),2.27-2.07(2H,m),2.06-1.86(2H,m,H6,H6’,H7,H7’),1.32(12H,d,J=6.2Hz,H11).13C NMR(101MHz,CDCl3)δ153.6(d,J=3.7Hz,C9),101.2(s,C1),84.5(d,J=6.3Hz,C8),84.3(d,J=6.3Hz,C8’),73.7(d,J=3.2Hz,C10),72.0(s,C2),70.9(d,J=16.1Hz,C5),70.6(s),70.5(s,C3,C4),55.3(s,OCH3),23.8(d,J=4.5Hz,C6),22.4(s,C11),21.7(d,J=142.3Hz,C7).31P NMR(162MHz,CDCl3)δ34.4.FT-IR(净,cm-1):ν(O-H)=3409(br),ν(C-H)=2923(m),ν(C=O)=1760(s),ν(P=O)=1269(s).LR-MS(ESI-)[M+HCOO]-计算值:549.2;实测值549.2。
虽然已经通过各种实施方式描述了本公开,但是常规修饰对于本领域技术人员而言将是显而易见的,因此这类修改意图在包括在本公开的范围内。
Claims (13)
1.一种治疗神经发育障碍(ND)的方法,所述神经发育障碍(ND)选自:安格曼综合征(AS)和自闭症谱系障碍(ASD),所述方法包括向已经诊断为ND的对象给予包含治疗有效量的IGF-2受体的特异性激动剂配体的组合物。
2.如权利要求1所述的方法,其中,治疗包括缓解发育标志、言语、智力、运动、社交行为和癫痫发作中的一个或多个。
3.如权利要求1所述的方法,其中,所述激动剂配体是IGF-2或其修饰物。
4.如权利要求1所述的方法,其中,所述激动剂配体是6-磷酸甘露糖(M6P)或其衍生物。
6.如权利要求4所述的方法,其中,给予所述M6P或其衍生物的量为1-2,000μg/kg体重。
7.如权利要求4所述的方法,其中,所述M6P或其衍生物不与另一部分偶联。
8.如权利要求4所述的方法,其中,所述M6P或其衍生物是所述组合物中唯一与IGF-2受体特异性结合的试剂。
9.如权利要求3所述的方法,其中,给予所述IGF-2的量为1-500μg/kg体重。
10.如权利要求9所述的方法,其中,所述IGF-2是所述组合物中唯一与IGF-2受体特异性结合的试剂。
11.如权利要求1所述的方法,其中,所述组合物基本上由以下组成:i)选自M6P和M6P衍生物的配体,以及ii)IGF-2。
12.一种化合物,选自:L3,L4,L5,L6,L7,L8和L9。
13.一种组合物,其包含如权利要求12所述的化合物和药学上可接受的载体。
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