Cholinergic Agents and Anticholinergic Agents 1 O H
- Slides: 105
拟胆碱药和抗胆碱药 Cholinergic Agents and Anticholinergic Agents 1
乙酰胆碱受体的分类 O H 3 C N O 乙酰胆碱受体 Acetylcholine Receptor, ACh. R 乙酰胆碱 Acetylcholine (Ach) 毒蕈碱受体 Muscarinic Receptor, (+)-毒蕈碱 Muscarine N N CH 3 (+)-烟碱 Nicotine M Receptor 烟碱受体 Nicotinic Receptor, N Receptor 5
Jean Nicot de Villemain (1530 -1600) was a French diplomat and scholar. Nicotiana tabacum 6
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第一节 拟胆碱药 Cholinergic Agents 一、M胆碱受体激动剂 Muscarinic receptor Agonists 二、乙酰胆碱酯酶抑制剂 Acetylcholinesterase Inhibitors 8
2000年发表视紫红质三维结构 Palczewski K, et al. Crystal Structure of Rhodopsin: A G Protein-coupled Receptor. Science 2000; 289: 739~745. 11
M受体激活后的信号转导 α β α γ GDP + β γ GDP Pi GDP receptor a subunit GTPase activity ACh GTP α GTP β γ α + β γ GTP phospholipase C adenylyl cyclase Ca 2+ channel effector c. AMP c. GPM IP DG Ca 2+ second massengers 13
胆碱酯类M受体激动剂 氯贝胆碱 Bethanechol Chloride O H 2 N CH 3 O N +(CH 3 )3 Cl- (±)-2 -[(Aminocarbonyl)oxy]-N, N, N-trimethyl 1 -propanaminium chloride 19
Bethanechol的手性: S-异构体的活性大大高于R-异构体. H CH 3 H O O CH 2 N +(CH 3)3 NH 2 S-(+)-Bethanechol H 3 C O O CH 2 N +(CH 3)3 NH 2 R-(-)-Bethanechol 20
乙酰胆碱的生物合成及降解 HO COOH Serine decarboxylase NH 2 HO Choline N-methyltransferase NH 2 Serine HO N+(CH 3)3 O Choline acetyltransferase CH 3 Choline O N+(CH 3)3 Acetylcholine O Acetylcholinesterase CH 3 OH Acetic acid + HO N+(CH 3)3 Choline 28
乙酰胆碱酯酶催化乙酰胆碱水解机制 N+ O Ser OH N+ C O N O CH 3 - O C OH CH 3 Glu Ser NH O C - O N His O O C Glu NH His ACh-ACh. E 可逆复合物 乙酰化酶 CH 3 O - Ser O OH N NH His 游离酶 C C Glu Ser H O O O H - O C Glu O N NH His 广义碱催化乙 酰化酶的水解 31
乙酰胆碱酯酶催化乙酰胆碱水解机制 ACh. E Ser OH + (CH 3)3 N O + CH 3 O (CH 3)3 N+ O CH 3 HO O Ser ACh. E A (CH 3)3 N+ OH + O Ser ACh. E H 3 C O B O ACh. E Ser OH + H 3 C OH 32
Neostigmine与乙酰胆碱酯酶的相互作用过程 ACh. E-Ser-OH + O (CH 3)2 N N+(CH 3)3 Br - HO Ser ACh. E N+(CH 3)3 Br - + O C O H 2 O OH ACh. E-Ser-OH + (CH 3)2 N O 37
Neostigmine的合成 38
Neostigmine Bromide同型药物 H 3 C CH 3 O N N+(CH 3)3 Br - 溴新斯的明 Neostigmine Bromide O O N(CH 3)2 O + N 溴吡斯的明 Pyridostigmine Bromide Br - CH 3 O N(CH 3)2 O (CH 3)3 N+ + N Br - CH 3 O N N O (CH 2)10 O O 苄吡溴铵 Benzpyrinium Bromide N+(CH 3)3. 2 Br- 地美溴铵 Demecarium Bromide 39
胆碱酯酶复能药 √ √ CH 3 C Ser H O O O H - O C Glu O N NH His x 42
第二节 抗胆碱药 Anti-cholinergic Agents 47
茄科生物碱类的结构特征 Tropine N Tropic Acid CH 3 O N CH 3 OH O N OH O O (-)-莨菪碱 天仙子胺 Hyoscyamine CH 3 O HO 东莨菪碱 Scopolamine CH 3 OH HO O O N OH O O 山莨菪碱 Anisodamine O 樟柳碱 Anisodine 57
东莨菪碱的半合成类似物 R H 3 C CH 3 H 3 C N+ O O OH N+ . Br- . Br - S S O O R = -CH 3 甲溴东莨菪碱 Scopolamine Methobromide R = -C 2 H 5 氧托溴铵 Oxitropium Bromide OH 噻托溴铵 Tiotropium Bromide M 1,M 3,长效吸入剂 R = -C 4 H 9 丁溴东莨菪碱 Scopolamine Butylbromide 季铵,中枢作用弱。 支气管 胃肠道 62
茄科生物碱类的中枢作用:氧桥↑ ,羟基↓ O N CH 3 OH > N > O 东莨菪碱 Scopolamine O O CH 3 OH O N ☻ CH 3 N HO O O OH > 樟柳碱 Anisodine 阿托品 Atropine O CH 3 HO OH O O 山莨菪碱 Anisodamine 64
CH 3 Br N+ CH 3 O O OH O N CH 3 格隆溴铵 H 3 C 奥芬那君 H 3 C OH N H 3 C CH 3 OH CH 3 丙环定 托特罗定 CH 3 H 3 C N+ OH CH 3 N H 3 C N O O 托吡卡胺 CH 3. I- NH 2 CH 3 异丙碘铵 71
Synthesis of Propantheline Bromide O COOH C 6 H 5 OH Cl Na. OH, Cu 醚化反应 亲核取代 OH O COOH 傅克酰化 O Na. CN 1) Na. OH CH 2 COOH 2) HCl 氰基水解 O O CH 3 HOCH 2 N(CH(CH 3)2)2 H 3 C O O 还原反应 O COOH CN 亲核取代 Zn, Na. OH H 2 SO 4 N CH 3 H 3 C O O + N CH 3 Br - CH 3 Br 酯化反应 成盐:季铵化 O O 75
毒标枪蛙 (poison-dart-frog) 毒箭蛙 (poison-arrow-frog) 88
四氢异喹啉类N受体拮抗剂的主要代谢方式 H 3 CO OCH 3 H N HO CH 3 O O O N a: Hofmann消除 b: 酯水解 OH CH 3 O OCH 3 H 3 CO b N HO CH 3 OH O H 3 CO OCH 3 H 3 CO N HO CH 3 OH O O H 3 CO OCH 3 b a O O O HO O OCH 3 HN OH H 3 C N HO CH 3 H 3 CO OCH 3 OCH OH H 3 CO OCH 3 OH O 94
Atracurium的同型药物 OCH 3 H 3 CO N CH 3 H 3 C + N O H 长效 ? Doxacurium Chloride H 3 CO N CH 3 OCH 3 H O + 2 Cl. OCH 3 H 3 CO OCH 3 O 多库氯铵 H 3 CO H 3 CO O + OCH 3 O O H 3 C + N O 米库氯铵 Mivacurium Chloride OCH 3 2 Cl. OCH 3 短效? 思考题:米库氯铵的体内主要代谢途径? 96
泮库溴铵的同型药物 O O O H 3 C H N H O + CH 3 H H HO O O H 3 C H H 3 C N N H H O H 3 C CH 3 H 3 C H N . 2 Br - H O H 哌库溴铵 Pipecuronium Bromide CH 2 H CH 3 O . Br - 罗库溴铵 Rocuronium Bromide H N O + + N H N 维库溴铵 Vecuronium Bromide H 3 C + N H 3 C O . Br - H O H 3 C N O H 3 C + N . Br - CH 2 H H O 瑞帕库溴铵 Rapacuronium Bromide 99
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