CN115844898A - 布那唑嗪在制备预防或治疗酒精使用障碍的药物中的应用 - Google Patents
布那唑嗪在制备预防或治疗酒精使用障碍的药物中的应用 Download PDFInfo
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Abstract
本发明涉及布那唑嗪在制备预防或治疗酒精使用障碍的药物中的应用，提供一种安全有效的戒酒药物。布那唑嗪是去甲肾上腺素能受体的抑制剂，是一种选择性α1受体阻滞剂，临床上主要用于治疗高血压和用于改善良性前列腺增生症患者的排尿症状。经实验证实，布那唑嗪可减少酒精成瘾小鼠对酒精自主摄取次数；明显抑制模型动物的饮酒量；另外，本发明人还发现布那唑嗪可减轻酒精依赖小鼠自发戒断中的躯体症状，提示布那唑嗪可用于制备预防或治疗酒精使用障碍的药物。
Description
(一)技术领域
本发明涉及布那唑嗪在制备预防或治疗酒精使用障碍的药物中的应用。
(二)背景技术
酒精是目前使用最广泛的精神活性物质，酒精不当使用现已成为一大公共卫生问题。
酒精使用障碍包括了酒精成瘾和酒精滥用。酒精成瘾是一种慢性易复发性脑病，主要特点是强迫性觅药、强烈的渴求，对酒精的使用失去控制，并且在无法获得酒精时出现负性情绪及躯体不适，与人类酗酒者相似，依赖乙醇的动物表现出增强的焦虑样行为和在停药期间增强的乙醇自身给药。长期的酒精滥用可以导致诸多躯体和精神心理问题，具体包括饮酒相关的车祸、癌症、抑郁和睡眠障碍等。对个人、家庭以及社会都造成了巨大的损失。
在对成瘾过程的研究当中可将其分为三个阶段，分别为狂饮/中毒，戒断/负面影响，全神贯注/期待，每一个阶段又对应了一个功能性神经回路的缺陷，为奖赏缺陷障碍，应激过度障碍，执行功能障碍。这三个阶段表明了滥用药物的使用者在没有药物的情况下从积极强化和自愿使用转变为具有消极强化的强制消费。在第一个阶段，狂欢/中毒阶段受到物质药代动力学和给药方式的影响，但依赖于NAc中DA的释放，对药物的急性强化作用以及愉悦和享受的感知至关重要。第二阶段为戒断阶段，在这一阶段由于药物的慢性影响，大脑不能独立地调节其从滥用药物中获得的愉悦和奖励体验，其中包括与奖励相关的神经递质水平的下调。这一阶段中应激系统与享乐系统起关键作用，由杏仁核中激活的去甲肾上腺素能神经元引起的负面情绪占主导地位。第三阶段的渴求阶段，情绪处于持续下调的状态，会通过寻求成瘾物质来改善该状态的快感缺失和其他令人不快和不希望看到的后果。此外，长期饮酒会导致焦虑增加和对压力的反应失调，这些前馈相互作用共同增强了饮酒的动机，并且是复发的常见原因。另一方面，酒精依赖间接或直接涉及大脑多个神经递质系统，如内源性阿片受体、P氨基丁酸(GABA)、谷氨酸、多巴胺和5-羟色胺等系统以及其他一砦神经肽等。目前虽然其具体机制仍未完全明了，但中脑腹侧背盖区(VTA)-伏隔核(NAc)-前额皮层(PFC)是成瘾性物质引起奖赏效应的最后通路，同时也是研究酒精依赖的重要脑区。重要的，研究发现去甲肾上腺素(NE)是中枢神经系统中的一种关键神经调节剂，起源于后脑的几个核团，广泛分布于整个大脑。NE改变其靶点的神经反应性，通过突触前和突触后G蛋白偶联受体改变正在进行的神经过程的活动。因此，它可以对参与酒精相关行为调节的神经回路产生广泛而复杂的影响。目前，酒精依赖临床治疗主要指导原则是减轻急性戒断症状、降低复发率。临床对酒瘾复发干预药物中，美国FDA批准用于酒精依赖辅助治疗的药物有三种：戒酒硫、纳曲酮和阿坎酸，这些药物在治疗酒精成瘾病患中存在较大的副作用，例如，戒酒硫主要通过阻断乙醇代谢过程中重要的酶系统而使乙醇代谢产物乙醛在体内蓄积，引起低血压、恶心及呕吐等一系列不适症状和体征，称为乙醇-戒酒硫反应。因此，急需研发安全有效的戒酒药物。
(三)发明内容
本发明目的是提供布那唑嗪在制备预防或治疗酒精使用障碍的药物中的应用，提供一种安全有效的戒酒药物。
本发明采用的技术方案是：
结构如式(I)所示的布那唑嗪在制备预防或治疗酒精使用障碍的药物中的应用：
去甲肾上腺素作为酒精使用障碍的新兴靶点，而布那唑嗪是去甲肾上腺素能受体的抑制剂，其化学名为1-[4-(4-氨基-6,7-二甲氧基-2-喹唑啉基)六氢-1H-1,4-二氮杂卓-1-基]-1-丁酮Chemicalbook；1-[4-(4-氨基-6,7-二甲氧基-2-喹唑啉基)六氢-1H-1,4-二氮杂庚-1-基]-1-丁酮，分子式为C19H27N5O3，是一种选择性α1受体阻滞剂，临床上主要用于治疗高血压和用于改善良性前列腺增生症患者的排尿症状。在目前的研究当中，布那唑嗪尚未应用于治疗酒精使用障碍。发明人研究发现，布那唑嗪在酒精成瘾中也能发挥作用，可以通过与去甲肾上腺素受体作用从而发挥一定的效果，因此对此药物进行研究，从而对其作用机制进行探索。
发明人经实验证实，布那唑嗪可减少酒精成瘾小鼠对酒精自主摄取次数；明显抑制模型动物的饮酒量；另外，本发明人还发现布那唑嗪可减轻酒精依赖小鼠自发戒断中的躯体症状，提示布那唑嗪可用于制备预防或治疗酒精使用障碍的药物。
具体的，所述药物为防治酒精成瘾的药物的药物。
具体的，所述药物为减少酒精摄入的药物、酒瘾复发干预药物或戒酒药物。
所述药物的给药方式为肌肉注射、皮下注射、静脉注射、口服给药、舌下含服、病灶内或脑内或植入的递送、喷雾给药中的一种或几种，优选为口服，肌肉、皮下或静脉注射。
所述布那唑嗪可加入药学可接受的辅料，制成下列之一的剂型：注射剂、胶囊剂、片剂、颗粒剂、混悬剂、乳剂、喷雾剂、散剂、脂质体、口服液、滴丸，优选剂型为注射剂。
可选的，布那唑嗪为其药学上可接受的盐，所述药学上可接受的盐为药学上常用的盐，进一步地，所述盐选自乙酸盐、盐酸、氢溴酸、硝酸、硫酸、磷酸、苯甲酸盐、富马酸盐、马来酸盐、琥珀酸、酒石酸、柠檬酸盐、草酸、乙醛酸、天冬氨酸、酒石酸盐、2，5－二羟基苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、月佳基磺酸盐、氢醌磺酸盐和对甲苯磺酸盐中的一种或几种。
本发明的有益效果主要体现在：本发明提供了布那唑嗪在制备预防或治疗酒精使用障碍的药物中的应用，为新药筛选提供了基础。
(四)附图说明
图1为布那唑嗪对酒精成瘾小鼠酒精自我摄取的行为影响；与正常组相比，****P<0.0001，与模型组相比，###P<0.001；
图2为布那唑嗪给药后对成瘾小鼠酒精偏好的影响；与正常组相比，****P<0.0001，与模型组相比，##P<0.01；
图3为布那唑嗪对酒精成瘾小鼠旷场实验的影响；
图4为布那唑嗪对酒精成瘾小鼠血清中NE浓度的影响；
图5为布那唑嗪对酒精成瘾小鼠大脑神经元病理变化的影响。
(五)具体实施方式
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此：
实施例1：
动物实验：自我摄取酒精小鼠模型的制作、分组给药并检测乙醇消耗。
该模型的制作目的是使用自身给药箱检查小鼠自愿自我服用乙醇的倾向。该设备的特点是每个实验腔室都安装有两个鼻戳孔，位于流体容器的对面侧，一个是活动的(加固剂配对)，另一个是非活动的。位于主动杆正上方的一种刺激灯，与增强剂输送协调照明，从而作为条件性刺激。此外，将一滴香草香精放置在一个小的皮氏培养皿中，直接放置在主动杠杆的下方，作为辨别性刺激，从而帮助杠杆辨别。给药箱连接到一台运行计算的软件进行分析。
小鼠适应性喂养一周后，进行自我酒精摄取模型的建立，首先将小鼠禁水22小时后放入只提供活动的鼻戳孔的自我给酒精箱中，以5％的蔗糖溶液为强化剂，进行固定比例1(FR1)的自我给药，10s内提供20～50μL，连续3天。此后五天，引入非活动鼻戳孔，以区分活跃的、增强剂配对的和非活跃的、非增强剂的反应。在最后三天内，活动的非活动的区分率达到60％的小鼠进入蔗糖20天消退模式。
蔗糖消退共分为五个阶段，分别为5S/5E，5S/7.5E，5S/10E，2S/10E，10E，进行天数分别为5，4，4，4，3天。此阶段结束后在固定比例3的条件下连续30次每天30分钟检查稳定的酒精消耗。
将成功建立模型的小鼠随机分为模型组(model)，苯肾上腺素组(Phenylephrine)，哌唑嗪组(Prazosin)，布那唑嗪组(Terazosin)，并设立对照组。其中苯肾上腺素为去甲肾上腺素受体的激动剂，其余为拮抗剂，另设正常组。除正常组外，其余各组小鼠每天一次性腹腔注射0.3ml已配置好溶液，苯肾上腺素(2mg/kg/d)，哌唑嗪(3mg/kg/d)，布那唑嗪(3mg/kg/d)，模型组注射等量的生理盐水。
从结果可知，在对小鼠进行分组给药后，对给药后的乙醇基线进行了测定，从图中折线图可看出，与模型组相比，给药组在一定程度上都抑制了酒精成瘾小鼠对于乙醇的响应值，从而说明了特拉唑嗪对于治疗酒精成瘾小鼠的自身给药具有一定的效果，如图1所示。
实施例2：布那唑嗪对成瘾小鼠酒精偏好的影响
给药结束后对每组小鼠进行一个为期四天的两瓶选择，目的是探究药物对酒精成瘾小鼠的酒精偏好的影响。第一天两瓶都装满水，第二天其中一瓶装满2％的乙醇，第三天为6％的乙醇，第四天为10％的乙醇，两个瓶子不定时交换位置，以防小鼠产生位置性偏好。溶液每天进行更换，并进行记录，从而对小鼠的乙醇偏好进行计算。计算公式为乙醇消耗量/(饮用水消耗量+乙醇消耗量)，结果如图2所示。
从结果中可以看出，模型组与正常组相比，具有较高的酒精偏好，而给药组与模型组相比，布那唑嗪和哌唑嗪都能有效降低自身给药酒精成瘾小鼠的酒精偏好。
实施例3：布那唑嗪对成瘾小鼠情绪焦虑的影响(旷场实验)
旷场实验(open field test)又称敞箱实验，是评价实验动物在新异环境中自主行为、探究行为与紧张度的一种方法。动物在酒精成瘾后，会产生一定的焦虑行为。小鼠在造模后及给药结束后进行自主行为活动的测试。小鼠在进入自我摄取酒精箱前1h进行测定。先将小鼠放在空旷地区自由探索5min，之后将小鼠放在OFT-100旷场实验箱的中心区域，进行15分钟的自主行为活动测试，结果如图3所示。
结果证明，模型组与正常组相比，总路程增多，中央穿越次数减少，小鼠更倾向于呆在边缘，说明酒精能造成小鼠的焦虑行为。而给药组与模型组相比，总路程减少，中央穿越次数增多，在中央有更多的活动轨迹，说明布那唑嗪和哌唑嗪都能在一定程度上减缓酒精对小鼠所造成的焦虑行为。
| 组别 | 总路程 |
| Control | 3072.289±526.613 |
| Model | 4235.418±653.581** |
| Bunazosin | 2974.018±509.814<sup>###</sup> |
| Prazosin | 3006.923±397.567<sup>###</sup> |
| Phenylephrine | 4229.009±740.185 |
实施例4：布那唑嗪对成瘾小鼠血清中去甲肾上腺素(NE)的测定
给药结束后采集血清使用Elisa试剂盒对血清中NE的浓度进行测量，结果如图4所示。
从结果中可以看出，模型组与正常组相比，血液中的去甲肾上腺素浓度增加。而进行药物治疗后，布那唑嗪组与哌唑嗪组的血液NE浓度都降低，说明酒精能够使小鼠血液中的去甲肾上腺素浓度增加，而布那唑嗪和哌唑嗪都能有效降低血液中NE浓度。
实施例5：成瘾小鼠脑杏仁核神经元尼氏染色
尼氏体是胞质内的一种嗜碱性物质，广泛分布于各种神经元中。尼氏体的功能是合成更新细胞器所需的结构蛋白、合成神经递质所需的酶类以及肽类的神经调质，其形状、数量和分布随不同的神经元而异。在代谢功能旺盛的神经元中尼氏体特别丰富。当神经元受到损伤或过度疲劳时，尼氏体可减少、解体甚至消失。在损伤或疲劳恢复过程中，尼氏体又重新出现、增多，并可至正常水平，故尼氏体可作为神经元功能状态的标志。
给药结束后，将小鼠处死后迅速将脑取出，并固定于10％甲醛溶液中，常规脱水包埋。石蜡切片厚5μm，常规脱蜡至水，用尼氏染色液(Nissl Stain,甲苯胺蓝法)置于50～60℃温箱浸染20～40min。蒸馏水稍洗。95％乙醇迅速分化。无水乙醇脱水，二甲苯透明，中性树胶封固。于光镜下观察神经元病理改变，结果如图5所示。
神经元细胞体包括一个具有褶皱核膜的大细胞核、稀疏的染色质和一个明显的核仁。在细胞体中细胞质是尼氏颗粒，能够代表粗面内质网并在很多神经元中产生特异的斑点状嗜碱性表现的嗜碱性颗粒。尼氏体会因为生理状态的变化而变化，尼氏体是神经元内蛋白质合成的重要部位，当神经元受到刺激时，胞体内的尼氏体数量会产生变化。如图五所示，模型组小鼠脑神经元由于受到乙醇的刺激，尼氏体的数量明显增多，排列也更加的紧密，说明此时小鼠的脑神经元处于异常的活跃状态。而给予抑制性药物布那唑嗪和哌唑嗪时，可以在一定程度上减轻乙醇对小鼠脑神经元所造成的影响，此时小鼠脑中尼氏体数量减少，排列也较为稀疏。同时在给与激动剂药物苯肾上腺素后，小鼠脑神经元中尼氏体数量增多，排列紧密，说明此时小鼠脑神经元与模型组一样处于异常的活跃状态，说明酒精能增强神经元的代谢功能，而给药组的尼氏体与模型组相比，排列松散，数量减少，说明布那唑嗪与哌唑嗪都能减缓酒精对神经元所造成的影响。
综上所述，本发明先成功建立了酒精成瘾小鼠自身给药模型，获得一个稳定的乙醇响应基线。在进行给药后，一系列结果表明，布那唑嗪能够降低自身给药小鼠对乙醇的响应值，并能够减缓酒精对小鼠所引起的焦虑行为。在对小鼠血清中去甲肾上腺素浓度的测定中，也表明了布那唑嗪能够降低酒精成瘾小鼠血清中的去甲肾上腺素浓度。小鼠脑杏仁核尼氏染色中，结果表明酒精能够增强大脑去甲肾上腺素能神经元的代谢功能，而给予布那唑嗪后，能够有效缓解此种情况。因此本发明证实，布那唑嗪可能通过影响去甲肾上腺素受体从而对酒精使用障碍产生治疗作用。
Claims (6)
1.结构如式(I)所示的布那唑嗪在制备预防或治疗酒精使用障碍的药物中的应用：
2.如权利要求1所述的应用，其特征在于所述药物为防治酒精成瘾的药物。
3.如权利要求2所述的应用，其特征在于所述药物为减少酒精摄入的药物。
4.如权利要求2所述的应用，其特征在于所述药物为酒瘾复发干预药物。
5.如权利要求2所述的应用，其特征在于所述药物为戒酒药物。
6.如权利要求1～5之一所述的应用，其特征在于所述布那唑嗪加入药学可接受的辅料，制成下列之一的剂型：注射剂、胶囊剂、片剂、颗粒剂、混悬剂、乳剂、喷雾剂、散剂、脂质体、口服液、滴丸。
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