CN1942179A - 用于治疗不安腿综合征和成瘾症的α-氨基酰胺衍生物 - Google Patents
用于治疗不安腿综合征和成瘾症的α-氨基酰胺衍生物 Download PDFInfo
- Publication number
- CN1942179A CN1942179A CNA2005800118905A CN200580011890A CN1942179A CN 1942179 A CN1942179 A CN 1942179A CN A2005800118905 A CNA2005800118905 A CN A2005800118905A CN 200580011890 A CN200580011890 A CN 200580011890A CN 1942179 A CN1942179 A CN 1942179A
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- Prior art keywords
- benzyl amino
- benzyloxy
- propionic acid
- acid amide
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明涉及某些α-氨基酰胺衍生物在治疗RLS和成瘾症中的用途。本发明的化合物能够基本没有副作用的减少或甚至终止RLS和成瘾症的症状。
Description
技术领域
本发明涉及α-氨基酰胺衍生物(单胺氧化酶B(MAOB)抑制剂、钠通道阻断剂、多巴胺重摄取抑制剂和谷氨酸盐水平调节剂的化学类)在治疗不安腿综合征(RLS)和成瘾症中的用途。
背景技术
不安腿综合征(RLS)是一种经过充分定义的、可识别的临床病种,其特征为在膝关节和踝关节之间的腿部深处以及较少见的在臂部有不适的蠕动、烧灼或牵拉感。该综合征在四肢静息时出现,特别是在傍晚和夜间出现,且通常经由运动缓解。其后果是出现睡眠障碍、睡眠潜伏期延长、伴有减少或缺乏慢波睡眠的总睡眠时间减少和睡眠效率降低。
流行病研究已发现RLS普遍发病于成人,其在普通群体中成人的终身流行率为9%到15%(Phillips B Epidemiology of restless legs syndrome inadults Archives of Internal Medicine 160(14)2137-2141 2000)。国际RLS研究组织标准(1995)定义RLS患者应存在下列症状(Walters AS Towarda better definition of the Restless Legs Syndrome Movement Disorders 10(5)634-642 1995):
1.伴随有感觉异常或感觉迟钝的想要运动四肢的愿望。
2.运动不止(患者在清醒时运动四肢以缓解不适)。
3.症状在休息时更加严重或仅在休息时存在,通过活动得到至少部分和暂时的缓解。
4.症状在傍晚或夜间加剧。
其它普遍特征是睡眠障碍、睡眠中周期性四肢运动(PLMS)和清醒时同样的不自主运动(Walters AS Toward a better definition of the RestlessLegs Syndrome Movement Disorders 10(5)634-642 1995)。
由于PLM经常伴随着夜间惊醒或觉醒,因而PLM的数量和相关参数被认为是RLS严重度的标志。
因为在睡眠和清醒期间的这些问题,RLS患者可能在其工作、社交生活和娱乐活动中都存在困难。
RLS的发病机制仍未知,但是近来证据支持该病可能是受多种影响控制的对正常中枢神经系统起搏器解除抑制的结果。对RLS的正电子成像(PET)研究支持多巴胺能系统在该病症发病机制中具有作用。Turjanski等人揭示,与对照者相比,RLS患者的尾和核壳中的18F-多巴摄取都有轻度降低,且在核壳中的降低具有显著性(p=0.04)。相同研究证明在这些患者的核壳中D2多巴胺受体结合显著下降(Turjanski N Neurology 52932-937 1999)。同样的,Ruottinen等人研究未经药物治疗的RLS患者群体并证明在核壳中18F-多巴摄取下降11%和在尾核中18F-多巴摄取下降12%(Ruottinen HM Neurology 54 502-504 2000)。这些数据提示存在轻度的纹状体突触前多巴胺能功能障碍。
尽管Restex(L-多巴制剂)近来已在德国投放入市场,目前在美国尚无指示用于治疗RLS的药物。用于治疗RLS症状的其它产品包括鸦片制剂、苯二氮卓类和一些抗惊厥药。多巴胺激动剂(如卡麦角林、普拉克索和罗匹尼罗)也已被建议用于RLS治疗。所有这些治疗都有如具有副作用、相互干扰、作用持续时间短和滥用潜力的缺点。可提供的证据表明多巴胺能系统的不足在RLS中具有重要作用。由于MAOB抑制剂影响多巴胺的代谢导致多巴胺在其受体时程的延长,我们提议使用α-氨基衍生物治疗RLS。多巴胺能系统不足具有重要作用的另一病症是成瘾症,其可被定义成特征为强迫性的寻找和摄取药物的病理行为。持续的使用药物被认为可以在涉及动机的神经回路中引起导致依赖、药物渴望和复发的长期的功能变化。
通常,滥用的甚至具有不同首要分子靶的不同药物(苯异丙胺、可卡因、海洛因、烟碱、醇)具有增加中脑边缘(mesolimbic)系统中多巴胺传递的普遍作用。已使用不同方法治疗成瘾症且它们中的大多数以调节多巴胺能系统为目的。
MAOB抑制剂在人和灵长类中影响多巴胺的代谢,导致多巴胺在其受体时程的延长。业已表明,使用MAOB抑制剂有利于其中存在多巴胺能不足(如在PD中)的病症治疗。
新的证据支持MAOB抑制剂有利于治疗成瘾症这一假说。在大鼠和人体内进行的研究已表明司立吉林(具体的MAOB抑制剂)在可卡因减毒作用中具有适度的抗强化(anti-reinforcing)效果并可以在停药过程中改善被认为导致复发事件的多巴胺不足(Schiffer等人,2003 Synapse 48:35-8)。
近来已观察到吸烟者血小板和脑中的MAOB活性降低。已推测在脑中MAOB活性的降低与烟碱成瘾性的增加有关。对另一MAOB抑制剂拉扎贝胺的多中心II期研究表明,拉扎贝胺(200mg/天)似乎增加戒烟的百分数(从17到30%)(Berlin等人,2002 Addiction 97:1347-1354)。
此外,业已表明,Na+通道阻断剂也可以有效治疗成瘾症。事实上近期的临床研究已显示托吡酯(topiramate)(Na+通道阻断剂)在治疗乙醇依赖中有效(Johnson等人,2003,The Lancet 361:1677-1685)。
目前成瘾症的治疗包括抗抑郁药、鸦片受体激动剂(如美沙酮)、鸦片受体拮抗物和部分激动剂(如纳屈酮和叔丁啡)、苯二氮卓类和用于醇减毒作用的安塔布司。这些治疗的缺点包括多种副作用和尚不令人满意的治疗功效。
由于有证据表明具有MAOB抑制活性的化合物和具有Na+通道阻断剂活性的化合物能够有效治疗成瘾症,我们提出使用α-氨基衍生物(本发明的单胺氧化酶B(MAOB)抑制剂和钠通道阻断剂的化学类)治疗成瘾症。
WO90/14334、WO94/22808、WO97/05102、WO97/0511和WO99/35215的内容在这里被引入作为参考,其公开了取代的苄氨基丙酰胺化合物在中枢神经系统具有活性和可以用作抗癫痫、抗帕金森、神经保护、抗抑郁和解痉安眠的药物(又见Pevarello P等人(1998),J.Med.Chemistry,41:579-590)。WO99/35125和WO99/35123揭示取代的苄氨基丙酰胺化合物在中枢神经系统具有活性并可以用作止痛药物。
发明内容
本发明提供了通过在治疗中体内使用某些α-氨基酰胺化合物治疗RLS和成瘾症的迅速和高效的方法,该方法是现存疗法的更好的替代。
在实施方案中,本发明包括至少一种药物的用途,该药物是式(I)的α-氨基酰胺化合物,或其异构体、混合物和可药用盐,其用于制备治疗不安腿综合征和成瘾症症状药物。:
其中:
●A是-(CH2)n-X-基团,其中n是0到5的整数,X是CH2、-O-、-S-或-NH-;
●s是1或2;
●R是呋喃基、噻吩基或吡啶环或苯环,任选地由独立选自卤素、羟基、氰基、C1-C6烷基、C1-C6烷氧基或三氟甲基的一个或两个取代基取代;
●R1是氢或C1-C6烷基或C3-C7环烷基;
●R2和R3是独立的选自氢;任选地由羟基或苯基取代的C1-C4烷基;任选地由独立的选自C1-C6烷基、卤素、羟基、C1-C6烷氧基或三氟甲基的一个或两个取代基取代的苯基;或R2和R3与它们连接的碳原子一起形成C3-C6环烷基环;和
●R4、R5是独立的氢、C1-C6烷基或C3-C7环烷基;或R4和R5与它们连接的氮原子形成5-7个原子的饱和杂环。
可药用
烷基和烷氧基可以是分支的或直链的基团。
本发明化合物的可药用盐包括,例如无机酸(如硝酸、盐酸、氢溴酸、硫酸和磷酸等)或有机酸(如乙酸、丙酸、羟基乙酸、乳酸、乙二酸、丙二酸、苹果酸、酒石酸、柠檬酸、琥珀酸、苯甲酸、肉桂酸、苯醇酸、甲二磺酸、对甲苯磺酸和水杨酸等)的酸加成盐。
一些式(I)的化合物可以有不对称的碳原子,因而或者作为外消旋混合物或者作为单独的光学异构体(对映体)存在。因此,式(I)的α-氨基酰胺的“可药用盐”这一术语还意其范围包括所有可能的异构体和它们的混合物,以及任何可药用代谢物、生物前体和/或前药,即该化合物具有的结构式不同于式(I)的α-氨基酰胺中的一种,但是在其施用于哺乳动物,特别是人时被体内直接或间接转变成具有式(I)的化合物。
优选的式(I)化合物中A是选自-CH2-、-CH2-CH2-、-CH2-S-、-CH2-CH2-S-和-(CH2)n-O-的基团,其中n是1到5的整数;
●s是1或2;
●R是苯环,任选地由独立选自卤素、三氟甲基、甲氧基或噻吩环的一个或两个取代基取代;
●R1是氢或C1-C4烷基;
●R2或R3之一是氢,且另一个是任选地由羟基或苯基(任选地由一个或两个卤素原子取代)取代的C1-C4烷基,或R2和R3都是甲基,或它们同与它们连接的原子一起形成环丙基或环戊基环;和
●R4、R5是氢或C1-C4烷基,或与它们连接的氮原子一起形成吡咯烷或哌啶环,和其可药用盐。
在有效剂量下可以单独使用或与其它式(I)的化合物组合使用而用于治疗患者RLS和成瘾症的式(I)具体化合物的实例包括:
2-(4-苄氧基苄氨基)丙酰胺;
2-[4-(2-甲氧基苄氧基)苄氨基]丙酰胺;
2-[4-(2-氟苄氧基)苄氨基]丙酰胺;
(S)-(+)-2-[4-(2-氟苄氧基)苄氨基]丙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-2-甲基丙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-N-甲基丙酰胺;
N-{2-[4-(2-氟苄氧基)苄氨基]}丙酰吡咯烷;
2-[4-(3-甲氧基苄氧基)苄氨基]丙酰胺;
2-[4-(3-氰苄氧基)苄氨基]丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]丙酰胺;
(S)-(+)-2-[4-(3-氟苄氧基)苄氨基]丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-2-甲基丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-N-甲基丙酰胺;
N-{2-[4-(3-氟苄氧基)苄氨基]}丙酰吡咯烷;
2-[4-(4-氟苄氧基)苄氨基]丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-2-甲基丙酰胺;
2-[4-(2-氯苄氧基)苄氨基]丙酰胺;
2-[4-(3-氯苄氧基)苄氨基]丙酰胺;
2-(4-苄氧基苄氨基)-3-羟基丙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-3-羟基丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-3-羟基丙酰胺;
2-(4-苄氧基苄氨基)-3-羟基-N-甲基丙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-3-羟基-N-甲基丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-3-羟基-N-甲基丙酰胺;
2-[4-(2-氯苄氧基)苄氨基]-3-羟基-N-甲基丙酰胺;
2-[4-(3-氰苄氧基)苄氨基]-3-羟基-N-甲基丙酰胺;
2-[4-(3-氰苄氧基)苄氨基]-2-甲基-3-羟基-N-甲基丙酰胺;
2-[4-(3-氯苄氧基)苯乙基氨基]丙酰胺;
2-{4-[2-(3-氟苯基)乙氧基]苄氨基}丙酰胺;
2-{4-[2-(3-氟苯基)乙基]苄氨基}丙酰胺;
2-[N-(4-苄氧基苄基)-N-甲基氨基]丙酰胺;
2-{4-[(3-氯苯氧基)苯乙基]氨基}丙酰胺;
2-(4-苄硫基苄氨基)丙酰胺;
2-[4-(2-氟苄硫基)苄氨基]丙酰胺;
2-[4-(3-氟苄硫基)苄氨基]丙酰胺;
2-[4-(3-苯基丙氧基)苄氨基]丙酰胺;
2-[4-(4-苯基丁氧基)苄氨基]丙酰胺;
2-[4-(5-苯基戊氧基)苄氨基]丙酰胺;
2-(4-苄氧基苄氨基)-3-苯基-N-甲基丙酰胺;
2-(4-苄氧基苄氨基)-3-甲基-N-甲基丁酰胺;
2-(4-苄氧基苄氨基)-2-苯基乙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-2-苯基乙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-2-苯基乙酰胺;
2-[4-(2-氟苄氧基)苄基-N-甲基氨基]-2-苯基乙酰胺;
2-[4-(3-氟苄氧基)苄基-N-甲基氨基]-2-苯基乙酰胺;
2-[4-(3-氯苄氧基)苄氨基]-2-苯基乙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-2-(2-氟苯基)乙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-2-(3-氟苯基)乙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-2-(2-氟苯基)乙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-2-(3-氟苯基)乙酰胺;
2-[4-(3-氯苄氧基)苄氨基]-2-(3-氟苯基)乙酰胺;
2-[4-(2-噻吩氧基]苄氨基]丙酰胺;
或它们的异构体、混合物和可药用盐。
在有效剂量下可以单独使用或与式(I)的其它化合物组合使用而用于治疗一种或多种患者的RLS或成瘾综合征的式(I)的优选化合物是(S)-(+)-2-[4-(2-氟苄氧基)苄氨基]丙酰胺或(S)-(+)-2-[4-(3-氟苄氧基)苄氨基]丙酰胺。
在一个实施方案中,被治疗的患者是需要缓解或抑制一种或多种的RLS或成瘾症症状的哺乳动物(包括人)。
具体而言,向需要上述治疗的哺乳动物施用一定剂量的如上所定义的式(I)的α-氨基酰胺,其每日剂量范围从约0.3到约100mg/kg体重。这里所用的“治疗”包括任何方法的照料或于哺乳动物(特别是人)的应用,其旨在a)预防该疾病或紊乱发生于可能易感染疾病/紊乱但尚未诊断为患病的受试者;b)抑制疾病/紊乱、或病症,即阻止其发展;或c)缓解疾病/紊乱、或病症,即引起疾病/紊乱、或病症的消退。
在包括人的哺乳动物中RLS和成瘾症状态可以因此而被抑制或缓解。
RLS症状的实例是在膝关节和踝关节之间的腿部深处有不停的运动、蠕动、烧灼或牵拉感。瞌睡和睡眠障碍是上述症状的直接结果。
成瘾症的实例是药物滥用、严重的酗酒、奖励缺乏症(rewarddeficiency syndrome,RDS)。
在另一方面,本发明包括作为可药用组合物的活性物质施用的式(I)的α-氨基酰胺,所述组合物具有治疗RLS和成瘾症的活性,其可以通过常规方法,例如通过将有活性物质与可药用、治疗惰性的有机和/或无机载体或赋形剂材料混合制备。
优选的用于在有效剂量下治疗患者的RLS和成瘾症的式(I)的化合物是(S)-(+)-2-[4-(2-氟苄氧基)苄氨基]丙酰胺或(S)-(+)-2-[4-(3-氟苄氧基)苄氨基]丙酰胺。式(I)的化合物和其可药用盐可以经由如以上引用的专利申请所描述的熟知的方法获得。
“组合疗法”(或“综合疗法”)包括施用本发明式(I)的α-氨基酰胺化合物和至少另一种物质,例如:
-多巴胺激动剂,如溴隐亭、卡麦角林、麦角乙脲、硫丙麦角林、罗匹尼罗、阿朴吗啡、sumanirole、罗替戈汀(rotigotine)、他利克索(talipexole)、二氢麦角隐亭和普拉克索、
-左旋多巴、左旋多巴和卡比多巴(SINEMET)、左旋多巴和缓释卡比多巴(SINEMET-CR)、左旋多巴和苄丝肼(MADOPAR)、左旋多巴和缓释苄丝肼(MADOPAR-HBS)、
-COMT抑制剂如托卡朋(tolcapone)和恩他卡朋(entacapone)、
-STALEVO、金刚烷胺
-和抗胆碱能剂,
它们作为特殊的治疗方案的部分,所述治疗方案旨在由这些治疗剂的共同作用提供有益效果。这类组合的益处包括减少常规药物(即不同于本发明的药物)的剂量从而减少这些常规药物的副作用。该组合的有利影响包括(但不限于)由治疗剂的组合产生的药物代谢动力学或药效学共同作用。这些治疗药物的组合施用通常在规定的时间内进行(一般由选择的组合物决定为数分钟、小时、天或周)。“组合疗法”可以是(但通常并非)旨在包括两种或更多的治疗剂作为分开的单独治疗计划部分的施用,其偶然和随机的产生了本发明所预期的组合效果。“组合疗法”旨在包括这些治疗剂以顺序方式的施用,即其中每种治疗剂在不同时间施用,和这些治疗剂或至少两种的治疗剂以基本同时的方式施用。可以例如通过给予患者具有混合比例的每种治疗剂的单个胶囊或多个的单独含有每种治疗剂的胶囊实现基本同时的施用。顺序的或基本同时的施用每种治疗剂可以通过任何合适途径实现,包括(但不限于)口服途径、静脉途径、肌内途径和从粘膜组织直接吸收。治疗剂可以通过相同的或不同的途径施用。例如,所选组合中的第一种治疗剂可以通过静脉注射施用,而该组合中的其它治疗剂可以口服施用。
另外,例如所有的治疗剂可以通过口服或静脉注射施用。施用治疗剂的顺序并不十分关键。“组合疗法”还可以包括如上所述治疗剂进一步结合其它生物活性成分和非药物疗法(如手术或放射治疗)的施用。在还包括非药物治疗的组合疗法中,非药物治疗可以在任何合适时间进行以从治疗剂与非药物治疗结合的共同作用中获得有益效果。例如,在合适的情况下,从治疗剂的施用中暂时取消非药物治疗几天甚至几周时,仍可获得有益的效果。
本发明的α-氨基酰胺组合物可以通过多种剂型施用,如以片剂、糖锭剂、胶囊、糖或薄膜包衣片剂、液体溶液、乳剂或混悬剂形式经口施用;以栓剂形式经直肠施用;如通过肌肉或静脉注射或输液经胃肠外施用;和以贴剂、软膏、乳剂、洗剂、溶液、凝胶、霜和鼻喷剂的形式经皮肤施用。
用于制备这类组合物的合适的可药用、治疗惰性的有机和/或无机载体或赋形剂材料包括例如水、明胶、阿拉伯胶、乳糖、淀粉、纤维素、硬脂酸镁、滑石、植物油、环糊精、聚亚烷基二醇等。式(I)的α-氨基酰胺组合物可以灭菌且可以含有本领域技术人员熟知的其他成分,例如防腐剂、稳定剂、湿润或乳化剂(如石蜡油、二缩甘露醇单油酸酯)、调节渗透压的盐、缓冲液等。
此外,固体的口服形式可以连同活性剂一起含有稀释剂(如乳糖、葡萄糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉)、润滑剂(如二氧化硅、滑石、硬脂酸、硬脂酸镁或硬脂酸钙和/或聚乙二醇)、结合剂(如淀粉、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮)、解聚剂(如淀粉、藻酸、藻酸盐或淀粉乙醇酸钠)、起泡混合物、染料、增甜剂、湿润剂(如卵磷脂、聚山梨酸酯、硫酸月桂酯)和通常无毒且药理无活性的用于药物制剂的物质。可以用任何已知方式制备药物制剂,例如通过混合、粒化、压片、糖包衣或薄膜包衣方法。
口服制剂包括可以通过常规方法(例如通过在片剂和颗粒上使用肠溶胞衣)制备的缓释制剂。
用于口服施用的液体分散剂可以是如糖浆、乳化剂和混悬液。糖浆还可以含有例如蔗糖或蔗糖连同甘油和/或甘露糖醇和/或山梨醇。
混悬液和乳化剂可以含有例如天然胶、琼脂、藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇作为载体。用于肌肉注射的混悬液或溶液可以连同活性化合物一起含有可药用载体,如无菌水、橄榄油、油酸乙酯、二醇类(如丙二醇)以及需要时还含有适量的盐酸利度卡因。用于静脉注射或输注的溶液可以含有例如无菌水作为载体,或优选的其可以是无菌、水性或等渗形式的盐溶液。
栓剂可以连同活性剂一起含有可药用载体,如可可脂、聚乙二醇、聚氧乙烯山梨聚糖脂肪酸酯表面活性剂或卵磷脂。
包含式(I)的α-氨基酰胺的组合物通常以单位剂量的形式含有例如每单位剂型20到7000mg的活性成分。取决于清除速率,每天给予1或2或3次适当的治疗。因此,理想的剂量可以在单一剂量中或作为以合适间隔施用的分开的剂量(例如每天施用2到4次或更多的亚剂量)存在。
包含式(I)的α-氨基酰胺的药物组合物每剂量单位(如胶囊、片剂、粉末注射、一茶匙量、栓剂等)可以含有从约20到7000mg的活性剂。
理想的治疗有效施用剂量可以由本领域技术人员容易的确定并将主要随着制剂的浓度、施用的方式和治疗的炎症状态或紊乱的发展而改变。此外,与治疗的具体受试者相关的因素,包括受试者年龄、体重、饮食和施用时间将产生调整剂量到合适的治疗有效水平的需要。
如上定义的本发明的用途和方法的优点很多,包括可能能够治疗基本上所有类型的RLS和成瘾症的症状。
实施例1
RLS的非盲法研究
对10个患有自发RLS的患者进行非盲法研究,每餐100mg的施用(S)-(+)-2-[4-(3-氟苄氧基]苄氨基]丙酰胺两周有效改善RLS症状。入选研究的患者要满足国际RLS研究团体所制定的最低诊断标准。患者的症状必须包括在至少6个月且在最近12周的至少15个夜晚有睡眠初始或睡眠持续方面的干扰,且其在基线评估中应该具有等于或大于15的IRLS 10(国际不安腿综合征)分数。进行身体检查、生化和血试验检测及心电图以确定满足选择的标准。在基线和治疗结束时进行两个晚上的多导睡眠描记法,以证明(S)-(+)-2-[4-(3-氟苄氧基]苄氨基]丙酰胺对睡眠的作用。通过下列评估等级评估有效性:国际不安腿综合征10(IRLS 10)、不安腿综合征生命质量(RLSQoL)、工作生产力和活动损伤量调查表(WPAI RLS)和临床总体印象(CGI部分I和CGI部分II)。
用(S)-(+)-2-[4-(3-氟苄氧基)苄氨基]丙酰胺治疗的患者在RLS症状上表现出显著的改善。
治疗两周后的分数与基线分数相比,在所有考虑的评估等级中都表现出降低速率趋势。
在该组患者中,(S)-(+)-2-[4-(3-氟苄氧基)苄氨基]丙酰胺具有良好的耐受性且没有不良反应的记录。
结果
入选该研究的10个患者证明在使用的全部评估等级有显著的改善。
入选的10个患者全部符合效力分析条件;全部完成了计划的14+3天的治疗。人口统计的基线数据表明平均年龄61.30岁的入选女性的70%很少具有伴发的基线疾病且没有身体检查上的异常。对于主要疾病,根据CGI标准并由IRLS-10分数确认认为其在70%的患者中对日常活动影响严重,该影响可以在约1/3的平常表现中(根据WPAI-RLS和RLS-QoLQ结果)被量化。PSG记录通过经由PLM觉醒指数8.90、睡眠效率72.62和睡眠期间惊醒次数的的基线值证实疾病对睡眠的影响。
CGI部分I在60%患者的疾病状态上有令人印象深刻的改善,另外40%则为顽固的疾病(图1)。这些改变具有统计上的显著性(P=0.031)。
CGI部分II在90%的患者中有不同程度的改善,且仅1位患者(10%)被认为没有改变(见表I)。
表I.自先前调查CGI部分II的改变
分数 | 总体 |
最终 极大程度改善N(%)很大程度改善N(%)较低程度改善N(%)没有变化 N(%) | 2(20)2(20)5(50)1(10) |
伴随着在全部患者中分数减少,IRLS-10等级具有总体分数上的统计显著性改善(p=0.002);该改善已在亚条目分析中经由达到统计显著性的“诊断特征”(p=0.002)和“疾病影响”(p=0.003)的改善和经由接近显著性的“相关特征”和“严重度”的改善得到确定(表II)。
表II.IRLS 10分数
参数 | 调查 | |||
基线 | 最终 | P(t检验) | ||
总体分数 | 平均值SD改变 | 27.504.33 | 21.804.80-5.70 | 0.002 |
诊断特征 | 平均值SD改变 | 11.201.75 | 8.501.51-2.70 | 0.002 |
相关特征 | 平均值SD改变 | 5.101.66 | 4.301.34-0.80 | 0.070 |
严重度 | 平均值SD改变 | 7.000.82 | 6.001.41-1.00 | 0.063 |
影响 | 平均值SD改变 | 4.201.62 | 3.001.56-1.20 | 0.003 |
如图2所示,RLS-QoLQ在总体分数上显著降低(p=0.002)。
WPAI-RLS在条目6有改善,该项给出在患者处理日常活动能力方面观察到的改善意见;事实上,如图3所示,损伤从34%到22%有统计显著性的降低(p=0.005)。
如图4、图5、图6所示,多导睡眠描记法记录(PSG)在PLM(清醒+睡眠)指数、PLM清醒指数、PLM睡眠指数和其它PSG参数趋势上相对基线具有统计显著性改善,而不改变整体睡眠结构。
总之,本试验揭示(S)-(+)-2-[4-(3-氟苄氧基]苄氨基]丙酰胺具有良好的安全记录并提供了在疾病和其临床表现上观察到的改善的证据。这些证据通过疾病相关因素的客观仪器测量(即PSG)得到加强。
一些动物模型被用于成瘾症的研究以检测测试化合物的效力。具体而言,进行了下列检测。发现所测试化合物在不同动物模型中降低某些药物滥用的行为效果,证明其对成瘾症具有潜在的治疗作用。
实施例2
小鼠中的可卡因相互作用研究
通常如安非他明和可卡因之类的精神振奋成瘾药在啮齿类和灵长类引起运动行为增加。一些具有抗瘾潜质的化合物可以预防由精神振奋药物引起的运动行为增加(Katz JL、Kopajtic TA、Myers KA、Mitkus RJ、ChiderM,Behavioral effects of cocaine:interactions with D1 dopaminergicantagonists and agonists in mice and squirrel monkeys.J Pharmacol ExpTher.1999 Oct;291(1):265-79)。
在可卡因诱导运动增加的小鼠模型中评估测试化合物的效果。
方法
受试对象:Swiss-Webster小鼠,雄性
仪器:自动光电管室
药物:腹腔注射可卡因20mg/kg,在注射可卡因之前即刻以不同剂量(10-100mg/kg)腹腔注射施用溶解于载体的测试化合物。
行为测试:动物(每试验组8只)接受腹腔注射可卡因(20mg/kg)或盐水以及测试化合物(10-100mg/kg)或其载体两者之一,并记录其运动活性1小时。
数据分析
时程:对于载体、单独的可卡因和单独的每种剂量的测试化合物+可卡因,每10分钟期间的平均值(+SEM)活性被做图。
最大效果:可卡因(20mg/kg)产生最大作用的30分钟时间期间被用于确定测试化合物的效果。对单个受试动物在30分钟期间的平均计数进行log 10变换以均一化方差用于随后的分析。进行ANOVA统计分析,将载体与单独可卡因的比值和每种剂量的测试化合物+可卡因与单独可卡因的比值相比较以确定显著性(p<0.05)的剂量效果。进行线性最小平方回归分析;在30分钟期间的平均计数对于受试动物的回归落于相对于测试化合物剂量的log 10值的曲线下降部分之上。从线性回归分析中确定AD50(减少可卡因诱导的兴奋50%的剂量)。
实施例3
大鼠药物辨别测定
药物辨别(DD)任务是评估化合物替代影响精神活动的药物(例如滥用的药物)的能力的方法。大鼠学习将内感受药物的刺激利用为信号,两个或三个操作特征的信号将产生食物释放(情景依赖性学习)。该任务构成了检验“主观”药物效果的最佳动物模型。此外,在某些实例中,DD方法可能具有独立测量一种药物的几种不同主观效果的能力,这些主观效果包括一些促使药物滥用(引起欣快的)的效果和其它阻止药物滥用(引起疼痛的)的效果。
果在大鼠可卡因辨别测试模型中评估所测试化合物促进或阻止药物滥用的效。
(Colpaert FC(1986)Drug discrimination:behavioral,pharmacological and molecular mechanisms of discriminative drug effects,in Behavioral Analysis of Drug Dependence,Goldberg SR和Stolerman IP编辑,161-193页,Academic Press,Orlando)。
方法
受试对象
在雄性Sprague-Dawley大鼠中进行研究。所有动物被养在具有12-h光照/黑暗周期(光照在7:00AM开始)、控制温度和湿度的动物饲养场。所有试验在8:00AM到3:00PM之间光照/黑暗周期的光照期进行。大鼠保持在其随意体重的约80到85%。
可卡因辨别
每天在测试后用约15g的标准实验室饲料喂大鼠至少30分钟使其在研究全程维持其体重。每天将受试动物放在两杠杆操作控制室中置于减弱光和声音的环境中接受测试。测试中始终存在白噪声以掩盖外来声音。通过装在前面板顶部中央的灯(场灯)进行周围照明。杠杆以17cm间隔设置,在每个杠杆和前面板之上装有成对的光源(光发射二极管;LED)。强化应答给予一个45mg的固体食物与放在该箱前面板的杠杆中间的食物托盘。最初在食物强化的10次应答固定比率(FR 10)程序下训练受试动物按压两个杠杆和辨别腹腔注射29μmol/kg的可卡因(10mg/kg)和腹腔注射的盐水。在注射可卡因后,仅在一个杠杆的应答被强化;在注射盐水后,在另一个杠杆的应答被强化。可卡因正确的杠杆和盐水正确的杠杆的分配在大鼠间得到平衡。注射后立即将大鼠放置于试验箱内。在场灯和LED照亮之前有一个场灯和LED熄灭且响应无预定结果的5分钟间期。仅在正确杠杆的应答被强化,对于在不正确杠杆的应答重新设定FR应答需要。每次食物提供接有全部照明熄灭的20秒间期,在此期间的响应无预定结果。实验期在20次食物提供或20分钟(任何首先发生)之后结束。注射可卡因(C)和盐水(S)的训练实验期每天进行,每周进行5天和按照双交替顺序(如SCCS)进行。
当试验动物表现达到标准(即在总体上和经历4个顺序实验期的第一个FR 10实验期达到至少85%的正确应答)开始测试。在注射后达360分钟的不同时间施用选择剂量的测试化合物以检查辨别刺激效果的时程。在一次测试实验期之后,要再次用于测试的受试动物需要完成两个顺序(可卡因和盐水)训练实验期并达到上述执行标准。重复测试时在测试之间至少间插两个训练实验期,直到在每个受试动物中确定完整的剂量效果。除了是在任一杠杆上的20次顺序应答被强化,测试实验期和训练实验期相同。
计算在可卡因辨别方法中研究的每只大鼠的总体应答率和发生在可卡因正确的杠杆上的应答百分数。计算在测试的每一药物剂量得到的各个测量值的平均值。如果在某一剂量下的大鼠应答少于一半,该剂量的可卡因正确应答百分数的平均值不被计算。至少20%可卡因正确应答被接受作为假定相对于盐水有显著性差异的保守标准;80%或更高的可卡因正确应答被认为与可卡因的训练剂量相似,且在此之间的可卡因正确应答水平被认为是部分的代替。
数据分析
依据从最长持续达20分钟的整个实验期收集的数据对可卡因辨别研究的结果进行评估。
如果某一受试个体在测试中没有完成一固定比率程序,它的数据被包括于应答率的平均值,但不被包括于可卡因杠杆应答百分数的平均值。对于代替可卡因的测试化合物(>80%药物正确应答)使用线性回归分析计算ED50。对于部分代替可卡因的测试化合物(>20%和<80%药物正确应答),给出产生最大代替的最低剂量和百分数。对于不能代替可卡因的化合物(<20%药物正确应答),计算其测试的最高剂量。
实施例4
大鼠药物自我给药测试
药物自我给药测试是被广泛用于研究药物(如可卡因)的强化性质和在这些补偿性质方面多种化合物的效果的方法。在本测试中训练大鼠“工作”以接受经口或经静脉的药物施用。该行为方法使可以评估测试化合物是否在成瘾药物的强化性质上具有效果(Caine S.B.;Lintz R;Koob G.F.:Intravenous drug self-administration techniques in animals.In:BehavioralNeuroscience:A Practical Approach.由A.Sahgal编辑,117-143页,OxfordUniversity Press,New York,1993;Fischman MW,Behavioralpharmacology of cocaine J.Clin Psychiatry.1988 Feb;49 Suppl:7-10)。
方法
受试对象
雄性Sprague-Dawely大鼠,重350-400g,一笼3只饲养,随意供给食物和水,维持于12-h光照-黑暗周期(光照在7:00am-7:00pm)。
自我给药
全部动物在开他敏(60mg/kg腹腔注射)和戊巴比妥钠(20mg/kg腹腔注射)麻醉下被手术植入常用硅橡胶颈静脉导管。导管由皮下穿过至头骨部分露出,在此处被以丙烯酸酯齿(dental acrylic)固定于四个包埋在头骨中的不锈钢螺丝钉上。在自我给药实验期内(一般每周6天),导管经由金属弹簧连接于一个旋转系统,该系统连于输注泵上。
手术后的七天中,动物被允许每天2-h进入箱侧壁距箱底3cm处装有金属杠杆的标准操作性条件作用箱。按压杠杆的压力需要平均为30克(在不同箱子中范围从25到35克)。箱子本身被放于声音减弱室。在每个操作室中有两个杠杆,一个杠杆产生药物注入,而另一个在整个实验期没有作用。一个有作用的杠杆按压产生4s时间的溶解于0.9%生理盐水的0.1ml盐酸可卡因(0.50mg/kg/注射)的静脉注射。旋转系统使动物可以在箱中自由活动。在注射开始的同时,在操作室同侧壁的杠杆上方1cm的刺激照明被开启20s,在此期间内杠杆是无效的。在信号照明没有点亮期间,杠杆按压在持续强化程序(固定比率1,FR-1)下被加强。一旦证明动物稳定的摄取药物三天(在三天中每日摄取的波动范围小于15%),自我给药程序转换为FR10直到稳定(15-20天),而后研究开始。在测试当天,在实验期开始前即刻用测试化合物腹腔注射动物做预处理。使用不同剂量的测试化合物。使用拉丁方设计使每个剂量在每只动物只测试一次。基线自我给药与药物测试日至少间隔两天。
数据分析
记录在120分钟实验期获得的强化总数,对重复的测量使用单因子方差分析(ANOVA)或在合适处使用学生t-检验进行数据的统计分析。使用Newman-Keuls后检定(posteriori test)对个体平均值进行比较。
实施例5
大鼠中可卡因诱导的行为敏化作用
药物成瘾是特征为强迫性寻找和摄取药物的病理行为。这些行为改变的一种动物模型是由向啮齿动物重复施用精神振奋药物而引起的运动活性的长期持续增加(Robinson等人,1993),其被称为药物诱导的行为敏化作用。在大鼠的可卡因诱导的行为敏化作用模型中评估测试化合物的效果。
方法
受试对象
使用在到达时体重为200-250g的雄性Wistar大鼠。
运动活性测量仪器
对运动活性的测量在16个相同的由金属丝悬挂的箱子(每个测量为36cm(L)×25cm(W)×20cm(H))中进行。每个箱子沿长轴装有两套红外发射检测光电元件,这两套光电元件距箱底1cm高和距箱前面和背面8cm。背景噪声由白噪声发生器提供。在箱子内的运动产生光电管信号中断,其由IBM-兼容的计算机自动记录。
敏化作用方法和处理
动物在实验前适应运动活性室连续2-3天。大鼠接受5次每日腹腔注射可卡因(15mg/kg)或盐水和测试化合物(40-100mg/kg腹腔注射)或其载体两者之一,记录运动活性3小时。在最后一次可卡因或盐水注射10天后(第15天),在无测试化合物条件下用15mg/kg可卡因激发动物,并再次监测运动活性3h。
在用可卡因处理的第15天,以腹腔注射载体进行预处理的动物表现出增加的运动应答(高于第一天20%,p<0.05)。在最后注射可卡因或盐水10天之后,在无测试化合物条件下以15mg/kg可卡因激发动物,并再次监测运动活性3h。以可卡因预处理的和没有接受测试化合物的大鼠被预期表现出应答可卡因的增加的运动活性(高于第一天30%,p<0.05)。如果用测试化合物预处理的大鼠在可卡因处理的5天内没有表现出运动活性的增加,测试化合物被认为具有预防精神振奋药物成瘾的效果(Koob,G.F.、Sanna P.P & Bloom F.E.Neuron 21,467-476 1998;Robinson T.E.&Berridge K.C.The neural basis of drug craving:an incentive-sensitizationtheory of addiction.Brain Res Rev 18,247-91,1993)。
数据分析
使用双功能ANOVA在包括四个实验组(即盐水/载体、盐水/测试化合物、可卡因/载体和可卡因/测试化合物)和两个时间点(第1天和第5天)的单因素水平对重复的测量数据(3小时内打断光束的总数)进行分析,继之进行简单的效果分析。再次使用双功能ANOVA在单因素水平分析重复的测量以比较第1天和攻击天,继之使用Newman-Keuls事后检定。
实施例6
猴药物辨别测定
可卡因辨别是广泛用于评估候选治疗剂的行为测定。由急性施用测试化合物产生的类似可卡因的行为效果的效力和时程在该方法中被测定。具体的,测试化合物或者单独的或作为可卡因的预处理施用于训练辨别0.4mg/kg可卡因和盐水的恒河猴。
方法
受试对象
受试对象是成年雄性恒河猴(Macaca mulatta)。猴以每天一餐3-4片猴饼干(Purina Monkey Chow Jumbo#5037)和一片新鲜水果外加操作实验期提供的水果味固体食物维持。水对于所有猴在全部时间自由供给。猴被养在控制湿度和温度的、有12小时光照-黑暗周期(光照从7am到7pm)的房间。
仪器
每只猴被单独养在通风良好的不锈钢室(56×71×69cm)。所有猴的房箱前壁被改装入一个操作面板(28×28cm)。在距操作面板顶部3.2cm处以2.54cm间距水平安装3个正方形半透明的应答键。每个键可以用红色或绿色刺激光(超亮LED)照明。操作面板还支持外部安装的固体食物分配器(Gerbrands,Model G5210),该分配器可以向安装在箱内操作应答面板下的食物容器释放1g固体食物。操作面板的运转和数据采集由置于单独房间的计算机完成。
辨别训练
药物辨别方法与其它研究所用相同(Lamas X、Negus SS、Hall E和Mello NK(1995)relationship between the discriminative stimulus effectsand plasma concentrations of intramuscular cocaine in rhesus monkeys.Psychopharmacology 121:331-338;Negus SS、Mello NK、Portoghese PS、Lukas SE和Mendelson JH(1995)Role of delta opiod receptors in thereinforcing and discriminative stimulus effects of cocaine in rhesusmonkeys.J Pharmacol Exp Ther 273:1245-1256;Negus SS、Mello NK、Lamas X和Mendelson JH(1996)Acute and ch ronic effects of flupenthixolon the discriminative stimulus and reinforcing effects of cocaine in rhesusmonkeys.J Pharmacol Exp THer 278:879-890)。
辨别实验期由多个周期组成并且每周实施5天。每个周期由15分钟间期和接着的5分钟应答期组成。在间期中,所有刺激灯熄灭且响应无预定的结果。在应答期,右、左边的应答键被红色或绿色光照明,猴在食物供给的固定比率(FR)30程序下应答可以得到高达10次的固体食物。对于一组的猴,左键由绿色光照明,右键由红色光照明。对另一组猴,应答键的颜色相反。中央键在任何时间都没有光照明,应答中央键无预定的结果。如果在5分钟应答期结束前给出所有可提供的食物,照明应答键的刺激光熄灭,该应答期剩余时间中的应答无预定的结果。在训练日,猴在每次间期开始后5分钟(即应答期前的10分钟)被肌肉注射盐水或0.40mg/kg可卡因。在注射盐水后,仅应答于绿色键(盐水正确键)给予食物,而接着施用0.40mg/kg可卡因后仅应答于红色键(药物正确键)给予食物。对于在不正确键的应答重新设定在正确键的FR需要。每日实验期由1到5个周期组成,且如果施用可卡因的训练剂量,仅在最后周期内施用。因此,训练日由0-5个盐水周期接0-1个药物周期组成。
在每个周期的应答期,三个独立的变量被确定:1)在给予第一次强化前的注射-正确应答的百分数[(在第一次强化前的注射-正确应答/在第一次强化前的总应答数)×100];2)整个应答期的注射-正确应答的百分数[(在整个应答期的注射-正确应答/在整个应答期的总应答数)×100];和3)应答率(在应答期的总应答/刺激光照明的总时间)。当在8次顺序训练实验期中有7次符合下列3个标准时,猴被认为已获得可卡因辨别:1)在给予第一次强化前的注射-正确应答的百分数大于或等于全部周期的80%;2)整个应答期的注射-正确应答的百分数大于或等于全部周期的90%;和3)在全部训练周期至少获得一次固体食物。
辨别测试
一旦猴符合可卡因辨别的标准水平,开始测试。除了在任一键应答产生食物供给外,测试实验期与训练实验期一致,可卡因或测试化合物施用如下。进行两组实验以表征将测试化合物单独施用或作为对可卡因的预处理施用的效果。在第一组实验中,测试化合物单独效果的时程被确定。在测试实验期的开始施用单剂量的测试化合物(1-100mg/kg),和在10、30、100和300分钟后开始5分钟的应答期。在第二组实验中,测定测试化合物预处理对可卡因辨别的影响。在测定累积的可卡因剂量效果曲线(0.013-1.3mg/kg)的测试实验期之前,在适当的时间施用单剂量的测试化合物。通常,测试药物被评估至其剂量产生可卡因剂量效果曲线的显著改变或降低整个实验期平均应答率至小于0.1应答/秒。
数据分析
对可卡因正确应答的百分数(整个应答期间)和应答率以测试化合物施用后的时间(用于时程研究)或以可卡因的渐增剂量(用于测试化合物预处理研究)的函数作图。仅当猴在某个周期发出至少30次应答时(即产生一次强化物给予的足够应答)该周期的可卡因正确应答的百分数才被包括于分析中。ED50值被定义为产生50%可卡因正确响应的测试化合物或可卡因的剂量,和使用线性内插法依据个体受试对象的剂量-效果曲线计算。对于每种测试化合物,依据在峰值效果的合适时间得到的数据计算ED50值。
实施例7
猴药物自我给药测试
实验动物的自我给药方法经常用于评估用于控制可卡因和相关精神振奋药物成瘾症的候选药物。通常,进行实验以确定药物是如何改变应答比率或决定在对固定或逐渐增加的应答数有强化结果(即固定比率(FR)或渐进比率程序)的单个程序下的静脉注射次数(Mello NK和Negus SS(1996)Preclinical evaluation of pharmacotherapies for treatment ofcocaine and opioid abuse using drug self administration procedures.Neuropsychopharmacology 14:375-424)。在这类研究中,对静脉注射自我给药行为的改变和由另一强化物(如提供食物)维持的行为的比较可以对候选药物的作用提供行为选择性的测量(Woolverton WL(1996)Intravenous self-administration of cocaine under concurrent VI schedulesof reinforcement.Psychopharmacology 127:195-203.;Negus SS、BrandtMR和Mello NK(1999)Effects of the long-acting monoamine reuptakeinhibitor indatraline on cocaine self-administration in rhesus monkeys.JPharmacol Exp Thet 291:60-69;Caine SB、Negus SS和Mello NK(2000)Effects of dopamine D1-like and D2-like agonists on cocaineself-administration in rhesus monkeys:rapid assessment of cocainedose-effect functions.Psychopharmacology 148:41-51)。
方法
受试对象
受试对象是成年雄性恒河猴(Macaca mulatta)。以每天一餐3-4片猴饼干(Purina Monkey Chow Jumbo#5037)和一片新鲜水果外加操作实验期提供的水果味固体食物维持猴。所有猴可以随时自由获取水。猴被养在控制湿度和温度的、有12小时光照-黑暗周期(光照从7am到7pm)的房间。
手术方法
双腔硅橡胶导管(内径0.7mm;外径2.0mm)被植入颈静脉或股骨静脉,从肩胛中部穿出。全部手术过程在无菌条件下进行。猴先用开他敏(5mg/kg)镇静,和用戊硫代巴比妥钠(10mg/kg静脉注射)麻醉。此外,用0.05mg/kg阿托品处理猴以减少流涎。在插入导气管后用异氟烷(1-1.5%于氧气中)维持麻醉。手术后施用阿司匹林或扑热息痛(80-160mg/天,口服)3天。每天施用抗生素普鲁卡因青霉素G(300000U/天,肌肉注射)5天。静脉注射导管通过由连接于弹性不锈钢绳和液体旋转阀门的惯用合适尺寸的尼龙外罩组成的系绳系统加以包护(LomirBiomedical、Malone,NY)。该弹性系绳系统允许猴自由移动。通过静脉注射施用速效巴比妥酸盐美索比妥钠(3mg/kg,静脉注射)对导管的畅通做定期的评估。如果静脉注射施用美索比妥钠在10秒内使肌肉张力消失,则认为导管是畅通的。
行为仪器
每只猴被单独养在通风良好的不锈钢室(56×71×69cm)。所有猴的房箱前壁被改造安装一个操作面板(28×28cm)。在距操作面板顶部3.2cm处以2.54cm间距水平安装3个正方形半透明的应答键。每个键可以用红色或绿色刺激光(超亮LED)照明。操作面板还支持外部安装的固体食物分配器,该分配器可以向安装在箱内操作应答面板下的食物容器释放1g水果味的固体食物。此外,两个灌注泵(B5P-1E型;Braintree Scientific,Braintree,MA,或980210型;Harvard Apparatus,South Natick,MA)被安装在每个箱子上方用于通过静脉注射导管的两条管腔传送盐水或药物溶液。操作面板的运转和数据采集由置于单独房间的计算机完成。
初始训练方法
用于评估可卡因和食物维持的应答与在其它研究所用相同(Negus SS、Mello NK、Portoghese PS和Lin CE(1997)Effect of kappa opioids oncocaine self-administration by rhesus monkeys.J Pharmacol Exp Ther282:44-55;Negus SS、Mello NK、Portoghese PS、Lukas SE和MendelsonJH(1995)Role of delta opiod receptors in the reinforcing anddiscriminative stimulus effects of cocaine in rhesus monkeys.J PharmacolExp Ther 273:1245-1256)。在基本方案下,食物和静脉注射可用于三个交替的部分。食物和静脉注射都可用于FR30强化程序。红灯结合给予食物和绿灯结合药物注射。食物和药物部分由5分钟时间间隔分开。完整的食物-药物-食物实验期持续120分钟和每天从3-5pm进行。在训练中,在药物部分中用于自我给药的溶液在0.032mg/kg/注射可卡因和盐水之间交替。训练猴直至达到下列稳定的可卡因自我给药标准:1)在每个实验期的药物因素期连续3天应答比率的改变不超过药物因素应答比率平均值的20%;2)由盐水替代第一天的药物因素应答比率下降所代表的盐水迅速耗尽。
药物自我给药测试
一旦猴达到可卡因和食物自我给药的高稳定水平标准即使用替代实验期开始测试,在替代实验期,用于盐水/可卡因训练剂量条件的不同剂量的可卡因(0.00032-0.1mg/kg注射)被替代。测试每种替代物一段时间(至少4天)和直到每天由可卡因和食物维持的强化数回归到基线水平时恢复可卡因的维持剂量。
测试化合物评估
使用预处理方法测试法评估测试化合物。第一个实验检查用盐水或测试化合物非随因处理对食物应答和可卡因应答的影响。在实验期之前肌肉注射(或腹腔注射和口服)施用测试化合物。测试化合物将被施用直至剂量产生或者在可卡因自我给药剂量-效果曲线的上升部分产生统计上显著的移动或者在第一次食物因素期间使应答消失。在第二次实验中将至少三个剂量的测试化合物作为在可卡因剂量-效果曲线峰值处单一剂量可卡因的预处理进行评估。这些初始研究被用于确定在药物自我给药方法中具有行为活性的测试化合物的剂量。一旦测试药物有行为活性的剂量被确定,施用该剂量作为对一系列不同的单一剂量可卡因的预处理。以此方式,可以在整体可卡因剂量-效果曲线确定测试药物的行为活性剂量的效果。测试化合物的其它剂量也可被测定。
数据分析
每天的注射总数或给予的固体食物被作为应答比率确定。使用单因素或双因素ANOVA评估在可卡因自我给药中测试化合物效果的数据。在显著性ANOVA后继之使用Duncan事后检定进行个体平均值比较。显著性标准设在p≤0.05。
Claims (9)
1.至少一种物质用于制备治疗不安腿综合征(RLS)和成瘾症的药物的用途,该物质是式(I)的α-氨基酰胺化合物,或其异构体、混合物和可药用盐或酯,
其中:
●A是-(CH2)n-X-基团,其中n是0到5的整数,X是CH2、-O-、-S-或-NH-;
●s是1或2;
●R是呋喃基、噻吩基,或吡啶环或苯环,任选地由独立的选自卤素、羟基、氰基、C1-C6烷基、C1-C6烷氧基或三氟甲基的一个或两个取代基取代;
●R1是氢或C1-C6烷基或C3-C7环烷基;
●R2和R3是独立的选自氢;任选地由羟基或苯基取代的C1-C4烷基;任选地由独立的选自C1-C6烷基、卤素、羟基、C1-C6烷氧基或三氟甲基的一个或两个取代基取代的苯基;或R2和R3连同与它们连接的碳原子一起形成的C3-C6环烷基环;和
●R4、R5独立地是氢、C1-C6烷基或C3-C7环烷基,或R4和R连同它们连接的氮原子形成5-7个原子的饱和杂环。
2.如权利要求1所定义的化合物的用途,其中A选自-CH2-、-CH2-CH2-、-CH2-S-、-CH2-CH2-S-或-(CH2)n-O-;n是从0到5的整数;s是1或2;R是苯环,任选地由独立选自卤素、三氟甲基、甲氧基或噻吩环的一个或两个取代基取代;R1是氢或C1-C4烷基;R2或R3中的一个是氢且另一个是任选地由羟基或苯基取代的C1-C4烷基或任选地由一个或两个卤素原子取代的苯基,或R2和R3都是甲基或可以与它们连接的原子一起形成环丙基环或环戊基环;和R4、R5是氢或C1-C4烷基,或与它们连接的氮原子一起形成吡咯烷或哌啶环。
3.如权利要求1或2所定义的化合物的用途,其中所述药物以每天约0.3到约100mg/kg体重的剂量施用。
4.如权利要求1到3中任一项所定义的化合物的用途,其中所述化合物选自:
2-(4-苄氧基苄氨基)丙酰胺;
2-[4-(2-甲氧基苄氧基)苄氨基]丙酰胺;
2-[4-(2-氟苄氧基)苄氨基]丙酰胺;
(S)-(+)-2-[4-(2-氟苄氧基)苄氨基]丙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-2-甲基丙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-N-甲基丙酰胺;
N-{2-[4-(2-氟苄氧基)苄氨基]}丙酰吡咯烷;
2-[4-(3-甲氧基苄氧基)苄氨基]丙酰胺;
2-[4-(3-氰苄氧基)苄氨基]丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-2-甲基丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-N-甲基丙酰胺;
N-{2-[4-(3-氟苄氧基)苄氨基]}丙酰吡咯烷;
2-[4-(4-氟苄氧基)苄氨基]丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-2-甲基丙酰胺;
2-[4-(2-氯苄氧基)苄氨基]丙酰胺;
2-[4-(3-氯苄氧基)苄氨基]丙酰胺;
2-(4-苄氧基苄氨基)-3-羟基丙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-3-羟基丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-3-羟基丙酰胺;
2-(4-苄氧基苄氨基)-3-羟基-N-甲基丙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-3-羟基-N-甲基丙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-3-羟基-N-甲基丙酰胺;
2-[4-(2-氯苄氧基)苄氨基]-3-羟基-N-甲基丙酰胺;
2-[4-(3-氰苄氧基)苄氨基]-3-羟基-N-甲基丙酰胺;
2-[4-(3-氰苄氧基)苄氨基]-2-甲基-3-羟基-N-甲基丙酰胺;
2-[4-(3-氯苄氧基)苯乙基氨基]丙酰胺;
2-{4-[2-(3-氟苯基)乙氧基]苄氨基}丙酰胺;
2-{4-[2-(3-氟苯基)乙基]苄氨基}丙酰胺;
2-[N-(4-苄氧基苄基)-N-甲基氨基]丙酰胺;
2-{4-[(3-氯苯氧基)苯乙基]氨基}丙酰胺;
2-(4-苄硫基苄氨基)丙酰胺;
2-[4-(2-氟苄硫基)苄氨基]丙酰胺;
2-[4-(3-氟苄硫基)苄氨基]丙酰胺;
2-[4-(3-苯基丙氧基)苄氨基]丙酰胺;
2-[4-(4-苯基丁氧基)苄氨基]丙酰胺;
2-[4-(5-苯基戊氧基)苄氨基]丙酰胺;
2-(4-苄氧基苄氨基)-3-苯基-N-甲基丙酰胺;
2-(4-苄氧基苄氨基)-3-甲基-N-甲基丁酰胺;
2-(4-苄氧基苄氨基)-2-苯基乙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-2-苯基乙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-2-苯基乙酰胺;
2-[4-(2-氟苄氧基)苄基-N-甲基氨基]-2-苯基乙酰胺;
2-[4-(3-氟苄氧基)苄基-N-甲基氨基]-2-苯基乙酰胺;
2-[4-(3-氯苄氧基)苄氨基]-2-苯基乙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-2-(2-氟苯基)乙酰胺;
2-[4-(2-氟苄氧基)苄氨基]-2-(3-氟苯基)乙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-2-(2-氟苯基)乙酰胺;
2-[4-(3-氟苄氧基)苄氨基]-2-(3-氟苯基)乙酰胺;
2-[4-(3-氯苄氧基)苄氨基]-2-(3-氟苯基)乙酰胺;
2-[4-(2-噻吩氧基)苄氨基]丙酰胺;
或其异构体、混合物和可药用盐。
5.如权利要求1到4中任一项所定义的化合物的用途,其中α-氨基酰胺是(S)-(+)-2-[4-(2-氟苄氧基)苄氨基]丙酰胺。
6.如权利要求1到4中任一项所定义的化合物的用途,其中α-氨基酰胺是(S)-(+)-2-[4-(3-氟苄氧基]苄氨基]丙酰胺。
7.与多巴胺激动剂和/或与左旋多巴、卡比多巴、苄丝肼和它们的组合物组合使用的权利要求1到6中任一项所定义的化合物的用途。
8.治疗患有不安腿综合征的受试者的方法,其包括向所述受试者施用治疗有效量的如权利要求1到6中任一项所定义的化合物。
9.根据权利要求8的治疗方法,还包括施用多巴胺激动剂和/或左旋多巴、卡比多巴、苄丝肼和它们的组合物。
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PCT/EP2005/004166 WO2005102300A1 (en) | 2004-04-22 | 2005-04-19 | α-AMINOAMIDE DERIVATIVES USEFUL IN THE TREATMENT OF RESTLESS LEGS SYNDROME AND ADDICTIVE DISORDERS |
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CN114667963B (zh) * | 2020-12-24 | 2024-04-26 | 中国科学院脑科学与智能技术卓越创新中心 | 一种非人灵长类动物药物成瘾性评估的装置 |
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EP1438956A1 (en) * | 2003-01-16 | 2004-07-21 | Newron Pharmaceuticals S.p.A. | Alpha-aminoamide derivatives useful as antimigraine agents |
DE602004025586D1 (de) * | 2003-08-25 | 2010-04-01 | Newron Pharm Spa | Alpha-aminoamid derivate zur verwendung als anti-inflammatorische wirkstoffe |
EP1588704A1 (en) | 2004-04-22 | 2005-10-26 | Newron Pharmaceuticals S.p.A. | Alpha-aminoamide derivatives useful in the treatment of restless legs syndrome and addictive disorders |
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Cited By (2)
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CN114667963A (zh) * | 2020-12-24 | 2022-06-28 | 中国科学院脑科学与智能技术卓越创新中心 | 一种灵长类动物药物成瘾性评估的装置 |
CN114667963B (zh) * | 2020-12-24 | 2024-04-26 | 中国科学院脑科学与智能技术卓越创新中心 | 一种非人灵长类动物药物成瘾性评估的装置 |
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