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单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Chapter 4,Analgesics,antitussives and expectorants,4.1 Analgesics,疼痛：是由创伤和疾病等多种原因引发的病症，剧烈的疼痛可引起生理功能紊乱，甚至休克。,Classification of Painkiller:,Narcotic Anangesics:作用于中枢神经系统，抑制痛觉神经从而消除或缓解疼痛，多用于剧痛acute pain。,Antipyretic analgesics:具有解热、镇痛、抗炎作用，用于钝痛(chronic pain)如牙痛或头痛。,Difference:different mechanism,Opioid receptor for the former,Arachidonic acid cyclooxygenase inhibitor of the latter,Opioid receptors:discovered in 1973 with three subtypes,receptor agonist:strong addiction,receptor agonist,addiction,receptor agonist,Narcotic analgesics includes opioid alkaloid morphine,its synthetic analogues and endogenous substance such as enkephalin,endorphin and dynorphin.,4.1.1 Morphine and its analogues,Opium是罂粟科植物罂粟的未成熟的蒴果被划破后流出的白色浆汁，枯燥后呈棕黑色膏状物。The immature fruit of Opium contains alkaloids,triterpenoids and steroids.,Morphine was seperated from Opium in 1805 and its chemical structure was identified in 1923.The total synthesis was finished in 1952.,Molecular structure and activity of morphine,天然的吗啡呈左旋性，右旋体无活性,5个手性中心：5R,6S,9R,13S,14R,5个环，A、B和C构成局部氢化的菲环，C和E构成局部氢化的异喹啉环,B/C呈顺式，C/D呈反式，C/E呈顺式,立体构像：三维的T,Physiological activity：analgesia,Side-effects:addiction,respiratory depression,Vomiting,constipation,euphoria,1,.To simplify,the chemical structure of morphine to deve,lop,synthetic morphine,analogues and m,orphine antagonists,.,2.To,discover the mixed agonist-antagonist analgesics with small addiction.,3.To discover the,efficient analgesics,such as the discovery of Etorphine,4.,To discover the endogenous opioid-like analgesics such as enkephalin,Modifications towards morphine,Heroine,Codeine,Ethylmorphine,Heterocodeine,Oxycodone,Hydromorphone,Oxymorphone,Hydrocodone,N-,-phenylethylnormorphine,N-CH3,用其他烷基、链烯烃或芳烃修饰,活性为吗啡的,4,倍,Mixed agonist-antagonist,Nalorphine,-receptor partial agonist,very weak analgesic effect.,Opioid antagonists and Antagonist analgesics,Naloxone and naltrexone are,-receptor,antagonists,without exciting activity.,Naloxone,naltrexone,是研究阿片受体的工具药物，可用于吗啡类中毒后的解救,解除呼吸抑制并使血压上升。,SAR of morphine,叔胺是镇痛活性的关键基团，N原子上引入不同的取代基可使受体冲动剂变为拮抗剂。,酚羟基被酰化和醚化后，活性和成瘾性均下降。,双键被复原后，活性和成瘾性均增加。,酚羟基被烃化酯化氧化或去除后，活性和成瘾性均增加。,-receptor agonist,(5,6-7,8-二脱氢-4,5-环氧-17-甲基吗啡喃-3,6-二醇盐酸盐三水合物,(5,6-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol hydrochloride trihydrate,Optical activity:Levorotary,Representative:Morphine Hydrochloride,(1)Acidic and alkaline.,(2)Easily to be oxidized into pseudomorphine,.Stability,has relationship with,pH,stable under acidic conditions(stable,st,at,pH4),easily be oxidized,under,neutral or alkaline conditions in sunlight(UV),and the reaction can be catalyzed by,heavy metal ions.,Chemical properties,盐酸吗啡水溶液与三氯化铁试液反响显蓝色；与甲醛硫酸试液反响呈紫堇色后变为蓝色；与钼硫酸试液反响呈紫色。,盐酸吗啡水溶液参加稀铁氰化钾试液后再与三氯化铁试液反响，生成蓝色的亚铁氰化铁,区别可待因。,吗啡与盐酸或磷酸加热反响生成阿扑吗啡，阿扑吗啡氧化生成暗紫红色邻醌化合物。阿扑吗啡水溶液在碳酸氢钠碱性条件下，加碘试液生成的氧化产物能溶于乙醚显宝石红色，水层显绿色。用于检查盐酸吗啡中的阿扑吗啡。,暗紫色,阿扑吗啡,Identification,apomorphine,Apomorphine is used as emetic,Mechanism,:opioid,-receptor agonist,Physiological activity,:analgesic,antitussive and sedative effects.,Side-effects,:addiction,respiratory depression,Vomiting,constipation,euphoria,Usage,:acute pain of cancer,4.1.2 Synthetic analgesics,4.1.2.1 Morphinanes,N-methylmorphinane,levorphanol,butorphanol,活性只有吗啡的,1/5,-receptor agonist,活性是吗啡的,4,倍,-receptor antagonist,-receptor agonist,用作镇痛药成瘾性小,Pentazocine:-receptor agonist and-receptor weak antagonist.,Phenazocine:-receptor agonist with analgesic effect 10 times than morphine.,氟痛新：,analgesic effect is stronger than pentazocine.,4.1.2.2 Benzomorphans,Representative:pentazocine,Mixed agonist-antagonist,:,-,receptor agonist,and,-,receptor antagonist,The first clinical non-narcotics analgesic.It can not be used as oral dosage because of first-pass effect and low bioavailability.Clinical for moderate pain.,吗啡,A typical-receptor agonist,analgesic effect is l/6 l/8 to that of morphine.,4.1.2.3 Piperidines,pethidine,Alphaprodine,Betaprodine,Anileridine,Piminodine,Fentanyl is opioid-receptor agonist,analgesic effect is about 500 times than that of pethidine and 80 times than that of morphine.,Fentanyl,Configuration of Fentanyl,alfentanil,sufentanil,carfentanil,name,ED,50,(mg/kg),intensity,LD,50,(mg/kg),LD,50,/,ED,50,pethidine,6.0,1,29.0,4.8,fentanyl,0.011,550,3.1,77,alfentanil,0.044,137,47.5,1080,sufentanil,0.00071,8500,17.9,25200,carfentanil,0.00034,17800,3.4,10000,-receptor agonist,Lovorotary-body presents stronger analgesic effect than dextrorotary-body,effect intensity of L-body similar to that of morphine.,4.1.2.4 Aminoketones,methadone,Configuration of Methadone,四高效冲动剂,镇痛作用强于埃托啡，动物实验结果其戒断病症及精神依赖性潜力均明显的轻于吗啡，但在临床使用中发现有较强的精神依赖性和躯体依赖性，耐受性形成快，成瘾性强，滥用潜力很大,Endogenous opioid peptides,Structure-Activity Relationship of Opiod Analgesics,1、分子中应具有一个平坦的芳香结构，可以和受体相应部位通过范德华引力相结合,2、应有一个碱性中心，通常为一个叔胺N原子，在生理PH条件下，可大局部电离为阳离子，以便与受体外表的阴离子部位结合。,3、碱性中心和平坦结构芳环应处在同一平面上，以便与受体结合，烃链局部在立体构型中应突出于平面前方，以便与受体空穴局部相契合。,4、芳环与一个季碳原子相连，通过季碳原子与叔胺N原子之间的距离相隔二个碳,5、分子中其它部位可与受体结合如氢键可增加镇痛效力。,structure-activity relationship of -r
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