Chapter 4 Analgesics, antitussives and expectorants,4.1 Analgesics,疼痛：是由創(chuàng)傷和疾病等多種原因引發(fā)的癥狀，劇烈的疼痛可引起生理功能紊亂，甚至休克。Classification of Painkiller: Narcotic Anangesics :作用于中樞神經(jīng)系統(tǒng)，抑制痛覺神經(jīng)從而消除或緩解疼痛，多用于劇痛（acute pain）。Antipyretic analgesics:具有解熱、鎮(zhèn)痛、抗炎作用，用于鈍痛(chronic pain)如牙痛或頭痛。Difference: different mechanismOpioid receptor for the formerArachidonic 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是罌粟科植物罌粟的未成熟的蒴果被劃破后流出的白色漿汁，干燥后呈棕黑色膏狀物。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,天然的嗎啡呈左旋性，右旋體無活性 5個手性中心：5R, 6S,9R,13S,14R5個環(huán) ，A、B和C構(gòu)成部分氫化的菲環(huán)，C和E構(gòu)成部分氫化的異喹啉環(huán)B/C呈順式，C/D呈反式，C/E呈順式立體構(gòu)像：三維的TPhysiological activity：analgesiaSide-effects: addiction, respiratory depression,Vomiting, constipation, euphoria,1. To simplify the chemical structure of morphine to develop synthetic morphine analogues and morphine 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、鏈烯烴或芳烴修飾,活性為嗎啡的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,是研究阿片受體的工具藥物，可用于嗎啡類中毒后的解救,解除呼吸抑制并使血壓上升。,SAR of morphine,叔胺是鎮(zhèn)痛活性的關(guān)鍵基團(tuán)，N原子上引入不同的取代基可使受體激動劑變?yōu)檗卓箘?酚羥基被酰化和醚化后，活性和成癮性均下降。,雙鍵被還原后，活性和成癮性均增加。,酚羥基被烴化酯化氧化或去除后，活性和成癮性均增加。,-receptor agonist,(5,6 ）-7,8-二脫氫-4,5-環(huán)氧-17-甲基嗎啡喃-3,6- 二醇鹽酸鹽三水合物 (5,6 ）-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6- diol hydrochloride trihydrateOptical 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 (stablest 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,鹽酸嗎啡水溶液與三氯化鐵試液反應(yīng)顯藍(lán)色；與甲醛硫酸試液反應(yīng)呈紫堇色后變?yōu)樗{(lán)色；與鉬硫酸試液反應(yīng)呈紫色。 鹽酸嗎啡水溶液加入稀鐵氰化鉀試液后再與三氯化鐵試液反應(yīng)，生成藍(lán)色的亞鐵氰化鐵, 區(qū)別可待因。 嗎啡與鹽酸或磷酸加熱反應(yīng)生成阿撲嗎啡，阿撲嗎啡氧化生成暗紫紅色鄰醌化合物。阿撲嗎啡水溶液在碳酸氫鈉堿性條件下，加碘試液生成的氧化產(chǎn)物能溶于乙醚顯寶石紅色，水層顯綠色。用于檢查鹽酸嗎啡中的阿撲嗎啡。,暗紫色,阿撲嗎啡,Identification,apomorphine,Apomorphine is used as emetic,Mechanism: opioid-receptor agonistPhysiological activity: analgesic,antitussive and sedative effects.Side-effects: addiction, respiratory depression,Vomiting, constipation, euphoriaUsage: acute pain of cancer,4.1.2 Synthetic analgesics,4.1.2.1 Morphinanes,N-methylmorphinane,levorphanol,butorphanol,活性只有嗎啡的1/5,-receptor agonist活性是嗎啡的4倍,-receptor antagonist-receptor agonist用作鎮(zhèn)痛藥成癮性小,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.,嗎啡,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,-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）高效激動劑,鎮(zhèn)痛作用強于埃托啡，動物實驗結(jié)果其戒斷癥狀及精神依賴性潛力均明顯的輕于嗎啡，但在臨床使用中發(fā)現(xiàn)有較強的精神依賴性和軀體依賴性，耐受性形成快，成癮性強，濫用潛力很大,Endogenous opioid peptides,Structure-Activity Relationship of Opiod Analgesics,1、分子中應(yīng)具有一個平坦的芳香結(jié)構(gòu)，可以和受體相應(yīng)部位通過范德華引力相結(jié)合2、應(yīng)有一個堿性中心，通常為一個叔胺N原子，在生理PH條件下，可大部分電離為陽離子，以便與受體表面的陰離子部位結(jié)合。3、堿性中心和平坦結(jié)構(gòu)芳環(huán)應(yīng)處在同一平面上，以便與受體結(jié)合，烴鏈部分在立體構(gòu)型中應(yīng)突出于平面前方，以便與受體空穴部分相契合。4、芳環(huán)與一個季碳原子相連，通過季碳原子與叔胺N原子之間的距離相隔二個碳5、分子中其它部位可與受體結(jié)合（如氫鍵）可增加鎮(zhèn)痛效力。,structure-activity relationship of -receptor agonist,Models of the Opiod Receptor,a. 陰離子受點,b. 適合芳環(huán)的平坦區(qū),c. 凹槽,具有一個堿性中心。此堿性中心在生理pH下部分解離后帶有正電荷，與受體表面的陰離子受點締合。具有一個平面的芳環(huán)結(jié)構(gòu)與受體的平坦區(qū)，通過范德華力相互作用。烴基鏈部分（嗎啡結(jié)構(gòu)中C15C16）凸出于平面，正好與受體的凹槽相適應(yīng),1、三點結(jié)合的受體模型,A,B,C,D,埃托啡PEO,2、 四點結(jié)合的受體模型,A 親脂部位 B 負(fù)離子部位C 凹槽 D 親脂部位（適合芳環(huán)的平坦區(qū)）,Codeine Phosphate,Chemical name: (5, 6 ) -7,8 - didehydrogen -4,5 - epoxy -3 - methoxy-17 - methyl morphinans - 6 - alcohol phosphate hemihydrate L-Optica Rotation,3、*鹽酸哌替啶（Pethidine Hydrochloride）,2）特征反應(yīng)：其水溶液與苦味酸（三硝基苯酚）的乙醇溶液反應(yīng)，生成黃色哌替啶苦味酸鹽沉淀。,1）化學(xué)名：1-甲基-4-苯基-4-哌啶甲酸乙酯鹽酸鹽，又名度冷丁。,3）代謝：,哌替啶酸,去甲基哌替啶,去甲哌替啶酸,4、*鹽酸美沙酮（Methadone Hydrochloride）,1）化學(xué)名：6-二甲氨基-4，4-二苯基-3-庚酮鹽酸鹽2）鑒別：水溶液與甲基橙試液反應(yīng)生成黃色復(fù)鹽沉淀。,3）代謝：,枸櫞酸芬太尼（Fentanyl Citrate）,Chemical name: N-phenyl-N-1 - (2 - phenylethyl) -4 - piperidine-yl amide citrate Effect: receptor agonist with efficient, high lipophilicity and short time acting. Analgesic effect happens quickly,analgesic effect 75-100 times stronger than morphine. Application: used in clinical surgery and post-operative analgesics for clinical cancer pain.,3）合成：,Butorphanol Tartrate,Chemical name: 17 - (cyclobutanemethyl) - morphinan -3,14 - diol tartrate Effect: -opioid receptor antagonist and receptor agonist. It can not be used as a oral dosage medicine bcause of first-pass effect.Application: to severe moderate pain and assistant narcosis.it is not in the list of abuse potential drug because of small addiction .,Nalbuphine Hydrochloride,Chemical name: 17 - (cyclobutanemethyl) -4,5 - epoxy - morphinan -3,6,14 - triol hydrochloride Effect: -opioid receptor antagonist, antagonist activity is l / 4 that of naloxone. opioid receptor agonist, analgesic effect is stronger than pentazocine but same to morphine. Application: t