CN101102759A - 治疗药物和酒精依赖的甘氨酸再摄取抑制剂 - Google Patents
治疗药物和酒精依赖的甘氨酸再摄取抑制剂 Download PDFInfo
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Abstract
本发明涉及治疗或预防人的药物成瘾,特别是酒精中毒的方法,包括给需要的患者施用有效量的Gly-T1抑制剂,特别是N-甲基-N-[[(1R,2S)-1,2,3,4-四氢-6-甲氧基-1-苯基-2-萘基]甲基甘氨酸或其药学可接受的盐。
Description
本发明涉及治疗或预防人的药物成瘾的方法,包括给需要的患者施用有效量的药物。特别地,该方法涉及治疗酒精中毒。该方法也涉及甘氨酸运载体1型抑制剂的医药应用。
对受折磨的人、他/她的亲属和所交往的人具有多种消极后果的药物成瘾例如酒精中毒会遗留破坏性的疾病,因此迫切地需要新的治疗方法。确实,在过去一些年中,已经证明了新的药物治疗剂例如纳曲酮和阿坎酸在治疗酒精依赖方面是有效的(Sass等人,1996;Volpicelli等人,1992;Berglund等人,2003)。该研究用高酒精消耗的动物模型预言了这些物质的有效性(Czachowski等人,2001;Olive等人,2002;Parkes和Sinclair,2000)。不幸地是,纳曲酮和阿坎酸并不是在所有酒精中毒的人中都有效,因此需要新的药物治疗。
经甘氨酸运载体(GlyT)蛋白将甘氨酸再摄取到突触前神经末梢或邻近的神经胶质细胞构成了有效的机理,通过这一机理可以中止甘氨酸的突触后作用,并将细胞外甘氨酸水平恢复到基础值。现在已知有两种类型的甘氨酸运载体蛋白,神经胶质运载体蛋白(1型),GlyT1,和甘氨酸神经运载体(2型),GlyT2。GlyT1催化从突触间隙中清除甘氨酸,而将甘氨酸再摄取和再载入到突出囊泡中则需要GlyT2(Gomeza等人,2003;Curr Opin Drug Discov Devel 6(5):675-82)。
本发明人提供了治疗或预防人的药物成瘾的方法,包括给需要的患者施用有效量的GlyT1抑制剂。特别地,根据本发明的方法提供了一种通过施用GlyT1抑制剂治疗或预防酒精中毒的方法。
本发明的一个特定实施方案是N-甲基-N-[[(1R,2S)-1,2,3,4-四氢-6-甲氧基-1-苯基-2-萘基]甲基甘氨酸(MTHMPNM甘氨酸的游离碱)或其药学可接受的盐或4-[3-氟-4-丙氧基苯基]-螺[2H-1-苯并吡喃-2,4’-哌啶]-1’-乙酸(FPPSBPAA的游离碱)或其药学可接受的盐的应用。这些化合物是甘氨酸再摄取1型抑制剂,其容易通过脑血屏障,并且主要对GlyT1蛋白具有作用,而对GlyT2蛋白的作用可忽略不计。对于这两种化合物制备其HCl盐,其分别具有MTHMPNM甘氨酸和FPPSBPAA的编码。已知这些化合物是GlyT1抑制剂,并可以根据已知的方法来制备。作为锂盐的MTHMPNM甘氨酸在WO 00/07978(Gibson等人)中进行了描述,FPPSBPAA的制备在WO01/36423(Gibson和Miller)中进行了描述。其他有用的GlyT抑制剂包括SSR504734、ALX5407、甘氨酰月桂酰胺、肌氨酸、NFPS和其他肌氨酸类似物、CP-802,079、Org 24461和Org 24598。
在此之前,已经提示发现了这些甘氨酸运载体1型抑制剂在治疗疾病例如癫痫和精神分裂症中的应用(Aragon和Lopez-Corcuera,2003)。
MTHMPNM甘氨酸是甘氨酸再摄取抑制剂,其容易通过脑血屏障,并且主要对GlyT1蛋白具有作用,而对GlyT2蛋白的作用可忽略不计。如果以6mg/kgi.p.施用于重量约500g的大鼠,期望该化合物在约2.5小时将纹状体的细胞外甘氨酸水平提高约50-70%。在其他实验中,口服13.5mg/kg或更大则诱导明显的行为改变。
抗成瘾作用可以维持较长的治疗时间。这与所报道的几种其他的物质例如选择性5-羟色胺再摄取抑制剂、5-HT1A受体激动剂和阿片拮抗剂的抗成瘾作用形成对照,其他物质通常迅速开始作用于乙醇消耗,但在治疗的1或2周后失去作用(Hedlund和Wahlstrom,1996;Hedlund和Wahlstrom,1998)。
我们的结果表明,通过选择性GlyT1抑制剂,例如MTHMPNM甘氨酸的方法提高内源性细胞外脑甘氨酸水平,在对临床表现具有预定值的大鼠模型中强烈地、长效地和可逆地降低了乙醇摄取和对乙醇的偏好。
由选择性甘氨酸再摄取抑制剂产生的对乙醇摄取的显著降低可以由调节中脑边缘多巴胺活性介导。在大鼠(Blomqvist等人,1993;Blomqvist等人,1997;Di Chiara和Imperato,1985;Imperato等人,1986)和人(Boileau等人,2003)的伏核中多巴胺输出增加涉及药物成瘾和酒精中毒的发展和表达(Koob and Bloom,1988;Robinson andBerridge,1993;Wise,1987;Wise and Rompre,1989)。因此,由于GlyT1抑制剂增加了内源性甘氨酸水平,这导致了在伏核和/或在腹侧背盖区中与甘氨酸受体相互作用,产生了对中脑边缘DA神经元的去抑制。接着该多巴胺活性与乙醇消耗降低有关。其他成瘾剂例如阿片、可卡因和兴奋剂滥用也依赖于多巴胺循环(turnover)增加。这证明了所讨论和图解的GlyT1抑制剂对乙醇依赖性的治疗作用能够应用于其他药物依赖性,特别是阿片、可卡因和兴奋剂滥用。
该治疗可以在药物滥用的发作期间开始和维持。在先前关于甘氨酸运载体抑制剂和它们可能的应用的公开文献中,可以参考很多可能的应用的条目列表,来治疗由于乙醇滥用或戒酒(WO2004/013100)产生的问题,治疗尼古丁依赖性(WO03/031435),或与γ乙烯基GABA联用,治疗与戒酒有关的惊厥性或非惊厥性癫痫发作(GB 2 138 680)。在WO2004/080454中,作为一种选择,建议与N-单甲基甘氨酸组合使用5-羟色氨酸来治疗尼古丁戒断。在所有这些文献中,都没有涉及比仅仅提及该选择进一步的教导,而且没有关于所提及的选择的实际应用的证明数据或其他动机或指示或证据。
在所述文献中可以制备甘氨酸运载体1型抑制剂。特别地,在WO00/07978和WO01/36423中公开了选择性的GlyT1抑制剂,其中可以分别发现制备N-甲基-N-[[(1R,2S)-1,2,3,4-四氢-6-甲氧基-1-苯基-2-萘基]甲基甘氨酸(MTHMPNM甘氨酸的游离碱)和4-[3-氟-4-丙氧基苯基]-螺[2H-1-苯并吡喃-2,4’-哌啶]-1’-乙酸(FPPSBPAA的游离碱)的方法。
可以根据制药科学领域的标准技术来制备施用于需要治疗物质成瘾问题的对象的组合物。对于人,该化合物可以以每kg体重0.001-50mg的剂量,优选以每kg体重0.01-20mg的剂量施用,其中最佳剂量可以根据下列因素来确定,诸如给药途径、需要的作用时间、制剂类型(延迟释放或立即释放)、患者的类型、需要的化合物的类型、化合物的效力以及所治疗受者的其他身体特性,诸如其他疾病的共发病、肝代谢能力等等。GlyT1抑制剂治疗可以与其它适合治疗成瘾的药物联合。由于这是可选择的,GlyT1抑制剂也可以在治疗物质成瘾的药物中作为唯一的活性成分使用。
可以根据在甘氨酸的生物化学中已知的技术来确定选择性运载体抑制和如何确定这种生物作用的方法。在下面的实施例中描述了一种具体的方法,以其为基础,可以得到标准pIC50值为至少6.0,或优选6.5,或甚至更好为7.0,用于明确术语甘氨酸运载体1型抑制剂的含义。
对于药物依赖性、酒精依赖性等的诊断标准可以参考DSM IV修订版。
参考文献
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实施例
在异源性表达人GlyT-1b运载体的CHO细胞中确定甘氨酸摄取的方法。
A:克隆:根据Kim,K.-M.等人Mol.Pharmacol.1994,
45,608-617所述的方法通过PCR产生cDNA。用ALF DNA sequencerTM(Pharmacia)通过双脱氧序列测定来证实序列,并克隆成表达构建体pcDNA3(Invitrogen)。
B:转染:如Sambrook,J.等人(1989)在Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,Cold SpringHarbor,NY所述,用标准磷酸钙技术将hGlyT-1b转染到CHO细胞中。
C:选择:在包含1mg.cm-3遗传霉素的生长培养基中选择稳定的转染的细胞1周。挑选个体克隆体用于如下所述的进一步分析和常规地阳性传代。
D:培养条件:稳定地表达hGlyT-1b基因的细胞是在具有包含遗传霉素(0.5mg.cm-3,Gibco)的Glutamax-1(Gibco)和补充了10%Fetalclone II(Hyclone)的DMEM-NUT.MIX F12中,在37℃和5%CO2大气中培养的。在标准80cm2通风烧瓶(2×10-6m过滤器,Nunc)中进行维持性培养,当融合时通过胰蛋白酶消化(Sigma)进行细胞的传代培养。
E:分析步骤:将用于摄取研究的细胞植入不含遗传霉素的96孔板(每孔17,000个细胞)中,并在使用前培养48小时。为测定干氨酸转运,用预热到37℃的Hanks平衡盐溶液(HBSS)将细胞洗涤两次。在将加入受试化合物溶解于0.200cm3HBSS前除去过量液体。将板在37℃培养5分钟,然后加入[3H]甘氨酸(0.050cm3,150×10-6M,248Bq.nmol-1,NEN),并继续培养10分钟。用冰冷HBSS洗涤细胞以使摄取中止,然后除去过量液体并向每个孔中加入0.200cm3闪烁混合体(scintillation cocktail)。用粘附性膜封闭该板,摇动以确保在平板计数器中闪烁计数前样品是均匀的。
F:数据分析:用标准曲线拟合法来分析数据,以得到活性化合物的pIC50值(其中pIC50是指引起摄取被抑制50%时受试化合物浓度的负对数)
G:结果:
在本说明书中化合物即甘氨酸运载体1型抑制剂的pIC50值是指pIC50值至少为6.0的那些化合物。
对大鼠酒精成瘾的作用
材料和方法
动物
由Beekay(Stockholm,Sweden)提供重量250-300g(约50天大)的雄性成年Wistar大鼠。将动物分成四组,在恒定笼温(25℃)和湿度(65℃)下圈养。在进行任何试验(对乙醇偏好(preference)的筛选)前,允许这些动物适应新环境1周。将它们保持在有规律的亮-暗条件(07:00a.m.亮,19:00p.m.暗)下,并自由摄取标准的大鼠食物(Beekay食物)和自来水。该实验经动物实验伦理委员会,Gteborg,Sweden批准。
对乙醇偏好的筛选
除了水瓶外,让大鼠连续接近乙醇溶液的瓶子。在两周的时间里逐渐增加乙醇的浓度(2-4-6%v/v)。然后将该动物分别圈养在塑料笼中。让它们继续使用含有自来水或6%乙醇溶液的两种瓶子。当使用Wistar大鼠时,早先的观察证明在该浓度下乙醇的消耗量是大约最大的(Fahlke,1994)。在6-7周的时间里测定水和乙醇的摄取。使用所消耗乙醇溶液的量(g)占总液体摄取(g)液体的百分比作为乙醇偏好的指数。根据它们对乙醇的偏好,将大鼠分为低度(<20%乙醇)、中度(20%-60%乙醇)或高度(>60%乙醇)偏好。
药物
将乙醇(AB Svensk sprit)与常规的自来水溶解(2-4-6%v/v),并置于常规的300ml塑料瓶中。MTHMPNM甘氨酸,一种对GlyT1具有主要作用(即对GlyT2活性忽略不计的)甘氨酸再摄取抑制剂是由NVOrganon友情提供的,将其溶解于NaCl(0.9%),并将所施用的(i.p.).NaCl(0.9%)用作载体。
实验方法
为了适应该试验方法,将约80天大的对乙醇高度偏好的雄性Wistar大鼠限制为在1周的时间里每天只饮用3小时的乙醇(6%v/v)和水,所谓(受限制地)饮用。然后,开始每日施用MTHMPNM甘氨酸或载体。MTHMPNM甘氨酸或载体是i.p.注射的。在乙醇和水之间做出选择后,允许大鼠休息约40分钟,并允许其饮用3小时。在第一个实验中,用MTHMPNM甘氨酸(6mg/kg)或载体刺激大鼠2周,监测乙醇和水的摄取。继续该试验,并在限制饮用(access)期后停止。
在第二项实验中,使用一组新的大鼠,以检查甘氨酸再摄取抑制剂的作用是否可以再现。用MTHMPNM甘氨酸(6mg/kg)或载体将大鼠再次治疗3天。此外,然后将大鼠暴露于剥夺乙醇(限制饮用)的条件下2周时间,在此期间仅允许其每天饮用3小时水。在限制饮用期后,用MTHMPNM甘氨酸或载体再次刺激大鼠,并再次暴露于乙醇下13天。在实验第二部分结束时,逐渐降低MTHMPNM甘氨酸的剂量(6-3-1.5mg/kg),以检查所观测到的作用是否是剂量依赖性的。
在施用药物后向大鼠提供水和乙醇(6%v/v)瓶约40分钟。根据下列信息来选择3小时的饮用期:如果i.p.剂量为6mg/kg,预期MTHMPNM甘氨酸可以将纹状体的甘氨酸水平提高约50-80%,并持续约2.5到3小时。
统计
用重复测定的方差分析(ANOVA)对乙醇和水的消耗数据进行统计学分析,然后由此借助Fisher保护性最小显著差数(PLSD)检验进行分析。用配对t-检验对不同时间获得的值进行依赖性比较。所有值用平均值±SEM来表示。认为概率值(P)小于0.05是统计学显著的。
结果
实验1
MTHMPNM甘氨酸显著地降低乙醇摄取(集体效应(group effect)[F(1,10)=9.239 p=0.0125],时间效应[F(10,100)=1.765,p=0.0769]和相互作用期限(interaction term)[F(10,100)=0.721,p=0.7031],第4-14天),其中进行这样的实验时,在限制饮用期间(第1-3天)各组间的乙醇摄取没有差异。
在用MTHMPNM甘氨酸和载体治疗的组中水摄取没有差异(集体效应[F(1,10)=0.028 p=0.8713],时间效应[F(10,100)=3.031,p=0.0022]和相互作用期限[F(10,100)=1.164,p=0.3243],第4-14天)。
对于乙醇的偏好(第4-14天),重复测定的ANOVA没有显示集体效应[F(1,10)=1.978,p=0.1899],时间效应[F(10,100)=2.495,p=0.0102],但没有相互作用期限[F(10,100)=0.764,p=0.6631]。
与载体治疗组相比,在MTHMPNM甘氨酸治疗组中总液体摄取显著降低(集体效应[F(1,10)=26.516,p=0.0004],时间效应[F(10,100)=1.622,p=0.1110]和相互作用期限[F(10,100)=1.247,p=0.2710],第4-14天)。但是,同样在限制饮用期间,两组之间的总液体摄取有显著的差异(集体效应[F(1,10)=6.254 p=0.0314],时间效应[F(2,20)=1.813,p=0.1890]和相互作用期限[F(2,20)=0.751,p=0.4845],第1-3天)。
实验2
用MTHMPNM甘氨酸或载体i.p.注射新的一组雄性对乙醇高度偏好的Wistar大鼠。在注射后约40分钟,将所有大鼠暴露于乙醇(6%v/v)和水的自由选择下3小时。首先,所有大鼠在13天期间每日接受MTHMPNM甘氨酸(6mg/kg)或载体。该时期后是剥夺乙醇(限制饮用)期,其间仅允许所有大鼠饮用水(3小时/天)。在限制饮用期的最后4天,再次每日用MTHMPNM甘氨酸(6mg/kg,i.p.)或载体给大鼠注射,但仍然只能饮用水。当限制饮用期结束后,在注射MTHMPNM甘氨酸(6mg/kg)或载体后40分钟开始将大鼠再次暴露于乙醇和水之间的选择中。在该时期的前7天(第17-23天),大鼠接受6mg/kg的MTHMPNM甘氨酸,接下来4天(第24-27天),剂量降低到3mg/kg,最终剂量在2天(第28-29天)中降低为1.5mg/kg。开始该实验,并在不施用药物或载体的限制饮用(限制饮用的)期(3天)终止该实验,并将大鼠暴露于乙醇(6%v/v)和水摄取的自由选择中,每天3小时。
可以看出,在MTHMPNM甘氨酸治疗的前6天中乙醇摄取显著地降低(集体效应[F(1,13)=19.013 p=0.0008],时间效应[F(5,65)=4.772,p=0.0009]和相互作用期限[F(5,65)=3.919,p=0.0036],第4-10天)。在治疗1周后,该降低甚至更为显著(集体效应[F(1,13)=29.362p=0,0001],时间效应[F(6,78)=12.809,p<0,0001]和相互作用期限[F(6,78)=3.131,p=0.0084],第11-17天)。在限制饮用2周后,与施用载体后相比,施用MTHMPNM甘氨酸(6mg/kg)后乙醇摄取显著地降低(集体效应[F(1,13)=5.554 p=0.0348],时间效应[F(6,78)=1.954 p=0.0824]和相互作用期限[F(6,78)=0.582,p=0.7439],第17-23天)。但是,在乙醇剥夺期后,两组的乙醇摄取都显著地增加(MTHMPNM甘氨酸第14天vs.第19天,p=0.0135,配对t-检验;载体:第14天vs.第19天p=0.0006,配对t-检验)。在转换为3mg/kg的MTHMPNM甘氨酸后,组间的差异减小(集体效应[F(1,13)=1.179 p=0.2973],时间效应[F(3,39)=6.092 p=0.0017]和相互作用期限[F(3,39)=1.398,p=0.2579],第24-27天),在剂量降低到1.5mg/kg后,完全消除了这种差异(集体效应[F(1,13)=0.032 p=0.8614],时间效应[F(1,13)=4.349 p=0.0573]和相互作用期限[F(1,13)=2.839,p=0.1158],第28-29天)。在实验开始时,在最后的限制饮用期(第30-32天),两组之间的乙醇摄取没有差异。
在实验的第一部分(限制饮用前),在MTHMPNM甘氨酸治疗期间两组中水摄取没有显著的不同。在限制饮用期后,与对照组大鼠相比,MTHMPNM甘氨酸治疗的大鼠显示了增加的水摄取的趋势(集体效应[F(1,13)=4.032p=0.0659],时间效应[F(6,78)=3.328,p=0.0057]和相互作用期限[F(6,78)=1.031,p=0.4114],第17-23天)。在载体组中,限制饮用前与限制饮用后相比水摄取没有显著的差异(p=0.0949,第14天vs.第19天,配对t-检验),而在限制摄取期后MTHMPNM甘氨酸治疗的大鼠显著地增加了它们的水摄取(p=0.0188,第14天vs.第19天,配对t-检验)。
在限制饮用初期,MTHMPNM甘氨酸和载体治疗组之间对乙醇的偏好没有差异。在MTHMPNM甘氨酸(6mg/kg)或载体治疗的前6天两组之间也没有显著的差异(集体效应[F(1,13)=2.613 p=0.1300],时间效应[F(5,65)=0.981,p=0.4360]和相互作用期限[F(5,65)=1.515,p=0.1974],第4-10天)。在用MTHMPNM甘氨酸治疗约1周后,在MTHMPNM甘氨酸治疗的大鼠中观测到对乙醇的偏好有显著降低(集体效应[F(1,13)=35.038 p<0,0001],时间效应[F(6,78)=1.495,p=0.1910]和相互作用期限[F(6,78)=0.583,p=0.7431],第11-16天)。在限制摄取2周(包括用MTHMPNM甘氨酸或载体预治疗4天)后,在MTHMPNM甘氨酸治疗期间对乙醇的偏好保持降低,尽管与在载体治疗期间相比并不显著(集体效应[F(1,13)=4.353 p=0.0572],时间效应[F(6,78)=0.225 p=0.9676]和相互作用期限[F(6,78)=0.219,p=0.9695],第
17-23天)。将MTHMPNM甘氨酸剂量降低到3mg/kg减小了组间差异(集体效应[F(1,13)=2.274 p=0.1555],时间效应[F(3,39)=7.202 p=0.006]和相互作用期限[F(3,39)=1.825,p=1.1586],第24-27天),在MTHMPNM甘氨酸剂量降低到1.5mg/kg后,完全消除了这种差异(集体效应[F(1,13)=1.726p=0.2117],时间效应[F(1,13)=0.355 p=0.5618]和相互作用期限[F(1,13)=0.269,p=0.6127],第28-29天)。在实验开始时,在最后的限制饮用期(第30-32天),两组之间的乙醇偏好没有差异。
在MTHMPNM甘氨酸治疗4天后,与对照组相比,总液体摄取显著地降低(集体效应[F(1,13)=46.181 p<0.0001],时间效应[F(8,104)=14.054,p<0.0001]和相互作用期限[F(8,104)=3.633,p=0.0009],第8-16天)。当将限制饮用期的最后部分的摄取与重新引入乙醇和水之间的选择后的摄取相比较时,用载体和MTHMPNM甘氨酸治疗的动物的总液体摄取都显著地增加(载体:第14天vs.第19天,p<0.0001,配对t-检验;MTHMPNM甘氨酸:第14天vs.第19天,p<0.0001,配对t-检验)。当两组互相比较时,在限制饮用期后总液体摄取没有差异。
讨论
该研究表明,在对乙醇高度偏好的大鼠中选择性甘氨酸再摄取抑制剂剂量依赖性低降低了自愿的乙醇摄取。MTHMPNM甘氨酸降低乙醇摄取的作用表现为逐步地发展,并且在第二个实验中在治疗4-6天后最为显著。然后,该作用可以在整个治疗期得以维持。仅仅是最高剂量的MTHMPNM甘氨酸(6mg/kg)对乙醇摄取具有显著作用。较低的剂量(3和1.5mg/kg)不会导致显著的降低,即使在3mg/kg后观测到了乙醇摄取略微降低。MTHMPNM甘氨酸对乙醇摄取的抑制作用是强烈的、与剂量相关的和可逆的,表明所观测到的作用是特异性的,而不是由于乙醇摄取的偶然波动。
在第二个实验中,将MTHMPNM甘氨酸(6mg/kg)和载体治疗的大鼠暴露于乙醇剥夺(限制饮用)中14天。限制饮用期影响了乙醇摄取,因为在限制饮用期后载体和MTHMPNM甘氨酸治疗的动物显然降低了它们的乙醇摄取。令人感兴趣地,在限制饮用期后与用载体治疗的组相比,在MTHMPNM甘氨酸治疗的组中乙醇摄取保持了显著的降低,即使这种差异不象之前那么显著。有些意外地,限制饮用期也增加了水摄取,特别是在MTHMPNM甘氨酸治疗的大鼠中,表明在限制饮用期后,MTHMPNM甘氨酸治疗的大鼠具有用水摄取补偿乙醇摄取减少的倾向。对此结果的其他解释可以是,由于一些非特定环境改变而在限制饮用期改变了大鼠的液体摄取水平,或乙醇诱导的脱水诱导了水摄取的增加。
MTHMPNM甘氨酸也会影响对乙醇的偏好。在第一个实验中,与载体治疗组相比,在MTHMPNM甘氨酸治疗的大鼠中,对乙醇的偏好降低,尽管这种差异没有达到统计学显著的水平。在第二个实验中,在限制饮用期前和后与对照组相比,MTHMPNM甘氨酸组中对乙醇的偏好显著地降低。在任何一个组中,限制饮用期都没有改变对乙醇的偏好。其原因可能是在该研究中使用的大鼠已经是对乙醇高度偏好的(约90%),因此,难以在这些动物中进一步增加对乙醇的偏好。
至于水摄取,在MTHMPNM甘氨酸治疗的大鼠和对照组中并没有显著的差异,其中在第一个实验和在第二个实验的第一部分中,MTHMPNM甘氨酸治疗的大鼠总的液体摄取显著降低。组间的差异显然主要是因为乙醇摄取的减少,在限制饮用期后当水摄取增加时这种差异减小。因此,在MTHMPNM甘氨酸治疗期间总的液体摄取降低并不总是必然的。总而言之,这些结果表明,大鼠可能没有遭受该化合物引发的毒理学作用。同时从总的行为判断,这些动物的行为并未受到在该研究中使用的MTHMPNM甘氨酸剂量的影响。在发现剂量的先导实验中,10mg/kg剂量的MTHMPNM甘氨酸在十分之一的大鼠中诱导行为改变,并持续了约10-15分钟。在限制饮用/实验期间,与载体治疗的大鼠相比,MTHMPNM甘氨酸治疗的大鼠的平均体重显著地降低。
Claims (3)
1.治疗或预防人的药物成瘾的方法,包括给需要的患者施用有效量的Gly-T1抑制剂。
2.根据权利要求1的方法,其中药物成瘾是酒精中毒。
3.根据权利要求1或2的方法,其中该化合物是N-甲基-N-[[(1 R,2S)-1,2,3,4-四氢-6-甲氧基-1-苯基-2-萘基]甲基甘氨酸或其药学可接受的盐。
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