Part 1 Analgesics 1) Types of Pain (acute, chronic) Somatic( 躯体 ) Superficial(Skin ) Deep (Conn. tissues Bones Joints Muscles) europathic( 神经 ) Viscer

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1 Chapter 7 Analgesics and Anesthetics

2 Part 1 Analgesics 1) Types of Pain (acute, chronic) Somatic( 躯体 ) Superficial(Skin ) Deep (Conn. tissues Bones Joints Muscles) europathic( 神经 ) Visceral( 内脏 ) Kidney stones Gastric torsion Angina etc. 剧烈疼痛使病人感觉痛苦引起血压降低, 呼吸衰竭, 甚至导致休克而危及生命

3 2) ormal and pathophysiological transmission of pain 中枢下行上行外周脊髓

4 3) Classification of Analgesics: 1Morphine and Derivatives (Morphine, Codeine) H 3 C R 1 R 2 R 1 =R 2 =H Morphine( 吗啡 ) R 1 =, R 2 =H Codeine( 可待因 ) R 1 =R 2 =C Heroin( 海洛因 )

5 4-phenylpiperidines (meperidine ) 2Synthetic Analgesics 4-phenylaminopiperidines (fentanyl) Aminoketones(methadone) Morphinane and Benzomorphane ( 吗啡烃及苯吗喃类 )(pentazocine) H 3 C Meperidine( 哌替啶 ) H 3 C HCl Methadone ( 美沙酮 ) Fentanyl( 芬太尼 ) H 3 C H H Pentazocine( 喷他佐辛 )

6 4)Morphine and Derivatives 1pium 阿片 Poppy Plant(Papaver somniferum 罂粟 ) Cultivated in: Middle East (Afghanistan and Pakistan) Thailand South America and Mexico

7 1840 Shanghai Jiao Tong University

9 2 Structure of morphine Structure features: Partial hydrogenated phenanthrene. atural morphine have five chiral carbon (5R,6S,9R,13S,14R). B/C:cis,C/D:cis,C/E:trans.

10 3 Actions of Morphine Actions analgesia 镇痛作用 chroniccontinuousdullpain( 隐痛 )superiortoacute discontinuoussharppain( 刺痛 ) relief of pain without the loss of consciousness accompaniedwithsedationandeuphoria 欣快 easy to fall asleep respiration depression 抑制呼吸 reducing the sensitivity of respiratory center to C 2 the most common cause of death in acute overdose

11 4 Mechanism of action L-enkephalin (L- 脑啡肽 ) M-enkephalin (M- 脑啡肽 )

12 5pioid Receptors µ(µ 1, µ 2 ): 镇痛成瘾作用强 δ (δ 1, δ 2 ): 镇痛成瘾作用弱 κ (κ 1,κ 1 ): 介于前两者之间 σ 产生致幻作用 µ 1 调节痛觉 µ 2 介导控制呼吸抑制研究方向 :µ 1 受体选择性激动剂,κ 受体选择性激动剂

13 6Structure modification H A E B 去 E 环 H C D 吗吗去 E C 环去 E C B 环 H A 去 C 环 H A 打打 B 环 A C B D B C 2 H 5 C H 3 C D CH 2 CHC( ) 2 D 那那那那 (Levorphanol) 喷喷喷喷 (Pentazocine) 哌哌哌 (Petidine) 苯吗苯苯苯苯

14 7 A drawing for the interaction of morphine and opioid receptor Cavity for part of piperidine ring Anionic site H H H 3 C Flat surface for aromatic ring H R' Hydrogen receptor (1) A basic center able to associate with an anionic site on the receptor surface. (2) A flat aromatic structure, coplanar with the basic center, allowing for van der Waals bonding to a flat surface on the receptor site to reinforce the ionic bond. (3) A suitably positioned projecting hydrocarbon moiety forming a three-dimensional geometric pattern with the basic center and the flat aromatic structure.

15 H 3 C R R.HCl R' R morphine R=R'=H codeine R= CH3, R'=H H H morphinan R=H levorphanol R = H H benzomorphan R=CH3 pentazocine R=CH2CH=C(CH3)2 H 3 C H 3 C H 3 C R H R' meperidine (pethidine) Dextropropoxyphene (Darvon) etorphine H

16 8SAR aloxone( 纳洛酮 ) 阿片受体拮抗剂 H Hydromorphone ( 氢吗啡酮 ) R 2 can be replace by various alkyl. As consequence a agonist may turn to a antagonist Phenol hydroxyl group to be ether or acylated, the activity and addiction decreased R R R The double bond is reduced, the activity and addictionare increased Hydroxyl group is removed, oxided to ketone, alkylation acylaion, the activity and addiction increased Codeine ( 中枢镇咳药 ) Heroin ( 毒品 )

17 5) Synthetic Analgesics 1Piperidines meperidine 盐酸哌替啶 H 3 C HCl CCH 2 Action The major use of meperidine is for analgesia. It exerts analgesic effect that lies between the dose of morphine and codeine, but it shows little tendency toward hypnosis. It is indicated for the relief of pain in most patients for whom morphine and other alkaloids of opium generally are employed, but it is especially of value where the pain is due to spastic conditions of intestine, uterus, bladder, bronchi, and so on. Its most important use seem to be in lessening the severing of labor pains. Chemical nane Ethyl-1-methyl-4-phenyl-4-piperidine carboxylate hydrochloride 1- 甲基 -4- 苯基 -4- 哌啶甲酸乙酯盐酸盐

18 Synthesis CH 2 Cl H(CH 2 CH 2 H) 2 Diethanolamine CH 2 (CH 2 CH 2 H) 2 SCl 2 Thionyl chloride CH 2 (CH 2 CH 2 Cl) 2 CH 2 C Benzy cyanide C CH 2 H H 2 S 4 (1)H 2 /Pd (2)HCH (3)Catalytic hydrogenation (4)HCl H 3 C HCl

19 24-phenylaminopiperidines Fentanyl Citrate 芬太尼 H CH CH CH Chemical nane -phenyl--[1-(2-phenylethyl)-4-piperidinyl]propanamide citrate - 苯基 --[1-(2- 苯乙基 )-4- 哌啶基 ] 丙酰胺枸橼酸盐 Action The analgesic effects of fentanyl are similar to those of morphine and other m opioids. Fentanyl is approximately 100 times more potent than morphine.

20 Synthetic route C H 2 /i C 6 H 5 CH 2 CH 2 H 2 CH 2 =CHC C C a C H 2, HCl C 6 H 5 H 2 C 6 H 5 H 2 /i -C 2 H H (C 2 H 5 C) 2 citratic acid H CH CH CH C C C C

21 3Aminoketones Methadone Hydrochloride 盐酸美沙酮 HCl H 3 C Chemical nane 6-(Dimethylamino)-4, 4-diphenyl-3-heptanone hydrochloride 6-( 二甲氨基 )-4,4 二苯基 -3- 庚酮盐酸盐 Action The primary uses of methadone hydrochloride are relief of chronic pain, treatment of opioid abstinence syndromes, and treatment of heroin users.

22 Synthetic route CH C H 3C Cl ah 2 C C + CH CH3 3 C C CH3 in hexane MgBr C 2 H 5 MgBr C CH3 C 2 H 5 H HCl C CH3 HCl

23 本节重点 : 1. 分类和代表性药物 : 中枢镇痛药可被分为阿片生物碱类和合成镇痛药两大类, 阿片生物碱类代表性药物有吗啡可待因等可待因等合成镇痛药又可分为哌啶类如哌替啶芬太尼等芬太尼等氨基酮类如美沙酮等氨基酮类如美沙酮等 2. 吗啡的结构修饰及构效关系 :6 位羟基被烷基化酰化酰化氧化成酮或去掉, 活性和成瘾性均增加 ;3 位酚羟基被酰化或醚化, 活性和成瘾性降低 ; 7,8 位双键被还原, 活性和成瘾性增加 ;17 位氮上有较大的烃基取代时, 可能从激动剂转化为拮抗剂 3. 中枢镇痛药与阿片受体的相互作用 :(1) 一般含有一个碱性中心可以与受体表面的阴离子部位结合 ;(2) 一个平面的芳香环结构与碱性中心共平面, 以范德华力与受体表面平坦区域结合 ;(3) 一个适当的烃基凸出部分与碱性中心及平面芳香结构形成一个三维几何图形, 可以与受体表面凹槽部分互补 4. 代表性药物 : 哌替啶途哌替啶芬太尼芬太尼美沙酮的结构美沙酮的结构命名命名合成和用

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PowerPoint Presentation 药物化学镇痛药 Analgesic 1 目录概述第一节第二节第三节吗啡及其衍生物合成镇痛药阿片受体 2 概述疼痛类型及其表现对疼痛的一般认识 : 炎症性疼痛内脏绞痛伤害性疼痛 ( 烫伤刀伤骨折 ) 神经痛牙痛对疼痛的关注趋势 3 疼痛的