CN106176740B - 紫堇达明抗成瘾的医药用途 - Google Patents
紫堇达明抗成瘾的医药用途 Download PDFInfo
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- CN106176740B CN106176740B CN201610515782.1A CN201610515782A CN106176740B CN 106176740 B CN106176740 B CN 106176740B CN 201610515782 A CN201610515782 A CN 201610515782A CN 106176740 B CN106176740 B CN 106176740B
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
Landscapes
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及异喹啉类先导化合物紫堇达明(l‑corydalmine，l‑CDL)用于治疗成瘾相关病症的用途，所述成瘾相关病症包括滥用海洛因、鸦片、海洛因、甲基苯丙胺(冰毒)、吗啡、大麻、可卡因等毒品成瘾、以及尼古丁、酒精等物质成瘾相关疾病、尤其是兴奋剂类新型毒品成瘾及其引发的脑损伤。
Description
技术领域
本发明涉及医药技术领域，具体涉及异喹啉类生物碱紫堇达明的医药用途，其可用于制备治疗与成瘾损伤相关的病症的药物，用于预防和治疗人类新型毒品成瘾及新型毒品引起的脑组织损伤，所述成瘾损伤相关病症包括滥用海洛因、鸦片、甲基苯丙胺(冰毒)、吗啡、大麻、可卡因等毒品成瘾以及尼古丁、酒精等物质成瘾相关疾病，尤其是兴奋剂类新型毒品成瘾及其引发的脑损伤。
背景技术
日趋严重的毒品问题已成为全球性的灾难。直接危害人民的身心健康，并给经济发展和社会进步带来巨大的威胁。据联合国的统计，全世界每年毒品交易额达5000亿美元以上，毒品蔓延的范围已扩展到五大洲的200多个国家和地区，而且全世界吸食各种毒品的人数已高达2亿多，其中17～35周岁的青壮年占78％，每年因吸毒而死亡的人数高达40余万，一些非洲国家的新增艾滋病病毒感染者中，注射吸毒者占30％。
反复使用毒品使人形成瘾癖，体内发生适应性改变，造成的强烈的身体依赖性。一旦停药，出现焦虑不安、忽冷忽热、起鸡皮疙瘩、流泪、流涕、出汗、恶心、呕吐、腹痛、腹泻等戒断反应，吸毒者为避免这种痛苦而千方百计地维持吸毒状态，并且因耐受而不断加大剂量。毒品还具有精神依赖的特征，使成瘾者难以抑制渴求用药的欲望，不顾一切地寻觅和使用毒品。即使经过脱毒治疗，对毒品的心理依赖性也很难消除，导致复吸率居高不下，成为世界医、药学界尚待解决的课题.。
根据人大禁毒委员会《2015中国毒品形势报告》公示，目前我国全国登记在册的吸毒人员234.5万名，毒品滥用呈现“一降一增“和“三个全覆盖“的特点，滥用海洛因等阿片类毒品依赖人员比例有所下降，吸食合成毒品人员比例急剧上升，吸毒人群覆盖各个年龄段、不同文化程度、各个社会职业群体。指出：在新发现的吸毒人员中，滥用阿片类毒品人员占17.4％，其中滥用海洛因人员占14.6％；滥用合成毒品人员占80.5％，其中滥用冰毒等苯丙胺类兴奋剂人员占73.2％。
成瘾物质主要通过抑制多巴胺的代谢和摄取，促进多巴胺合成，升高奖赏相关脑区内多巴胺水平，增强多巴胺系统的功能，产生奖赏效应和精神依赖。以甲基苯丙胺(MA，冰毒)和摇头丸(MDMA)为代表的新型毒品在药理作用上属中枢兴奋药，，兴奋中枢神经，具有欣快、警觉及抑制食欲之作用，重复使用会成瘾；中毒症状包括多话、头痛、错乱、高烧、血压上升、盗汗、瞳孔放大、食欲丧失。大剂量使用导致神经中毒反应、幻觉和精神分裂样症状，引起精神错乱，思想障碍，类似妄想性精神分裂症，多疑、幻听、被害妄想等；长期滥用导致器官性脑症候群。有高血压及脑中风之危险。停用之戒断症状包括精神呆滞、昏睡、易怒、忧虑，有自杀的倾向。
目前，国内外批准上市的戒毒药物美沙酮、丁丙诺啡是阿片受体激动剂、，主要用于替代阿片类的药理作用，控制对药物的渴望并减少戒断症状,但是这些药物本身也具有依赖性，一旦停用，仍会出现戒断症状。阿片受体拮抗剂纳洛酮、纳屈酮等可抑制吸毒产生的欣快感和身体依赖，但它自身的不良反应与稽延性戒断症状交织在一起，相互影响，制约了它的接受率和坚持率。非阿片类药物可乐定及洛非西丁能激动肾上腺素能α2受体和作用于咪唑啉受体，降低大脑去甲肾上腺素的活性，减轻包括流泪、流涕、出汗、腹泻、寒战、肌肉疼痛、胃痉挛等大部分阿片类戒断症状。
目前，国内外均没有针对新型毒品的药物，临床仅采用苯二氮卓类镇静药物和氯氮平、利培酮或喹硫平等抗精神病药物对症治疗。
四氢原小檗碱同类化合物(tetrahychroprotoberberines,THPBs)是从中药延胡索中分离出的异喹啉类生物碱。左旋四氢帕马丁(l-tetrahydropalmatine，l-THP)，又称罗通定，是中药延胡索中的有效生物碱成分之一，主要有镇痛、镇静、安定作用。l-THP是一种新型脑内多巴胺受体阻滞剂，近年来研究显示l-THP在治疗成瘾方面具有良好的前景。但是l-THP具有明显的镇静作用，临床应用受到限制。因此我们合成系列四氢原小檗碱同类化合物，从中筛选出生物活性比l-THP更强而镇静作用更弱的先导化合物紫堇达明(l-corydalmine,l-CDL)，发现它在治疗各类成瘾性障碍，尤其用于治疗人类新型毒品成瘾及所导致的脑组织损伤方面的优势。
发明内容
发明人发现异喹啉化合物紫堇达明在治疗成瘾相关病症的独特作用，所述的异喹啉类化合物紫堇达明均包括其药学上可接受的盐。
本发明的一个方面涉及下式的异喹啉类化合物紫堇达明在制备用于治疗成瘾相关病症的药物中的用途：
紫堇达明(R,S)：R1＝R2＝OCH3，R3＝OCH3，R4＝OH。
所述异喹啉类化合物紫堇达明包括其手性拆分对映异构体及其药学上可接受的盐。
在一个实施方式中，所述成瘾相关病症为与成瘾损伤相关的疾病、新型毒品成瘾和新型毒品引起的脑组织损伤。
本发明的另一方面涉及一种用于治疗成瘾相关病症的药物组合物，所述的药物组合物由异喹啉类先导化合物紫堇达明及一种或多种药学上可接受的载体或赋形剂制备而成。本发明的药物组合物中还含有一种或多种用于治疗同类疾病的其他活性成分。
本发明提供的药物组合物可为临床上可接受的任何剂型形式，包括口服及消化道外给药形式的各种剂型。用于口服时，可以是片剂、胶囊、软胶囊、液体胶囊、颗粒剂、滴丸剂、糖浆剂、干混悬剂、口服溶液、口服混悬液、口腔崩解片、口腔速溶膜、缓释片、控释片、缓释胶囊、控释胶囊、肠溶片、肠溶胶囊；用于消化道外给药形式时，可以是水针剂、冻干粉针剂、无菌粉针剂、输液、滴眼剂、滴鼻剂、喷鼻剂、肺吸入剂、经皮贴剂、搽剂、软膏剂、乳膏剂、栓剂、皮下植入剂、长效注射剂、微针制剂。本发明药物组合物优选片剂、缓释片、缓释胶囊、水针剂、皮下植入剂和长效注射剂。
所述药学上可接受的载体或赋形剂可选自适合于口服制剂的药用赋形剂，包括填充剂、粘合剂、崩解剂、润滑剂、助溶剂、表面活性剂、吸附载体、空白丸芯载体、致孔剂、成膜剂。
所述药学上可接受的载体或赋形剂可选自适合于消化道外给药形式制剂的药用赋形剂，包括溶剂、抗氧剂、吸附剂、助溶剂、pH调节剂、渗透压调节剂、吸收促进剂、生物可降解基质、立体保护剂
在一个实施方式中，所述成瘾相关病症为与成瘾损伤相关的疾病、新型毒品成瘾和新型毒品引起的脑组织损伤。
附图简要说明
图1 l-CDL对MA诱导小鼠高活动性的影响(n＝48)
小鼠单次ipMA2mg·kg-1后，其活动性明显增高。在ipMA前igl-CD组小鼠的自主活动计数呈剂量依赖性降低，l-CDL2.5、5、10mg·kg-1/可以显著性地降低MA对小鼠自主活动的增强效应(P<0.01)。
图2 l-CDL对MA行为敏化的影响(n＝48)
2.5，5和10mg/kgl-CDL剂量依赖地抑制MA诱发的行为敏化的获得。
图3 l-CDL抑制甲基苯丙胺自身给药(n＝24)
l-CDL2.5，5、10mg·kg-1剂量依赖地抑制甲基苯丙胺自身给药行为。
图4A、4B l-CDL抑制尼古丁自身给药
l-CDL(3mg·kg-1)单次给药能够抑制大鼠的尼古丁自身给药(P<0.01)。图
图5 l-CDL抑制可卡因自身给药(n＝24)
l-CDL(10、30、60mg·kg-1能够减少大鼠的自身给药，**p<0.01。
图6 l-CDL对吗啡自身给药的影响(n＝24)
l-CDL(10、30、60mg·kg-1)能够减少吗啡成瘾大鼠的自身给药，**p<0.01。
图7 l-CDL抑制甲基苯丙胺引起的脑小胶质细胞损伤
甲基苯丙胺与LPS激活小胶质细胞，促进一氧化氮(NO)释放，l-CDL可抑制甲基苯丙胺引起的NO释放，以LPS作为小胶质细胞活化的阳性对照。抑制小胶质细胞激活。且作用效果优于罗通定(l-THP)**p<0.01,***p<0.001vs对照组；#p<0.05,##p<0.01,###p<0.001vs甲基苯丙胺给药组。
发明详述
现在将详细地依据本发明的某些实施方案进行说明。虽然本发明将结合所列举的实施方案进行描述，但是应当理解，它们并不意图将本发明限制于那些实施方案。相反，本发明意图涵盖可被包括在由权利要求所限定的本发明范围之内的所有替代、修改和等同。本领域技术人员将认识到类似或等同于本文中描述的那些的许多方法和材料可用于本发明的实施中。本发明决不限于这里所描述的方法和材料。
术语“治疗”是指治疗性处理和预防性或防范性措施，其中其目的是预防或减缓(减轻)不期望的病理变化或紊乱。对于本发明的目的，有益或期望的临床结果包括但不限于：症状的减轻、疾病程度的降低、疾病的稳定(即不恶化)的状态、疾病进展的延缓或减慢、疾病状态的改善或缓和以及缓解(无论是部分还是完全)，无论是可检测的还是不可检测的。“治疗”还可以指与未接受治疗的情况下所预期的相比延长的存活。需要治疗的那些对象包括已有所述病症或紊乱的那些以及倾向于患上所述病症或紊乱的那些，或要预防所述病症或紊乱的那些。
术语“手性”是指具有与镜像伴体不可重叠的特性的分子，而术语“对映体”是指作为互不重叠的镜像的化合物的两个立体异构体。
本文所用的立体化学定义和惯例一般遵循S.P.Parker,Ed.,McRaw-HiffDictionary of Chemical Terms(1984),McGraw-Hill Book Company,New York；及Eliel,E.和Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,NewYork,1994。本发明的化合物可含有手性中心，并且因此存在不同的立体异构形式。意图是，本发明化合物的所有立体异构形式构成本发明的部分。对于给定的化学结构，这些立体异构体除了它们是彼此的镜像外是相同的。特定的立体异构体还可被称为对映异构体，且此类异构体的混合物通常称为对映体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体。
如本文所用，术语“药学上可接受的盐”是指本发明化合物的药学上可接受的有机或无机盐。示例性的盐包括但不限于：硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐，甲烷磺酸盐(甲磺酸盐)、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐、和双羟萘酸盐。药学上可接受的盐可涉及包含另一种分子，如乙酸根离子、琥珀酸根离子或其它抗衡离子。抗衡离子可以是稳定母体化合物电荷的任何有机或无机部分。此外，药学上可接受的盐可在其结构中具有多于一个带电原子。其中多个带电原子是药学上可接受的盐的部分的情况可具有多个抗衡离子。因此，药学上可接受的盐可具有一个或多个带电原子和/或一个或多个抗衡离子。
如果本发明的化合物是碱，那么期望的药学上可接受的盐可以通过本领域可用的任何合适方法来制备，例如，用无机酸或有机酸处理游离碱，无机酸如盐酸、氢溴酸、硫酸、硝酸，甲烷磺酸、磷酸等，有机酸如乙酸、三氟乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷酸如葡糖醛酸或半乳糖醛酸、α-羟酸如柠檬酸或酒石酸、氨基酸如天冬氨酸或谷氨酸、芳族酸如苯甲酸或肉桂酸、磺酸如对甲苯磺酸或乙烷磺酸等。
如果本发明的化合物是酸，则期望的药学上可接受的盐可通过任何合适的方法制备，例如，用无机或有机碱处理游离酸，如胺、碱金属氢氧化物或碱土金属氢氧化物等。适合的盐的示例包括但不限于：衍生自氨基酸如甘氨酸和精氨酸、氨、伯胺、仲胺、叔胺、环胺如哌啶、吗啉和哌嗪的有机盐，衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
短语“药学上可接受的”表示该物质或组合物必须与构成制剂的其他成分和/或用其进行处理的哺乳动物化学和/或毒理学上相容。
用于制备治疗与成瘾损伤相关的病症的药物，用于预防和治疗所述成瘾损伤相关病症尤其是新型毒品成瘾及其引发的脑损伤。
“成瘾损伤相关的病症”主要是指但不限于，由于滥用海洛因、吗啡、甲基苯丙胺(冰毒)、可卡因、大麻等毒品成瘾以及尼古丁、酒精等成瘾性物质导致的躯体和心理依赖症状群。
“新型毒品成瘾”主要是指但不局限于苯丙胺类兴奋性毒品成瘾，新型毒品引起的脑组织损伤主要是指甲基苯丙胺引起的脑白质病变和神经元损伤。
实施例
紫堇达明(l-CDL)最初是从中药延胡索中分离出的异喹啉类生物碱[1-2]。通过对l-THP的代谢研究发现，人血浆中含量最高的产物是10-去甲基的硫酸结合物，即紫堇达明的硫酸结合物，浓度与罗通定相当或更高。其它产物是3-去甲基硫酸结合物。人尿中，含量最高的产物也是10-去甲基的硫酸结合物，其次是3-去甲基硫酸结合物。说明罗通定在体内主要通过代谢成紫堇达明起作用。我们打通并优化了化学合成路线，临床前研究证实l-CDL具有多巴胺受体D1、D2、D3拮抗作用和5羟色胺受体(5-HT1A)激动作用。
材料和方法
实验动物：昆明种小鼠，体重20-26g，SD大鼠，体重250-300g，由军事医学科学院动物中心提供。Long Evans大鼠，雄性，(体重规格)
l-CDL，自行合成，纯度98％，溶于蒸馏水中，配制成所需浓度的溶液。
甲基苯丙胺(MA)，由北京大学中国药物依赖性研究所提供,溶于生理氯化钠溶液(NS)，给药体积10ml/kg。
小动物自主活动检测仪(JZZ98-CM),中国医学科学院制造。
大鼠自身给药装置(Med Associates公司，Saint Albans,VT,USA)：包括电脑主机、刺激器、大鼠操作箱、输液管(外包保护管)、恒速输液泵。(型号)
实施例
1、l-CDL对甲基苯丙胺(MA)诱导小鼠高活动性的影响
行为敏化是动物成瘾的主要行为特征之一，作为评价药物精神依赖潜力的模型，目前已得到广泛的应用。反复间断给予成瘾性药物后，能增加实验动物的自主活动，这种随着反复给药而出现的行为反应增强称为行为敏化。行为敏化与药物成瘾有着重要的关系，目前已证明成瘾药物诱导的行为敏化对觅药行为和复吸行为的发生和维持有着重要的影响。
动物：昆明种小鼠,由军事医学科学院动物中心提供。雌雄各半,动物随机分组,每组10—14只,入组时体重(18—22)g,室温(22士1)℃,光照时间8:00—20:00,饮水及进食自由。
小鼠随机分为5组，Veh，MA组和MA+l-CDL三个剂量组。Veh和MA组动物分别给予Veh，l-CDL组给予不同剂量药物25min后，Veh组小鼠腹腔注射(ip)NS，其余组动物ipMA2mg/kg。然后，放入检测仪中，立即测定小鼠自主活动，记录1h的自主活动数。
结果表明(参见图1)，小鼠单次ipMA2mg·kg后，其活动性明显增高。在ipMA前igl-CDL组小鼠的自主活动计数呈剂量依赖性降低，l-CDL2.5,5,10mg/kg可以显著性地降低MA对小鼠自主活动的增强效应(P<0.01)。**P<0.01，与对照组比较；##p<0.01与MA组比较。
实施例2、l-CDL对小鼠甲基苯丙胺(MA)诱发行为敏化获得的影响
昆明种小鼠，连续7d给予溶剂或l-CDL25min后腹腔注射MA。第12天，腹腔注射2mg/kg MA激发后测定各组动物的活动性。MA组动物1h的活动计数明显高于溶剂组(P<0.01)，表明实验动物经慢性MA处理后，可建立对l-CDL的行为敏化。而l-CDL可抑制MA敏化的获得，2.5，5和10mg/kg l-CDL剂量依赖地抑制MA诱发的行为敏化的获得。结果见图2
实施例3、l-CDL对甲基苯丙胺自身给药的影响
自身给药试验(self-administration SA)，是一种操作式行为实验，它是利用药物强化效应改变动物接触药物前后的行为，模拟人类药物成瘾的用药期、戒断期和复吸的过程。是研究药物成瘾机理和评价药物抗成瘾效能的最直接方法。是目前成瘾研究领域最为理想的动物行为学模型。
材料与方法
Long Evans大鼠，雄性，体重250-300g。室温(22士1)℃,光照时间8:00—20:00,饮水及进食自由。
①静脉插管：用戊巴比妥纳40mg/kg麻醉，结扎远心端，在近心端处做V型切口，将硅胶管从切口处缓缓插入右侧颈内静脉,右心房入口处见回血顺利后，固定硅胶管，缝合切口。将硅胶管从颈部皮肤下穿过，从头顶穿出，硅胶管的另一端与接头相连固定于头顶，盖上保护帽，送回动物房。
②自身给药行为训练：大鼠自身给药装置(Med Associates公司，Saint Albans,VT,USA)：包括电脑主机、刺激器、大鼠操作箱、输液管(外包保护管)、恒速输液泵。大鼠恢复一周后放入自身给药操作箱，接头与输液管(外包保护管)、恒速输液泵相连接。操作箱前壁两侧装有两个压杆可供动物选择。按下有效压杆动物可获得可卡因注射。由计算机按设置的程序自动控制进行。每天训练3小时。用甲基苯丙胺训练动物获得自身给药行为(0.05mg/kg/每次压杆)固定比率FR1(压杆一次获得一次药物注射)程序训练7天，压杆同时灯光与声音启动。为避免甲基苯丙胺过量，最大药物输入次数(infusion)设定为50次。在3小时内药物输入40-50次，且在连续3天内药物输入次数变异小于10％的动物认为合格。这时可以将合格的动物随机分组，大鼠腹腔给予溶剂对照或受试药l-CDL 10,30,60mg/kg，30分钟后放入操作箱测定3小时。测定完后送回动物房。以后每天同样进行自身给药测定，直到药物代谢完毕及动物自身给药行为又恢复正常，动物可以再次分组进行下一次药物测定。每只动物给药不超过3次。
结果表明l-CDL剂量依赖地抑制甲基苯丙胺自身给药行为(参见图3)。
实施例4、l-CDL对尼古丁自身给药的影响
具体实验步骤同实施例3，每天训练3小时。用尼古丁训练动物获得自身给药行为(20μg/kg/每次压杆)固定比率FR1(压杆一次获得一次药物注射)程序训练10天，在3小时内输入尼古丁40-50次，且在连续3天内药物输入次数变异小于10％的动物认为合格。将合格动物随机分为几组，腹腔注射给予l-CDL 3mg/kg，30分钟后放入自身给药操作箱，如图4A和B所示，l-CDL(3mg·kg-1)能够减少大鼠的尼古丁自身给药。提示l-CDL具有抑制尼古丁成瘾的效应。
实施例5、l-CDL对可卡因自身给药的影响
大鼠静脉插管手术步骤同上。大鼠手术恢复一周后放入自身给药操作箱，先用高剂量可卡因(1mg/kg/每次压杆)固定比率FR1程序训练3天，5天后改为可卡因(0.5mg/kg/每次压杆),利用FR2方法训练2周左右。在3小时内可卡因输入40-50次，且在连续3天内药物输入次数变异小于10％的动物认为合格。将合格动物随机分为几组，腹腔注射给予l-CDL 10，30，60mg/kg，30分钟后放入自身给药操作箱，测定3小时内动物自动压杆次数，代表可卡因的注射次数(Infusions)。如图5所示，l-CDL(10,30,60mg·kg-1)能够减少大鼠的自身给药。提示l-CDL具有抑制可卡因成瘾的效应。
实施例6、l-CDL对吗啡自身给药的影响
大鼠静脉插管手术步骤与训练同上。大鼠手术恢复一周后放入自身给药操作箱，先用吗啡利用FR2方法训练2周左右。在3小时内输入吗啡40-50次，且在连续3天内药物输入次数变异小于10％的动物认为合格。将合格动物随机分为几组，腹腔注射给予l-CDL 10，30，60mg/kg，30分钟后放入自身给药操作箱，测定3小时内动物自动压杆次数，代表吗啡的注射次数(Infusions)。如图5所示，l-CDL(10、30、60mg·kg-1)能够减少大鼠的自身给药，提示l-CDL具有抑制吗啡成瘾的效应。
实施例7、l-CDL对甲基苯丙胺引起的神经细胞损伤具有保护作用
多巴胺能神经元毒性与胶质细胞活化有关，小胶质细胞激活后产生氧自由基、TNF-α和IL-β等产物损伤多巴胺能神经元。氧化产物及IL-6，和TNF-α等细胞因子的生成是MA持续对多巴胺能神经毒性的重要因素，我们的实验结果异喹啉类化合物对甲基苯丙胺诱发的小胶质细胞激活产生的一氧化氮生成有抑制作用，且在相同剂量下作用紫堇达明效果优于罗通定(l-THP)。提示异喹啉类化合物紫堇达明对甲基苯丙胺等毒品诱发的小胶质细胞激活有抑制作用，对兴奋性毒品诱发的脑损伤具有保护作用。
如图5所示l-CDL能够显著降低甲基苯丙胺引起的小胶质细胞活化时释放的一氧化氮，并且作用比罗通定l-THP更强。
实施例8、l-CDL在大鼠体内的药代动力学研究
建立l-CDL在SD大鼠血浆中的LC-MS/MS检测方法，研究其在大鼠体内的药代动力学特征，并进行生物利用度研究。
SD大鼠10只，随机分成两组，每组5只，一组尾静脉注射给药l-CDL 3mg·kg-1，于给药前和给药后2、5、15、30min和1、2、4、8、12、24h采血，血浆样品处理后使用LC-MS/MS测其浓度；另一组经口服灌胃给药10mg·kg-1，于给药前和给药后5、15、30min和1、2、4、8、12、24h采血，血浆样品处理后使用LC-MS/MS测其浓度。
l-CDL静注后的消除半衰期为(4.14±1.66)h，AUC值为(1390.34±253.93)ng·mL-1·h。口服吸收快，消除缓慢，消除半衰期为(7.04±3.93)h，AUC为(2408.01±630.49)ng·mL-1·h，生物利用度达到了55.8％。
综上所述，从上述实施例结果来看：
1、紫堇达明口服生物利用度高：已建立的l-CDL血浆LC-MS/MS方法简单、快速、灵敏度高、精确度好、基质干扰小，结果显示l-CDL吸收快速，消除缓慢，口服生物利用度高于l-THP。
2、紫堇达明抗新型毒品成瘾的效应明确：l-CDL对急性给予甲基苯丙胺诱发的高活动性有抑制作用，对慢性给予甲基苯丙胺诱发的小鼠行为敏化也有抑制作用
3、紫堇达明抑制大鼠甲基苯丙胺自身给药，说明紫堇达明具有开发成为抗新型毒品成瘾的潜能，而且对海洛因、吗啡、尼古丁、大麻可卡因等精神活性物质成瘾也有戒毒治疗作用
4、紫堇达明对甲基苯丙胺引起的脑损伤具有保护作用：l-CDL可抑制甲基苯丙胺等毒品诱发的小胶质细胞激活和对脑神经系统的损伤且作用优于l-THP，证明l-CDL对甲基苯丙胺引起的脑损伤具有保护作用。
5、紫堇达明具有多靶点药理机制：紫堇达明是异喹啉类生物碱的先导化合物，同时也是l-THP体内代谢产物，具有多巴胺D1、D2、D3受体拮抗作用和5-HT1A激动双重作用，不仅对新型毒品成瘾的戒断症状有效，而且对甲基苯丙胺类精神依赖和脑损伤有治疗作用。
Claims (2)
1.下式的异喹啉类化合物紫堇达明、其手性拆分对映异构体及其药学上可接受的盐作为唯一的活性成分在制备用于治疗成瘾相关病症的药物中的用途：
R1＝R2＝OCH3，R3＝OCH3，R4＝OH；
其中所述成瘾相关病症为由甲基苯丙胺、尼古丁、可卡因或吗啡引起的病症。
2.根据权利要求1所述的用途，其中由甲基苯丙胺引起的病症是由甲基苯丙胺引起的脑组织损伤。
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