Chapter 7 Chapter 7 Analgesics and AnestheticsAnalgesics and Anesthetics

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Part 1 Analgesics 1) Types of Pain (acute, chronic)

Somatic( 躯体）

Superficial （ Skin ）

Deep （ Conn. tissues Bones Joints Muscles ）

Visceral （内脏）Kidney stonesGastric torsionAngina etc.

Neuropathic （神经）

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。

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2) Normal and pathophysiological transmission of pain

上行

下行

外周

脊髓

中枢

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3) Classification of Analgesics:

①Morphine and Derivatives (Morphine, Codeine)

O

NH3C

R1O OR2

R1=R2=H Morphine( 吗啡）

R1=CH3, R2=H Codeine( 可待因）

R1=R2=COCH3 Heroin( 海洛因）

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②Synthetic Analgesics

4-phenylpiperidines (meperidine )

4-phenylaminopiperidines (fentanyl)

Aminoketones(methadone)

Morphinane and Benzomorphane

（吗啡烃及苯吗喃类）（ pentazocine)

Methadone ( 美沙酮） Pentazocine （喷他佐辛）

NH3C

OOCH3

N

N

OCH3

OCH3

CH3

N CH3H3C

HCl

CH3

CH3

N

H

CH3H3C

HO

Fentanyl( 芬太尼）Meperidine( 哌替啶）

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4 ） Morphine and Derivatives

① Opium 阿片

Poppy PlantPoppy Plant (Papaver somniferum (Papaver somniferum 罂罂粟粟 ))

– Cultivated in:Cultivated in:•Middle East (Afghanistan and Middle East (Afghanistan and Pakistan)Pakistan)•ThailandThailand•South America and MexicoSouth America and Mexico

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② Structure of morphine

Structure features:

Partial hydrogenated phenanthrene.

Natural morphine have five chiral carbon

(5R ， 6S ， 9R ， 13S ， 14R).

B/C ： cis， C/D ： cis， C/E ： trans.

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③ ③ Actions of Morphine of Morphine

Actionsanalgesia 镇痛作用chronic continuous dull pain( 隐痛） superior to acute

discontinuous sharp pain （刺痛）relief of pain without the loss of consciousness

accompanied with sedation and euphoria 欣快easy to fall asleep

respiration depression 抑制呼吸

reducing the sensitivity of respiratory center to COreducing the sensitivity of respiratory center to CO22

the most common cause of death in acute overdosethe most common cause of death in acute overdose

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④ Mechanism of action

L-enkephalin （ L- 脑啡肽）

M-enkephalin （ M- 脑啡肽）

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⑤ Opioid Receptors

μ(μ1, μ2) : 镇痛、成瘾作用强

δ (δ1, δ2): 镇痛、成瘾作用弱

κ (κ1 ,κ1): 介于前两者之间

σ 产生致幻作用

μ1 调节痛觉

μ2 介导控制呼吸抑制

研究方向： μ1 受体选择性激动剂， κ 受体选择性激动剂

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⑥ Structure modification

O

OH

N CH3

OH

OH

N CH3

OH

N CH2CHC(CH3)2CH3

CH3

N CH3

OOCC2H5

A

B

CD

E

A

B

CD

A

B

D

A

D

È¥E»·

È¥E¡¢C »·

È¥E¡¢C¡¢B »·

È¥C »· ´ò¿ªB »·

Âð·È

ÄÇÂå·Ç¶û£¨Levorphanol£© ÅçËû×óÐÁ£¨Pentazocine£© ßßÌæण¨Petidine£©

±½Âðà«ÑÜÉúÎï

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N

O

H3C

OH

OR'

⑦ A drawing for the interaction of morphine and opioid receptor

N

O

OH

O H

Anionic site

Flat surface for aromatic ring

Hydrogen receptor

Cavity for part of piperidine ring

(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.

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N

O

H3C

OR

OR'

morphine R=R'=H

codeine R= CH3, R'=H

N

CH3

OH

OH

R

N

R

OH

CH3

CH3.HCl

morphinan R=H

levorphanol R = OH

benzomorphan R=CH3

pentazocine R=CH2CH=C(CH3)2

N

H3C

O

CH3

N

H3C

O CH3

O

CH3

H3C

O

N

R

OH

OCH3O

HO

R'

CH3

meperidine (pethidine) Dextropropoxyphene (Darvon) etorphine

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⑧ SAR

O

N

R2

RO OR13

6

17

7

8

R2 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

Hydroxyl group is removed, oxided to ketone, alkylation acylaion, the activity and addiction increased

The double bond is reduced, the activity and addictionare increased

O OHO

N

Codeine

( 中枢镇咳药）

Heroin

( 毒品）

Hydromorphone

( 氢吗啡酮）

Naloxone( 纳洛酮 )

阿片受体拮抗剂

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5) Synthetic Analgesics

① Piperidines

【 meperidine 盐酸哌替啶】

N

COOCH2CH3

H3CHCl

Chemical nane

Ethyl-1-methyl-4-phenyl-piperidine carboxylate hydrochloride 1- 甲基 -4- 苯基 -4 哌啶甲酸乙酯盐酸盐

ActionThe 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.

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Synthesis

NH3CCl

Cl

C6H5CH2CN

NaNH2NH3C

CN

H2SO4

H2O

NH3CCOOH

C2H5OH

NH3CCOOC2H5

NH3CCOOC2H5

.HCl

NH3CHCl

CH2ClNH(CH2CH2OH)2

DiethanolamineCH2N(CH2CH2OH)2

SOCl2

Thionyl chloride

N

CN

CH2N(CH2CH2Cl)2

CH2CN

Benzy cyanide

CH3CH2OH

H2SO4

N (1)H2/Pd (2)HCHO

(3)Catalytic hydrogenation (4)HCl

OO

CH3OO

CH3

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② 4-phenylaminopiperidines

【 Fentanyl Citrate 芬太尼】

N

N

OCH3

COOH

COOH

COOHHO

Chemical naneN-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide citrateN- 苯基 -N-[1-(2- 苯乙基 )-4- 哌啶基 ] 丙酰胺枸橼酸盐

ActionThe analgesic effects of fentanyl are similar to those of morphine and other m opioids. Fentanyl is approximately 100 times more potent than morphine.

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Synthetic route

COOH

COOH

COOHHO

H2/NiC6H5CH2CH2NH2

CH2=CHCOOCH3

NCOOCH3

COOCH3

NaOCH3

N

O

COOCH3C6H5NH2

NH N

N C6H5

H2O, HCl

N

O

H2/Ni

N

NH(C2H5CO)2O

N

NCH3

O

N

NCH3

O

citratic acid

-CO2

CN

N

COOCH3

C

OCH3

ON

COOCH3

O

OCH3 N

O

COOCH3

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③Aminoketones

【 Methadone Hydrochloride 盐酸美沙酮】

OCH3

CH3

N CH3H3C

HCl

Chemical nane6-(Dimethylamino)-4, 4-diphenyl-3-heptanone hydrochloride 6-( 二甲氨基 )-4 ， 4 二苯基 -3- 庚酮盐酸盐

ActionThe primary uses of methadone hydrochloride are relief of chronic pain, treatment of opioid abstinence syndromes, and treatment of heroin users .

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Synthetic route

CH CNH3C

NCH3

CH3

Cl

NaNH2

CCN

NCH3

CH3

CH3CCN

NCH3

CH3

CH3

+

in hexane

C2H5MgBrC

NCH3

CH3

CH3

NMgBr

C2H5OH

HClC

NCH3

CH3

CH3

O CH3

HClCH3

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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。合成镇痛药又可分为哌啶类如哌替啶、芬太尼等。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、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、芬太尼、美沙酮的结构、命名、合成和用途