CN1592616A - 与神经甾体活性降低相关的疾病的治疗中的gaba增强剂 - Google Patents
与神经甾体活性降低相关的疾病的治疗中的gaba增强剂 Download PDFInfo
- Publication number
- CN1592616A CN1592616A CNA018190936A CN01819093A CN1592616A CN 1592616 A CN1592616 A CN 1592616A CN A018190936 A CNA018190936 A CN A018190936A CN 01819093 A CN01819093 A CN 01819093A CN 1592616 A CN1592616 A CN 1592616A
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- Prior art keywords
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- gaba
- neurosteroid
- disorder
- disease
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明提供了非甾体类化合物的用途,此化合物可作用于GABA受体从而治疗与神经甾体活性降低相关的紊乱。非甾体类化合物可为GABA激动剂、GABA摄取抑制剂或GABA能活性的增强剂。
Description
本发明提供了非甾体类化合物的用途,这些化合物为与神经甾体活性降低相关的紊乱的治疗中的GABA激动剂、GABA摄取抑制剂或GABA能(GABAergic)活性的增强剂。
发明背景
主要的抑制性神经递质γ-氨基丁酸(GABA)分为两个主要类型:GABAA受体为配体门控离子通道超家族的成员;以及GABAB受体是G-蛋白偶联的受体。
GABAA受体是以受体亚基的不同家族的五聚体形成的。此组装形式在大多数受体中包括2个α亚基、2个β亚基和1个γ或δ亚基,其确定了功能性受体的药理学。苯并二氮卓类的结合位点位于α和γ亚基间的界面上,而GABA和其他GABAA激动剂的结合位点位于α和β亚基间的界面上。
确实存在的GABAA受体组装形式包括α1β2γ2、α1β2/3γ2、α3βγ2/3、α5β3γ2/2、α6βγ2、α6βδ、α4βδ和α4β2γ2等。含有α1亚基的亚型存在于绝大多数脑区域,并且有助于许多苯并二氮卓类的功能作用。
在许多临床状况下,抑制性GABA系统的活性降低被假设为所考虑的病理学的潜在机制。这些状况包括癫痫、焦虑、紧张、睡眠障碍和疼痛。然而,虽然在大量的状况下GABAA受体复合体正调节剂如苯并二氮卓类是非常有效的,但普遍一致认为非选择性苯并二氮卓类产生了太多的副作用,因此需要化合物来替代目前使用的药物(Costa andGuidotto Trends Pharmacol.Sci.1996,17,192-200)。
含有α4的受体主要存在于丘脑区域(Sur et al.1999)。最近的研究(Sassoè-Pognetto et al..J Comp Neurol 2000,15,420:481-98;Mody,2000,Presentation at GABA2000 meeting July 23 to July29.)已经证明,这些受体中的一些可定位于突触外,这样就使得它们成为潜在的令人感兴趣的药物靶。
在苯并二氮卓类和GABA激动剂间存在差异。其中之一是在含有α4和δ的受体中苯并二氮卓类是无活性的,而GABAA激动剂的作用是不依赖于亚基组成的(如Ebert et al.Mol.Pharmacol.1997,52,1150-1156)。另一差异是,苯并二氮卓类作用于GABA复合体的特定位点,因此使得GABA受体经历了可影响GABA促进氯通道开放效率的变构改变。GABA受体调节剂表现出相当的副作用。对于紊乱如焦虑和经前烦躁性紊乱(dysphoric disorder)来讲,丘脑区域的调节可能起重要的作用。在这些区域中发现了大量含有α4β3δ/γ2的受体,这使得其与这些受体的相互作用尤其令人感兴趣。由于高密度的含有α4的受体定位在突触外,(Sur et al.Mol.P)armacol.1999,56,110-115;Sassoè-Pognetto et al.J Comp Neurol 2000,15,420:481-98;Mody,2000,Presentation at GABA2000 meeting July 23 to July29),因此个体突触外受体上相对低水平的激活作用将积累为对神经元的显著抑制,这样就存在开发用于这些受体的高功能选择性化合物的可能性。
已经证明卵巢激素孕酮及其代谢物对大脑兴奋性具有很深的影响。孕酮及其代谢物水平随月经周期各阶段而变化。已经证明,孕酮及其代谢物在月经开始前水平下降。也很好的证明了月经开始前某些生理症状的每月重复。与经前综合征(PMS)或经前烦躁性紊乱(PMDD)相关的这些症状包括紧张、焦虑和偏头疼。正遭受PMS的患者存在经前存在经后消失的每月重复的症状。以类似的方式,孕酮减少也与女性癫痫患者癫痫发作频率增加暂时相关。在孕酮代谢物减少时观察到更直接的关联。此外,对于具有主要的普通癫痫小发作的患者来讲,癫痫短暂发作与PMS症状出现间存在相互联系。
也与低孕酮水平相关的综合征为出生后抑郁症(PND)。分娩后孕酮水平立刻显著下降从而导致发生PND。PND的症状范围为轻度抑郁到需要住院治疗的精神病。PND也与严重的焦虑和激惹性相关。与抑郁症相关的PND易于利用经典的抗抑郁剂治疗,并且遭受PND的女性PMS发病率增加。
一般认为经前烦躁性紊乱(PMDD)是孕酮水平,尤其是作为GABA能活性正调节剂的孕酮代谢物水平的快速下降的结果(Gallo and Smith,1993 Pharmacol.Biochem.Behav.46,897-904)。
已经研究了对GABAA受体有直接作用的神经活性甾体的效用进行了研究。虽然神经甾体类如阿法沙龙和3α-5α-二羟基孕酮可与所有类型的GABA受体相互作用,利用含有α4β3δ的受体得到的数据表明对这些受体的效能和效力要高于其他类型的GABAA受体。已经开发了神经甾体来治疗PMDD和其他适应症,然而,其副作用使得这些化合物的绝大多数停止了使用。此外,一系列研究证明,作为安眠药的神经甾体长时间应用导致代偿性机制,最终产生依赖性(Lancel et al.JPharmacol.Exp.Ther.1997,282,1213-1218)。
本发明提供了可作为激动剂或GABA摄取抑制剂或作为GABA能活性增强剂从而直接与GABAA受体识别位点相互作用的非甾体类化合物,它们都对与神经甾体激活减少相关的疾病状态具有有益的效用。
与在短期治疗后产生耐受性的苯并二氮卓类和神经甾体相比,GABAA激动剂和GABA摄取抑制剂或GABA能活性增强剂对包括经前综合征、出生后抑郁症和与绝经后相关的烦躁性紊乱在内的疾病的治疗效果显著较佳。
本发明也提供了可用于治疗与神经甾体激活减少相关的疾病的特异性非变构GABA激动剂化合物。已知这些化合物在治疗其他疾病和紊乱方面是有用的。
发明详述
本发明提供了增加脑中GABA活性的非甾体类化合物在制备用于治疗由神经甾体激活减少所导致的紊乱的药物中的用途。
脑中GABA活性提高可通过给予GABA激动剂来实现。GABA激动剂为化合物,如托加比特、酚加宾、加巴喷丁、唑尼沙胺、蝇蕈醇、巴氯芬、β-苯基-GABA、AFAA和同型-β-脯氨酸。给予GABA前体药物如progabine同样可影响脑中的GABA活性。
也可通过GABA摄取抑制剂如硫加宾或GABA氨基转移酶抑制剂如氨己烯酸或匹伐加宾来实现提高大脑中GABA的活性。
本发明提供了非甾体类化合物的用途,其中该化合物为GABA能活性的增强剂。
在本发明的一个优选实施方案中,该化合物具有对含有α4亚基的GABA复合体的亲和力。
在本发明的一个优选实施方案中,上述的非甾体类化合物为非异构的受体激动剂。
本发明提供了上述非甾体类化合物的用途,其中该化合物为GABA摄取抑制剂。
本发明提供了上述化合物的用途,其中的非甾体类化合物选自THIP(加波沙朵)、环丙基GABA、槟榔次碱、蝇蕈醇、咪唑-4-乙酸、加巴喷丁和硫加宾。
本发明也提供了上述的用途,其中疾病或紊乱是由神经甾体水平波动引起的。
在本发明的一个优选实施方案中,疾病或紊乱是由神经甾体水平下降引起的。
在本发明的一个特定实施方案中,疾病或紊乱是由神经甾体水平的反复的周期性下降引起的。
在本发明的另一特定实施方案中,疾病或紊乱是由神经甾体水平的显著下降引起的。
在本发明进一步的实施方案中,疾病或紊乱是由与年龄相关的神经甾体水平下降引起的。
在本发明的一个优选实施方案中,神经甾体为孕酮。
在本发明的一个更优选实施方案中,神经甾体为孕酮的代谢物。
在本发明的一个优选实施方案中,疾病或素乱为经前紊乱、出生后抑郁症或与绝经后相关的烦躁性紊乱。
本发明也提供了上述的用途,其中以单位剂量进行药物给药。
在本发明的一个优选实施方案中,单位剂量为含有约10μg/kg-10mg/kg体重,优选25μg/天/kg-1.0mg/天/kg,最优选0.1mg/天/kg-1.0mg/天/kg体重的活性成分。
在一个更优选的实施方案中,单位剂量为含有0.1mg/天/kg-1.0mg/天/kg体重的活性成分。
在本发明的一个实施方案中,神经甾体激活是由激素引起的。
在一个优选实施方案中,其为孕酮。在另一优选实施方案中,其为孕酮代谢物。
按照本发明,上述化合物可用作化合物基或用作其药学可接受的酸加成盐或用作这些盐的脱水物或水合物。
按照本发明,可以采用合适的途径如口服或肠胃外方式给予上述化合物或其药学可接受的盐,并且其可以任何合适的形式,如以片剂、胶囊、粉剂、糖浆或溶液、或用于注射的分散体形式进行给药。优选地,按照本发明的目的,本发明的化合物是以固体药物实体,适宜的为片剂或胶囊,或以适于注射的悬浮液、溶液或分散体形式进行给药的。
固体药物制剂的制备方法在本领域中是众所周知的。因此,片剂可通过将活性成分与普通的佐剂和/或稀释剂混合并且随后在方便的压片剂中对混合物进行压制而制备。佐剂或稀释剂的示例包括玉米淀粉、乳糖、滑石粉、硬脂酸镁、明胶、乳糖、树胶等。只要它们能够与活性成分相容,也可使用其他佐剂或添加剂如色素、香料、防腐剂等。
本发明中的化合物最方便以单位剂型如片剂或胶囊口服给药,其中含有的活性成分量约为10μg/kg-10mg/kg体重,优选25μg/天/kg-1.0mg/天/kg。
在孕酮水平波动的假妊娠模型中检测化合物的作用,尤其是如Gallo et.al.Pharmacol.Biochem.Behav.1993,46,897-904中的实施例所描述的对孕酮水平快速下降的作用。
结果
PMS的啮齿类动物模型
此处描述的模型是在大鼠中建立的PMS激素停药模型,其建立在烦躁行为主要是与患有PMS的女性激素水平下降(也即“激素停药”)相关这一流行假说之上。以前的工作(Nature 392:926-930,1998;J.Neurosci.18:5275-5284,1998)已经证明,在3周的时间中给予激素,在去除皮下孕酮填充植入物24小时去除高水平的生殖甾体,即孕酮,在雌性大鼠中产生了增加的焦虑和降低的发作阈值状态。
电生理学数据进一步提供了α4亚基增加的证据,这表明海马细胞对苯二氮卓类(BDZ)氯羟去甲安定的GABA-加强作用的强烈不敏感性(BDZ不敏感性是含有α4的GABA受体的特征)。
实验详述
动物
在14小时光照和10小时黑夜循环且不限制食物和水的条件下,对雌性小鼠(Charles River)进行成对饲养。在昼夜循环的光照部分中对所有动物进行检验。在雌性小鼠中,如以前所描述在检测前的一个完整周期中通过进行阴道冲洗物显微镜检测(Smith,1987)或通过测定阴道阻抗(Bartlewski,1999;Bartos,1977;Koto,1987;Koto,1987)确定它们的动情周期。只有那些处于间动情期的雌性小鼠用作实验对象。
药物和激素给药
给予孕酮(P),而不是3α,5α-THP,这是因为已知P的升高的循环水平,例如在动情(或月经)周期中或紧张之后(Persengiev,1991;Barbaccia,1996;Barbaccia,1997;Korneyev,1993;Wilson,1997;Elman,1997;Vallee,2000;Purdy,1991;Korneyev,1993)易于在大脑中转化为3α,5α-THP,使得3α-5αTHP水平足以加强GABA能抑制(Schmidt,1994;Smith,1987;Seiki,1975;Bitran,1995;Karavolas,1976;Vallee,2000)并调节GABAA-R亚基表达[Weiland,1995]。
依动物体重将利用据硅酮管(Nalgene Co,1/16″ i.dx1/8″o.d.)制备的孕酮移植物切割成适当大小(10mm管/100g),利用晶体孕酮进行填充,并利用硅橡胶医用粘合剂(Dow Corning)进行密封。在含有1%明胶和0.9%盐的水溶液中对密封的胶囊水浴(37℃)并轻轻振荡培育过夜。假植入物为同样大小的空密封管。随后利用氧气中的2%氟烷(2-溴-2-氯-1,1,1-三氟乙烷)将大鼠麻醉并在腹部皮下植入胶囊。也是在同样的氟烷麻醉条件下取出植入物,在麻醉条件下皮下植入(Smith,1998;Moran,1998)大鼠腹部21天。已经证明此方法可相关于升高的P循环水平(40-50ng/ml血浆,约130-160nM)而导致高生理范围(6-12ng/gm海马组织)的3α,5α-THP的CNS水平(Smith,1998)。
以完全相同的方式在对照动物中植入空(假)聚硅酮胶囊。在取出植入物(P停药)24小时后将动物处死或进行检测。
在进行检测的那一天,对动物注射THIP(1.25mg/kg)或盐水,注射40分钟后进行检测。
行为检测
在具有低的、间接的白炽光和低噪音水平的房间中,在高出地面50cm的正(plus)迷宫上对小鼠进行检验。正迷宫由2个封闭的臂(50×10×40cm)和2个开放的臂(50×10cm)组成,在(Pellow,1985)中对其有详细解释。如(Fernandes,1996)中所述,开放的臂在前半部分外有一个小轨道。
四个臂的底都用间隔25cm的网格线进行标记。在进行检测的当天,为了适应环境,在检测前将每只鼠置于检测房间内,为时30-40分钟。进行检测时,从正迷宫的中央平台中的起始盒中出来后,每只动物进行10分钟检测。鼠必需四爪全部通过开放平台的线,这样才认为其进入了臂。从进入开放臂开始记录在开放臂中停留的时间(以秒计)。在开放臂中停留的时间减少说明焦虑水平较高(Pellow,1985)。记录的其他行为测定结果包括超过轨道的时间(以秒计)。一般认为,实验动物在无轨道的正迷宫的开放部分停留的时间量比在有轨道的正迷宫的开放部分停留的时间量对抗焦虑剂(即可增加在开放臂中停留的时间的药物)更敏感(Fernandes,1996)。为了测定普遍的运动活性,计算了跨过的总网格数目。最后,也对饲养时间(以秒计)进行了评分。
实验者对所有条件是未知的,并且利用随机区组设计对动物进行检验。
统计分析
利用双向ANOVA(植入条件x注射条件)对从正迷宫获得的数据进行分析,随后利用post-hoc ANOVA和post hoc t-检验进行分析。如表1所例示的,孕酮停药(PWD)小鼠在开放臂中的时间较对照动物显著要少。
表1
开放臂停留时间的平均值表
作用:性别/状况
行排除:stvw PWD+M F/M D
计数 平均值 标准差 标准误
(F)C(F)PWD(F)C THIP(1.25)(F)PWD THIP(1.25)
14 | 79.629 | 59.231 | 15.830 |
13 | 20.968 | 24.292 | 6.737 |
3 | 38.377 | 48.816 | 28.184 |
3 | 157.023 | 36.838 | 21.268 |
此外,剂量为1.25mg/kg的THIP完全逆转了孕酮停药作用。当对跨过的网格数进行计数时获得了相似的结果(表2)。
表2
跨过网格的平均值表
作用:性别/状况
行排除:stvw PWD+M F/M D
计数 平均值 标准差 标准误
(F)C(F)PWD(F)C THIP(1.25)(F)PWD THIP(1.25)
14 | 43.643 | 18.270 | 4.883 |
13 | 33.308 | 18.531 | 5.140 |
3 | 52.000 | 18.028 | 10.408 |
3 | 83.333 | 16.166 | 9.333 |
测定了在轨道外停留的时间(表3)。
表3:
轨道外停留时间的平均值表
作用:性别/状况
行排除:stvw PWD+M F/M D
计数 平均值 标准差 标准误
(F)C(F)PWD(F)CTHIP(1.25)(F)PWD THIP(1.25)
14 | 6.795 | 7.041 | 1.882 |
13 | 2.077 | 4.699 | 1.303 |
3 | 10.060 | 17.424 | 10.060 |
3 | 29.503 | 6.699 | 3.868 |
从动物模型结果可以看出,THIP能够完全抵消孕酮停药。
Claims (14)
1.增加脑中GABA活性的非甾体类化合物在制备用于治疗由神经甾体激活减少所导致的紊乱的药物中的用途。
2.根据权利要求1的非甾体类化合物的用途,其中该化合物为非变构的GABA激动剂。
3.根据权利要求1或2的非甾体类化合物的用途,其中该化合物具有对含有α4亚基的GABA复合体的亲和力。
4.根据权利要求1的非甾体类化合物的用途,其中该化合物为GABA摄取抑制剂。
5.根据权利要求1的非甾体类化合物的用途,其中该化合物为GABA能活性的增强剂。
6.根据上述任意一项权利要求的用途,其特征在于非甾体类化合物选自THIP(加波沙朵)、环丙基GABA、槟榔次碱、蝇蕈醇、咪唑-4-乙酸、加巴喷丁和硫加宾。
7.根据权利要求1的用途,其中该疾病或紊乱是由神经甾体水平波动引起的。
8.根据权利要求7的用途,其中该疾病或紊乱是由神经甾体水平下降引起的。
9.根据权利要求7或8的用途,其中该疾病或紊乱是由神经甾体水平的反复周期性下降引起的。
10.根据权利要求7-9的用途,其中该疾病或紊乱是由神经甾体水平的显著下降引起的。
11.根据权利要求7-10的用途,其中该疾病或紊乱是由与年龄相关的神经甾体水平下降引起的。
12.根据权利要求7-11的用途,其中该神经甾体为孕酮。
13.根据权利要求7-11的用途,其中该神经甾体为孕酮代谢物。
14.根据上述任意一项权利要求的用途,其中该疾病或紊乱为经前紊乱、出生后抑郁症或与绝经后相关的烦躁性紊乱。
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CN110996910A (zh) * | 2017-05-24 | 2020-04-10 | 奥维德医疗公司 | 抑郁障碍的治疗 |
CN114404437A (zh) * | 2022-03-15 | 2022-04-29 | 山东中医药大学 | 没食子酰芍药苷在制备gabaa受体抑制剂中的应用 |
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GB0402118D0 (en) | 2004-01-30 | 2004-03-03 | Merck Sharp & Dohme | Polymorphic forms of a GABAA agonist |
KR20070034070A (ko) * | 2004-06-29 | 2007-03-27 | 하. 룬드벡 아크티에셀스카브 | 신경병성 통증, 섬유근통 또는 류마티스성 관절염의 치료 |
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KR102049522B1 (ko) * | 2018-06-05 | 2019-11-27 | 충남대학교산학협력단 | Gaba를 유효성분으로 하는 살모넬라 감염질환의 예방 및 치료용 조성물 |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103547240A (zh) * | 2011-06-16 | 2014-01-29 | 索雷斯生命科学公司 | 用于人类自主神经系统的平衡和维持健康的系统和方法 |
CN103547240B (zh) * | 2011-06-16 | 2016-03-30 | 索雷斯生命科学公司 | 用于人类自主神经系统的平衡和维持健康的系统和方法 |
CN110996910A (zh) * | 2017-05-24 | 2020-04-10 | 奥维德医疗公司 | 抑郁障碍的治疗 |
CN115105499A (zh) * | 2017-05-24 | 2022-09-27 | 奥维德医疗公司 | 抑郁障碍的治疗 |
CN114404437A (zh) * | 2022-03-15 | 2022-04-29 | 山东中医药大学 | 没食子酰芍药苷在制备gabaa受体抑制剂中的应用 |
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