M受体拮抗剂的构效关系

M受体拮抗剂的构效关系 第六章 拟胆碱药与抗胆碱药 一. 基本要求 1(熟悉拟胆碱药、抗胆碱药、拟肾上腺素药、组织胺H受体结抗剂和局部1 麻醉药的发展和结构类型。 2(掌握代表药物的化学结构、命名、理化性质、体内代谢。 3(熟悉各类药物的结构改造方法、构效关系、化学合成方法和药物作用的靶点。 二. 教学内容 1(掌握代表药物氯贝胆碱、溴新斯的明、硫酸阿托品氢溴酸山莨菪碱溴丙胺太林、右旋氯筒箭毒碱、肾上腺素、盐酸麻黄碱、沙丁胺醇、盐酸曲吡那敏、盐酸苯海拉明、马来酸氯苯那敏、盐酸赛庚啶、盐酸西替利嗪、阿司咪唑、盐酸普鲁卡因、盐酸利多卡因、盐酸达克罗宁的化学结构、命名、理化性质、体内代谢。 2(熟悉上述代表药物的结构类型、构效关系和结构改造方法和化学合成方法。 三. 教学学时:3学时 四. 重点、难点和要点 传入神经和传出神经共同组成外周神经系统。影响传出神经系统功能的药物依其药理作用的不同，传统上被分为四大类，即拟胆碱药、抗胆碱药、拟肾上腺素药和抗肾上腺素药。抗肾上腺素药目前在临床上多用于治疗心血管系统疾病，所以抗肾上腺素药将在循环系统用药中介绍。 组织胺作为一种重要的神经化学递质，广泛存在于哺乳动物的几乎所有组织中，发挥一系列复杂的生理功能。迄今为止至少发现了3类组胺受体，并分别命名为H受体、H 受体和H 受体。目前临床上使用的抗变态反应药主要为组胺123 H受体拮抗剂，而抗溃疡药物主要为H受体拮抗剂。由于本书将抗溃疡药归入12 消化系统用药，所以本章将介绍组胺H受体拮抗剂。 1 局部麻醉药是一类重要的外周神经系统用药，本章将在第五章中介绍。 拟胆碱药 Cholinergic Drugs coefficient not greater than 1.3; High efficiency: control 1 hour travel time between any two points within the various groups within the area up to half an hour, 1-hour access to the airport, 45min reached the city's main traffic hub, external highway for half an hour with the main channels connecting bus 1.5 hours between any two groups of core areas; Intensive: 2030 transit share rate of around 35%, 2050 bus sharing rate of 45% per cent. 3rd chapter, Yibin city, traffic situation and General ... 3.1.1 city traffic status 1, external transport passenger and cargo traffic in Yibin city, traffic at the present main railway, highway, waterway and air four modes of passenger and freight transport, thereand cultural heritage, highlighting the cultural taste and shape characteristics of the city in Yibin. According to forecasts, vision 2050 population will reach 2.1 million people in the center of Yibin city, urban land is around 210km2. Figure 2.6-1 2050 figure 2.7 land use planning in the Center City, Yibin city development requires the development of bus rapid transit construction and socio-economic development trends, Yibin city coordination, supporting urban space layout and infrastructure networks, transport organized, internal and external traffic hub smoothly linking, realizing sustainable development of Yibin city integrated transportation system. Concrete can be summarized as, accessible, efficient, intensive and sustainable. Accessibility: Central built-up area road network density of about 7.0km/km2; bus line density of 3-4 km/km2, bus transfer 躯体神经、交感神经节前神经元和全部副交感神经的化学递质均为乙酰胆碱。乙酰胆碱在突触前神经细胞内合成。神经冲动使之释放并作用于突触后膜上的乙酰胆碱受体，产生效应。之后，乙酰胆碱分子被乙酰胆碱酯酶催化水解为胆碱和乙酸而失活。胆碱经主动再摄取返回突触前神经末梢，再为乙酰胆碱合成所用。所以理论上其中每一个环节都可能经药物的影响达到增强或减弱乙酰胆碱作用的结果。但事实上，迄今成功应用于临床的胆碱能神经系统用药，包括拟胆碱药和抗胆碱药都是作用于胆碱受体和乙酰胆碱酯酶2个环节之一。笼统地讲，拟胆碱药是一类具有和乙酰胆碱相似作用的药物，按其作用环节和机制的不同，可分为胆碱受体激动剂和阿乙酰胆碱酯酶抑制剂2种类型。 一(胆碱受体激动剂 与乙酰胆碱结合的受体称为胆碱受体，分M,胆碱受体和N,胆碱受体。乙酰胆碱直接作用于M,胆碱受体和N,胆碱受体，分别产生M样作用及N样作用，是胆碱受体激动剂。 氯贝胆碱 Bethanechol Chloride NH+2N-.ClO 乙酰胆碱具有十分重要的生理作用，在胃部极易被酸水解，在血液中也极易经化学水解或胆碱酯酶水解。并且乙酰胆碱的作用选择性不高，无临床实用价值。为了寻找性质较稳定，同时具有较高选择性的拟胆碱药物，以乙酰胆碱作为结构改造的先导物。Bethanechol 是人们对乙酰胆碱进行结构改造获得成功的一个例子。乙酰胆碱分子可分为如下3部分，通过对各个部分的结构改造，出如下构效关系。 341ON2 O 位置1 被乙基或苯基取代活性下降。 位置2 若有甲基取代，N样作用大为减弱，M样作用与乙酰胆碱相似。 位置3 若有甲基取代可阻止胆碱酯酶的作用，延长作用时间，且N样作用coefficient not greater than 1.3; High efficiency: control 1 hour travel time between any two points within the various groups within the area up to half an hour, 1-hour access to the airport, 45min reached the city's main traffic hub, external highway for half an hour with the main channels connecting bus 1.5 hours between any two groups of core areas; Intensive: 2030 transit share rate of around 35%, 2050 bus sharing rate of 45% per cent. 3rd chapter, Yibin city, traffic situation and General ... 3.1.1 city traffic status 1, external transport passenger and cargo traffic in Yibin city, traffic at the present main railway, highway, waterway and air four modes of passenger and freight transport, thereand cultural heritage, highlighting the cultural taste and shape characteristics of the city in Yibin. According to forecasts, vision 2050 population will reach 2.1 million people in the center of Yibin city, urban land is around 210km2. Figure 2.6-1 2050 figure 2.7 land use planning in the Center City, Yibin city development requires the development of bus rapid transit construction and socio-economic development trends, Yibin city coordination, supporting urban space layout and infrastructure networks, transport organized, internal and external traffic hub smoothly linking, realizing sustainable development of Yibin city integrated transportation system. Concrete can be summarized as, accessible, efficient, intensive and sustainable. Accessibility: Central built-up area road network density of about 7.0km/km2; bus line density of 3-4 km/km2, bus transfer 大于M样作用。 位置4 带正电荷的氮是活性必须的，氮上以甲基取代为最好，若以氢或大基团如乙基取代则活性降低，若3个乙基则为抗胆碱活性。 对亚乙基桥部分，当改变主链长度时，活性随链长度增加而迅速下降。据此有人提出了“五原子”，即在季铵氮原子和乙酰基末端氢原子之间以不超过5个原子的距离(H-C-C-O-C-C-N),才能获得最大拟胆碱活性。亚乙基桥上的氢原子若被乙基或含碳更多的烷基取代则导致活性下降。若1个甲基取代时，由于空间位阻，在体内不易被胆碱酯酶所破坏，因此作用时间可延长。若甲基取代在β位，则M样作用与乙酰胆碱相同，氮N样作用大大减弱，成为选择性M受体激动剂。 对乙酰氧基部分，当乙酰基位丙酰基或丁酰基等高级同系物取代时，活性下降。这与“五原子规则”时符合的。当乙酰基上的氢原子被芳环或较大分子量的基团取代后，则转变位抗胆碱作用。乙酰胆碱作用时间短和不稳定是由于其分子中酯基的快速水解。于是以相对不易水解得 基团取代乙酰氧基就成为一条合理途径。氨甲酰基由于氮上孤电子对的参与，其羰基碳的亲电性较乙酰胆碱低，因此不易被化学和酶促水解。 综合上述构效关系，让3部分的最佳结构组合起来就得到了Bethanechol Chloride，选择性的作用于M受体，口服有效。 目前对M胆碱受体激动剂的设计和合成研究的焦点集中在开发治疗阿尔茨海默(Alzheimer’s Disease，AD)和其他认知障碍疾病的药物。AD 是老年性痴呆的主要原因。AD患者的认知减退归因于大脑皮层胆碱能神经元的变性，变性是中枢乙酰胆碱的释放明显降低，结果使M1受体处于刺激不足的状态。由于M1受体的活化对学习和记忆非常重要，刺激不足会导致认知减退。因此选择性中枢拟胆碱药目前被认为使较有前途的抗痴呆药物的主要类型之一。虽然迄今还没有正式药物上市，但研究中的大量化合物的疗效已经预示出令人鼓舞的前景。 二(乙酰胆碱酯酶抑制剂 进入神经突触间隙的乙酰胆碱会被乙酰胆碱酯酶(AChE)迅速催化水解，终结神经冲动的传递。抑制AChE将导致乙酰胆碱的积累，从而延长并增强乙酰胆碱的作用。乙酰胆碱酯酶抑制剂(AChE inhibitors)，又称为抗胆碱酯酶药因不与胆碱能受体直接相互作用，属于间接拟胆碱药。 coefficient not greater than 1.3; High efficiency: control 1 hour travel time between any two points within the various groups within the area up to half an hour, 1-hour access to the airport, 45min reached the city's main traffic hub, external highway for half an hour with the main channels connecting bus 1.5 hours between any two groups of core areas; Intensive: 2030 transit share rate of around 35%, 2050 bus sharing rate of 45% per cent. 3rd chapter, Yibin city, traffic situation and General ... 3.1.1 city traffic status 1, external transport passenger and cargo traffic in Yibin city, traffic at the present main railway, highway, waterway and air four modes of passenger and freight transport, thereand cultural heritage, highlighting the cultural taste and shape characteristics of the city in Yibin. According to forecasts, vision 2050 population will reach 2.1 million people in the center of Yibin city, urban land is around 210km2. Figure 2.6-1 2050 figure 2.7 land use planning in the Center City, Yibin city development requires the development of bus rapid transit construction and socio-economic development trends, Yibin city coordination, supporting urban space layout and infrastructure networks, transport organized, internal and external traffic hub smoothly linking, realizing sustainable development of Yibin city integrated transportation system. Concrete can be summarized as, accessible, efficient, intensive and sustainable. Accessibility: Central built-up area road network density of about 7.0km/km2; bus line density of 3-4 km/km2, bus transfer 溴新斯的明 Neostigmine Bromide +NON-.Br O Neostigmine 的化学结构由3部分组成，即季铵碱阳离子部分、芳香环部分及氨基甲酸酯部分。分子中引入季铵离子一方面增强与胆碱酯酶的结合，另一方面降低中枢作用。引入N，N,二甲基氨基甲酸酯后不易水解。Neostigmine Bromide 及其类似物溴吡斯的明和苄吡溴铵为疗效较好的抗胆碱酯酶药。 如果酰化酶水解乙酰胆碱过程非常缓慢，在相当长一段时间内造成AChE的全部抑制，如有机磷毒剂，使体内乙酰胆碱浓度长时间异常增高，引起支气管收缩，继之惊厥，最终导致死亡。所以这种不可逆胆碱酯酶抑制剂对人体使非常有害的。 抗胆碱药 Anticholinergic Drugs 对于因胆碱能神经系统过渡兴奋造成的病理状态，可用抗胆碱药物治疗。目前临床上使用的抗胆碱药主要是阻断乙酰胆碱与胆碱受体的相互作用，即胆碱受体拮抗剂。按照药物的作用部位及对胆碱受体亚型选择性的不同，抗胆碱药通常分为3类:?M胆碱受体拮抗剂，可逆性阻断节后胆碱能神经支配的效应器上的M受体，呈现抑制腺体(唾液腺、汗腺、胃液)分泌，散大瞳孔，加速心律，松弛支气管和胃肠道平滑肌等作用。?神经节阻断剂，在交感和副交感神经节选择性拮抗N胆碱受体，稳定突触后膜，阻断神经冲动在神经节中的传递，主要呈现1 降低血压的作用，临床用于治疗重症高血压。?神经肌肉阻断剂，与骨骼肌运动终板膜上的N受体结合，阻断神经冲动在神经肌肉接头处的传递，表现为骨骼2 肌松弛作用，临床用作辅助麻醉药。 一(茄科生物碱类M胆碱受体拮抗剂 硫酸阿托品 Atropine Sulphite coefficient not greater than 1.3; High efficiency: control 1 hour travel time between any two points within the various groups within the area up to half an hour, 1-hour access to the airport, 45min reached the city's main traffic hub, external highway for half an hour with the main channels connecting bus 1.5 hours between any two groups of core areas; Intensive: 2030 transit share rate of around 35%, 2050 bus sharing rate of 45% per cent. 3rd chapter, Yibin city, traffic situation and General ... 3.1.1 city traffic status 1, external transport passenger and cargo traffic in Yibin city, traffic at the present main railway, highway, waterway and air four modes of passenger and freight transport, thereand cultural heritage, highlighting the cultural taste and shape characteristics of the city in Yibin. According to forecasts, vision 2050 population will reach 2.1 million people in the center of Yibin city, urban land is around 210km2. Figure 2.6-1 2050 figure 2.7 land use planning in the Center City, Yibin city development requires the development of bus rapid transit construction and socio-economic development trends, Yibin city coordination, supporting urban space layout and infrastructure networks, transport organized, internal and external traffic hub smoothly linking, realizing sustainable development of Yibin city integrated transportation system. Concrete can be summarized as, accessible, efficient, intensive and sustainable. Accessibility: Central built-up area road network density of about 7.0km/km2; bus line density of 3-4 km/km2, bus transfer NCH3 H2SO4.H2O OH O 2 O Atropine 化学结构中具有莨菪烷(Tropane)骨架，莨菪烷3α位带有羟基即为莨菪醇。α,羟甲基苯乙酸简称莨菪酸。由(,),莨菪酸与莨菪醇形成的酯称为(,),莨菪碱。由于莨菪酸在提取分离过程中极易发生消旋化，所以Atropine是莨菪碱的外消旋体，其抗胆碱活性主要来自S(-)-莨菪碱，虽然S(,),莨菪碱抗M胆碱作用比消旋的Atropine强2倍，但左旋体的中枢作用比右旋体强8,50倍，毒性更大。临床应用Atropine更安全，而且外消旋体更易制备。 Atropine具有外周及中枢M胆碱受体拮抗作用，但对M1和M2受体缺乏选择性。将Atropine做成季铵盐，因难以通过血脑屏障，而不能进入中枢神经系统，不呈现中枢作用。如溴甲阿托品主要用于胃及十二指肠溃疡、胃酸过多症、胃炎、慢性下痢、痉挛性大肠炎等。 氢溴酸山莨菪碱 Anisodamine Hydrobromide NCH3 HO OH.HBr O O Anisodamine 是上世纪60年代我国学者从我国特有茄科植物唐古特山莨菪根中提取的生物碱，其氢溴酸盐又称“654”，天然品称“654,1”，人工合成品胃消旋体，称“654,2”。与Atropine的结构比较6位多了1个羟基。 氢溴酸东莨菪碱 Scopolamine Hydrobromide coefficient not greater than 1.3; High efficiency: control 1 hour travel time between any two points within the various groups within the area up to half an hour, 1-hour access to the airport, 45min reached the city's main traffic hub, external highway for half an hour with the main channels connecting bus 1.5 hours between any two groups of core areas; Intensive: 2030 transit share rate of around 35%, 2050 bus sharing rate of 45% per cent. 3rd chapter, Yibin city, traffic situation and General ... 3.1.1 city traffic status 1, external transport passenger and cargo traffic in Yibin city, traffic at the present main railway, highway, waterway and air four modes of passenger and freight transport, thereand cultural heritage, highlighting the cultural taste and shape characteristics of the city in Yibin. According to forecasts, vision 2050 population will reach 2.1 million people in the center of Yibin city, urban land is around 210km2. Figure 2.6-1 2050 figure 2.7 land use planning in the Center City, Yibin city development requires the development of bus rapid transit construction and socio-economic development trends, Yibin city coordination, supporting urban space layout and infrastructure networks, transport organized, internal and external traffic hub smoothly linking, realizing sustainable development of Yibin city integrated transportation system. Concrete can be summarized as, accessible, efficient, intensive and sustainable. Accessibility: Central built-up area road network density of about 7.0km/km2; bus line density of 3-4 km/km2, bus transfer NCH3 O OH.HBr O O 与Atropine 的结构比较Scopolamine 6，7位多了1个氧桥。 对比上述Atropine、Scopolamine和Anisodamine 等茄科生物碱的化学结构，很容易看出他们的区别只是6，7位氧桥和6位羟基的有无。氧桥和羟基的存在与否，对药物的中枢作用有很大影响。氧桥使分子的亲脂性增大，中枢作用增强。而羟基使分子极性增强，中枢作用减弱。Scopolamine有氧桥，中枢作用最强，对大脑皮层明显抑制，临床作为镇静药，是中药麻醉的主要成分，并且对呼吸中枢有兴奋作用。Atropine 无氧桥，无羟基，仅有兴奋呼吸中枢作用。Anisodamine有6位羟基，中枢作用最弱。 二(合成M胆碱受体拮抗剂 溴丙胺太林 Propantheline Bromide N OO .BrO Propantheline 是从Atropine的结构改造中发展出的合成抗胆碱药之一。Atropine等茄科生物碱类由于药理作用广泛，临床应用中常引起多种不良反应。对Atropine进行结构改造，寻找选择性高，作用强，毒性低及具有新适应症的新型合成抗胆碱药，就成为胆碱能药物的发展方向之一。 分析Atropine的结构可以发现，虚线框中的部分位氨基醇酯，与乙酰胆碱很相似，只是醇氧原子与氨基氮原子之间相距3个碳原子，但其构象的空间距离与乙酰胆碱的2个碳的距离相当，托品烷的双环结构对维持活性构象意义重大。因此氨基乙醇酯被认为是“药效基本结构”。Atropine 的酰基部分带有苯基，这是与乙酰胆碱不同的关键所在，显然酰基上的大基团对阻断M受体功能十分重要。coefficient not greater than 1.3; High efficiency: control 1 hour travel time between any two points within the various groups within the area up to half an hour, 1-hour access to the airport, 45min reached the city's main traffic hub, external highway for half an hour with the main channels connecting bus 1.5 hours between any two groups of core areas; Intensive: 2030 transit share rate of around 35%, 2050 bus sharing rate of 45% per cent. 3rd chapter, Yibin city, traffic situation and General ... 3.1.1 city traffic status 1, external transport passenger and cargo traffic in Yibin city, traffic at the present main railway, highway, waterway and air four modes of passenger and freight transport, thereand cultural heritage, highlighting the cultural taste and shape characteristics of the city in Yibin. According to forecasts, vision 2050 population will reach 2.1 million people in the center of Yibin city, urban land is around 210km2. Figure 2.6-1 2050 figure 2.7 land use planning in the Center City, Yibin city development requires the development of bus rapid transit construction and socio-economic development trends, Yibin city coordination, supporting urban space layout and infrastructure networks, transport organized, internal and external traffic hub smoothly linking, realizing sustainable development of Yibin city integrated transportation system. Concrete can be summarized as, accessible, efficient, intensive and sustainable. Accessibility: Central built-up area road network density of about 7.0km/km2; bus line density of 3-4 km/km2, bus transfer 根据这一思路，通过基团变换，设计合成了多种季铵类和叔胺类抗胆碱药。这些M受体拮抗剂的化学结构有共同点，可用下式代表他们的基本结构。这一结构与胆碱受体激动剂有相似之处，这是因为M受体拮抗剂与激动剂共同竞争M受体，均通过含氮的正离子部分与受体的负离子位点结合，而分子中其他部分与受体的附加部分结合，则产生拮抗剂与激动剂的区别。 O NCHOCCH3 OHCH2 Atropine 下面对M受体拮抗剂的构效关系加以讨论。 R1 XCRCHN22n R3 M胆碱受体拮抗剂基本结构 1(在M受体上乙酰胆碱结合位点周围是一个疏水区，拮抗剂上相应与此的R和R部分的较大基团，通过疏水性力或范德华力与M受体疏水区结合，阻碍12 乙酰胆碱与受体的接近和结合。当R和R为碳环或杂环时可产生强烈的拮抗活12 性，尤其2个环不一样时活性更好，如格隆溴铵和奥芬溴铵，R和R分别为苯12环、环戊基和苯环、环己基。两药均用于胃及十二指肠溃疡、慢性胃炎、胃酸分泌过多及痉挛等。 2(R可以是H，OH，CHOH或CONH。由于R为OH或CHOH时，可32232通过形成氢键使之与受体结合增强，比R为H时抗胆碱作用强，所以大多数M3 受体拮抗剂的R为OH。 3 3(大多数强效抗胆碱药结构中X是酯键,COO,，但是酯键并不是抗胆碱活性所必需的。X也可以是,O,，如奥芬那君;还可以去掉酯键，如苯海索、丙环定和比哌立登等，因疏水性较大，易进入中枢，属于中枢抗胆碱药，临床用于抗震颤麻痹。 4(大多数强效抗胆碱药物中，氨基部分通常为季铵盐或叔胺结构。它们本身为N正离子或与酸成盐后形成N正离子，与M受体的负离子部位结合，对形coefficient not greater than 1.3; High efficiency: control 1 hour travel time between any two points within the various groups within the area up to half an hour, 1-hour access to the airport, 45min reached the city's main traffic hub, external highway for half an hour with the main channels connecting bus 1.5 hours between any two groups of core areas; Intensive: 2030 transit share rate of around 35%, 2050 bus sharing rate of 45% per cent. 3rd chapter, Yibin city, traffic situation and General ... 3.1.1 city traffic status 1, external transport passenger and cargo traffic in Yibin city, traffic at the present main railway, highway, waterway and air four modes of passenger and freight transport, thereand cultural heritage, highlighting the cultural taste and shape characteristics of the city in Yibin. According to forecasts, vision 2050 population will reach 2.1 million people in the center of Yibin city, urban land is around 210km2. Figure 2.6-1 2050 figure 2.7 land use planning in the Center City, Yibin city development requires the development of bus rapid transit construction and socio-economic development trends, Yibin city coordination, supporting urban space layout and infrastructure networks, transport organized, internal and external traffic hub smoothly linking, realizing sustainable development of Yibin city integrated transportation system. Concrete can be summarized as, accessible, efficient, intensive and sustainable. Accessibility: Central built-up area road network density of about 7.0km/km2; bus line density of 3-4 km/km2, bus transfer 成药物,受体复合物起重要作用。N上取代基通常以甲基、乙基、丙基或异丙基为好。 5(环取代基到氨基氮原子之间的距离以n,2为最好，碳链长度一般在2,4个碳原子之间，再延长碳链则活性降低或消失。 三(N胆碱受体拮抗剂 N胆碱受体拮抗剂按照对受体亚型的选择性不同，可分为神经节N受体阻1断剂和神经肌肉接头处N受体阻断剂，前者用作降压药，后者可使骨骼肌松弛，2 临床作为肌松药，用于辅助麻醉。临床上常用的肌松药见课本。 参考和辅助资料 1(《药物化学》教学，桂林师范高等专科学校，2007。 2(《药物化学》，张彦文主编，高等教育出版社。 3(《药理学》统编教材第四版，人民卫生出版社。 coefficient not greater than 1.3; High efficiency: control 1 hour travel time between any two points within the various groups within the area up to half an hour, 1-hour access to the airport, 45min reached the city's main traffic hub, external highway for half an hour with the main channels connecting bus 1.5 hours between any two groups of core areas; Intensive: 2030 transit share rate of around 35%, 2050 bus sharing rate of 45% per cent. 3rd chapter, Yibin city, traffic situation and General ... 3.1.1 city traffic status 1, external transport passenger and cargo traffic in Yibin city, traffic at the present main railway, highway, waterway and air four modes of passenger and freight transport, thereand cultural heritage, highlighting the cultural taste and shape characteristics of the city in Yibin. According to forecasts, vision 2050 population will reach 2.1 million people in the center of Yibin city, urban land is around 210km2. Figure 2.6-1 2050 figure 2.7 land use planning in the Center City, Yibin city development requires the development of bus rapid transit construction and socio-economic development trends, Yibin city coordination, supporting urban space layout and infrastructure networks, transport organized, internal and external traffic hub smoothly linking, realizing sustainable development of Yibin city integrated transportation system. Concrete can be summarized as, accessible, efficient, intensive and sustainable. Accessibility: Central built-up area road network density of about 7.0km/km2; bus line density of 3-4 km/km2, bus transfer