Chapter 7 Analgesics

Analgesics

Agents that decrease pain are referred to as analgesics or as analgetics （止痛药） .

Drugs used to relieve pain include:

the nonsteroidal anti-inflammatory agentsanesthetics (general or local) central nervous system (CNS) depressantsopioid agents

Opioid agents

Opioid analgesics historically have been called narcotic ( 麻醉性 ) analgesics.

Narcotic analgesic literally means that the agents cause sleep or loss of consciousness in the conjunction with their analgesic effect. The term narcotic has become associated with the addictive properties of opioids and other CNS depressants.

Because the great therapeutic value of the opioids is their ability to cause analgesic without causing sleep (narcosis 昏迷状态 ) ， the term narcotic analgesic is not used further in this chapter.

Opium alkaloids

The use of the juice (opium in Greek) or gum from the unripe seed pods of the poppy ( 罂粟 ) is among the oldest recorded medications.

The pharmacist Surturner first isolated an alkaloid from opium in 1803. He named the alkaloid morphine, after the Greek god of dreams.

Codeine, thebaine(蒂巴因 ), and papaverine (罂粟碱 ) are other medically important alkaloids that were later isolated from opium gum.

Morphine and its analogous( 类似物 )

Morphine was among the first compounds to undergo structure modification.

Ethylmorphine (the 3-ethyl ether of morphine ) was introduced as a medicine in 1898.

Diacetylmorphine, which may be considered to be the first synthetic prodrug, was synthesized in 1874 and introduced as a nonaddicting analgesics, antidiarrheal( 止泻剂 ), and antitussive agent ( 止咳药 ) in 1898.

Opiate

The term opiate was used extensively until the 1980s to describe any natural or synthetic agent that was derived from morphine.

An opiate was any compound that was structurally related to morphine.

Opioid

The discovery, in the mid-1970s, of peptides in the brain that had pharmacologic actions similar to those of morphine prompted a change in nomenclature ( 命名 ).

The peptides were not easily related to morphine structurally; yet, their actions were similar to the actions of morphine.

The term opioid, meaning opium-like or morphine-like in terms of pharmacologic action, was introduced.

Opioids include:

alkaloid opioids ， such as morphine;synthetic analgesics, such as pethidine;endogenous opioids, such as enkephalinsopioid antagonists, such as naloxone.

Principal pharmacologic effects of opioids

(-)-Morphine and its congeners modify the effects of pain impulses on the CNS. Awareness of the pain may persist or diminish but the ability to interpret, integrate, and react to pain is decreased with attendant sedation, euphoria( 欣快 ), and reduced anxiety and suffering.

The only other useful effect of opioids on the CNS is cough suppression.

Side effect of Opioids

Constipation （便秘）Respiratory depression, which is the cause of

death from opioid overdoseDependenceTolerance, which refers to the need to increase

the dose of opioid over a period of time in order to achieve the same level of analgesia or euphoria.

吗啡连续反复使用，易产生耐受性和成瘾性，须严格按照国家颁布的《麻醉药品管理办法》管理。

Opioid receptors

Narcotic analgesics(agonists and antagonists) are stereospecific binding, chemically specific binding, and competitive binding with opioid receptors.

Opioid receptors are classified:

μ ： μ1 、 μ2

κ ： κ1 、 κ2 、 κ3

δ ： δ1 、 δ2

Section 1 Morphine and related opioid agonists

(1)Opioid alkaloid(2)Morphine’s derivatives(3)Synthetic analgesics

(1) opioid alkaloid

(-)- Morphine Hydrochloride(-)-Codeine Phosphate

(-)-Morphine Hydrochloride

CH3N

OHO OH

AB

EC

D1

2

3 4 56

7

81410

11

17

9

. HCl. 3H2O

(-)-Morphine Hydrochloride

(5α,6α)-7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3,6-diol hydrochloride trihydrate

HN

1

2

3 4 56

7

81410

11

17

9

morphinan

The Structure of (-)-Morphine

Morphine is composed of five fused rings, and the molecule has five chiral centers with absolute stereo- chemistry (5R, 6S, 9R, 13S and 14R).

The naturally occurring isomer of morphine is levo [(l) or (-)] rotatory. (+)-morphine has been synthesized, and it is devoid of analgesic and other opioid activities.

CH3N

OHO OH

AB

EC

D1

2

3 4 56

7

81410

11

17

9

The configuration of (-)-morphine

B/C and C/E are cis, and C/D is trans.Morphine is shaped like a three-dimensional "T" with rings

A, B, and E forming a near perfect vertical plane and rings C and D forming a more distorted horizontal plane. The D ring is in the chair conformation and the C ring is a boat with atoms 6 and 14 fore and aft. The "T" is skewed.

N

HOHHH

H3CH

O

OHA

EB

CD

吗啡的理化性质

1. 吗啡是从阿片中提取得到的。2. 吗啡显弱酸性 , 可与强碱成盐。 3. 吗啡显碱性，可与酸成盐，临床上常用其盐酸

盐或硫酸盐。4. 吗啡具有左旋性。5. 吗啡及其盐易被氧化。

Oxidation of (-)-morphine

N

OHO OH

CH3N

HO O OH

CH3N

HO O OH

CH3N

HO O OH

CH3

O

+

Pseudomorphine morphine N-oxide or Dimorphine

Its stability is related with pH of solution. it is the most stable in the solution (pH=4).

在中性或碱性条件下极易氧化，在日光、重金属离子存在下可催化此反应，所以盐酸吗啡注射液放置过久颜色变深，在制备制剂及贮存时应加以注意。

Identification of apomorphine in morphine

N

HO O OH

CH3

HO OH

N

CH3

HCl or H3PO4

O O

HN

CH3

I2

NaHCO3

Apomorphine

醚层显宝石红水层显绿色

催吐剂

Identification of little morphine in codeine (1)

N

CH3O O OH

CH3

N

HO O OH

CH3

HCl

N

HO O OH

CH3

NO

NH4OH

marron(ºì ×ØÉ«)

NaNO2

2-nitrosomorphine

HCl

NaNO2

Identification of morphine in codeine (2)

A. 水溶液与三氯化铁试液反应显蓝色 ( 酚羟基 )。

B. 水溶液加入稀铁氰化钾试液后再与三氯化铁试液反应，生成蓝色 ( 酚羟基 ) 。

C17H19O3N+K3Fe(CN)6 → C34H36O6N2

C34H36O6N2+ K4Fe(CN)6 + FeCl3 → blue

Metabolism of morphine

N+

HO O OH

CH3

HN+

RO O OH

CH3

H

R=Glu or SO3-

N+

HO O OH

H

HN+

HO O O-Glu

CH3

H

CYP450

N-demethylation

morphine

first pass effect

activityNomorphine

The use and action in the body of morphine

It is available in intramuscular, subcutaneous( 皮下的 ), oral, rectal, epidural( 硬膜外的 ) and intrathecal( 鞘内的 ) dosage forms.

Morphine is three to six times more potent when given intramuscularly than it is given orally. The difference in activity is due to extensive first-pass 3-O-glucuronidation of morphine -- an inactive metabolite. its bioavailability is about 25%.

Pharmacologic activity of (-)- morphine

(-)-Morphine, which is a μopioid agonist, is the natural product prototype for this class of analgesics.

Morphine hydrochloride or sulfate is the most often used analgesic for severe, acute, and chronic pain.

Overdoses of morphine as well as all μ agonists in this section can be effectively reversed with naloxone ( 盐酸纳洛酮 ) .

Side effects of (-)-morphine

Sedation( 镇静 ), dizzy( 眩晕 ), vomit( 呕吐 ), drowsiness( 嗜睡 ), constipation （便秘）

Tolerance, dependenceRespiratory depression, which is the cause of

death from opioid overdose.

(-)-Codeine Phosphate

(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol phosphate sesquihydrate

CH3N

OCH3O OH

. H3PO4 . 1.5H2O

Synthesis of Codeine

N

HO O OH

CH3 N

CH3O O OH

CH3

C6H5N+(CH3)3OH-

morphine codeine

可待因的理化性质

可待因具有左旋性。较吗啡稳定，但遇光仍易变质。水溶液加氨试液后无沉淀。与三氯化铁试液反应不显色。

Stability of Codeine

CH3N

OCH3O OH

protection from light

It is more stable than morphine.

Identification of little morphine in codeine

N

HO O OH

CH3

HCl

N

HO O OH

CH3

NO

NH4OH

marron(ºì ×ØÉ«)

NaNO2

2-nitrosomorphine

N

CH3O O OH

CH3

HCl

NaNO2

Metabolism of codeine

N+

CH3O O OH

CH3

H

N+

CH3O O OH

H

H

CYP450

N+

HO O OH

CH3

HN+

RO O OH

CH3

H

R=Glu or SO3-

N+

HO O OH

H

HN+

HO O O-Glu

CH3

H

CYP450

CYP450

O-Demethylation

N-demethylation N-demethylationCodeine morphine

nomorphine

10%

Pharmacologic activity

Codeine is a weak μ agonist, which has about 1/10 analgesic potency of morphine.

Codeine phosphate is used extensively to treat moderate-to-mild pain and it is a more effective antitussive ( 止咳剂 ) agent than morphine.

Codeine causes less sedation, nausea( 恶心 ), vomiting, constipation, tolerance, dependence and has less effect on the gastrointestinal and urinary tracts than morphine.

(2) Structural modification of morphine

CH3N

OHO OH

H

SARs for morphine derivativesDrugs Substituent Activity

Codeine （可待因） 3-OCH3 10×decrease

Ethylmorphine( 乙基吗啡 ) 3-OCH2CH3 10×decrease

Heteromorphine( 异可待因 )

6-OCH3 10×increase

（ toxicity ）Heroin （海洛因） 3,6-diOAc increase

Hydromorphone( 氢吗啡酮 )

6-keto, 7,8-dihydro 10×increase

Oxymorphone( 羟吗啡酮 ) 6-keto, 7,8-dihydro, 14β-OH 10×increase

Hydrocodone( 氢可酮 ) 3-OCH3, 6-keto, 7,8-dihydro, decrease

Oxycodne （羟考酮） 3-OCH3, 6-keto, 7,8-dihydro,14-OH decrease

N-2-phenylethyl-morphine

N-β －苯乙基吗啡NCH2CH2Ph 14×increase

Nalorphine （烯丙吗啡） NCH2CH=CH2 μ antagonist

Importance to structural modification of morphine

In the structure of morphine (or any other opioid) are likely to cause a change in the affinity and intrinsic activity of the new compound for each of the opioid receptor types, i.e., a selective μ agonist may shift to become a selective К agonist.

In addition, the new compound has different physical properties than its parent. The different physical properties (e.g. solubility, partition coefficient, pKa) result in different pharmacokinetic characteristics for the new drug and can affect its in vivo activity profile.

Heroin

CH3N

OAcO OAc

H

The 3,6-diacetyl derivative of morphine is known commonly as heroin.

Heroin was synthesize from morphine in 1874 and was introduced to the market in 1898 by the friedrich Bayer Co. in Germany.

The reason that heroin has higher activities

Heroin itself has relatively low affinity for μ opioid receptors; however, its high lipophilicity compared with morphine results in enhanced penetration of the blood-brain barrier.

Once in the body, esterases hydrolyze the 3-acetyl group to produce 6-acetyl-morphine. This latter compound has μ agonist activity in excess of morphine.

The reason that heroin is limited

Heroin provides an “euphoric rush” that makes this compound a popular drug of abuse.

Repeated use of heroin results in the development of tolerance, physical dependence that is often destructive to the user and to society.

In addition, the use of unclean or shared hypodermic ( 皮下 ) needles for self-administering heroin often results in the transmission of AIDs, hepatitis, and other infections.

(3) Synthetic Analgesics

A. Morphinans （吗啡喃类）B. Benzomorphans （苯吗喃类）C. Piperidines （哌啶类）D. Phenylpropylamines （苯丙胺类）E. Aminotetralins （氨基四氢萘类）F. Cyclohexane derivatives( 环己烷衍生物 )

A. Morphinans （吗啡喃类）R'N

R

AB

C

D

morphinan

Removal of 3,4-epoxide bridge in the morphine structure results in compounds that are referred to as morphinans.

The synthetic produce yields compounds as racemic mixtures, but only the levo (-) isomers possess opioid activity. The dextro isomers have useful antitussive activity.

CH3N

OHO OH

H

morphine

Levophanol( 左啡诺 )

17-methylmorphinan-3-ol tartrate dihydrateLevophanol is about 8 times more potent as an

analgesic in humans than morphine. Levophanol’s increased activity is due to an increase

in affinity for μ opioid receptors and its greater lipophilicity, which allows higher peak concentrations to reach the brain.

CH3N

HO

C

C HHO

OHH

COOH

COOH

. . 2 H2O

The configuration of levophanol

N

HH

H3C

OHA

B

D C

levophanol

N

HOHHH

H3CH

O

OHA

EB

CD

morphine

Butophanol （布托啡诺）

Butorphanol is a μ antagonist and К agonist. The mixed agonist / antagonist is an antagonist analgesic and has less dependence liability.

CH2N

HO

OH

B. Benzomorphans （苯吗喃类）

Synthetic compounds that lack both the epoxide ring and the C ring of morphine retain opioid activity.

Compounds having only the A,B, and D rings are named chemically as derivatives of 6,7-benzomorphan or benzomorphans.

R'N

HO

AB

D

R

R

Pentazocine ( 喷他佐辛 )

Pentazocine has an agonist action on κ opioid receptors--an effect that produces analgesia, and pentazocine is weak antagonist at μ receptors.

Pentazocine is a mixed agonist/antagonist and has less dependence.

CH2CH=C(CH3)2N

HO

CH3

CH3

C. Piperidine （哌啶类）

4-phenylperidines （ 4- 苯基哌啶类）

4-anilidopiperidines （ 4- 苯胺基哌啶类）

Pethide （哌替啶）

The analgesic activity of pethide was discovered during biologic screening of compounds that were designed as anticholinergics( 抗胆碱能类 ) patterned on the structure of atropine.

Pethide is a typical μ agonist with 1/6~1/8 the potency of morphine.

N

C6H5 COOC2H5

CH3

The conformation of pethidine

Analgesic compounds in the 4-Phenylpiperidine class may be viewed as A, D ring analogs of morphine.

It created great interest because the structural simplicity of the drug and the synthesis of fragments of the morphine molecule to provide a nonaddictive and potent analgesic was futile.

NH3C

A

D C£ O£ C2H5

O

NH3C A

D

COOC2H5

N

HOHHH

H3CH

O

OHA

EB

CD

Alphaprodine （阿法罗定）

N

C6H5 OCC2H5

CH3

CH3

O

α- prodine is the 3-methyl reversed ester derivatives of pethidine.

α- prodine is as active as morphine. It has a more rapid onset and shorter duration of action than morphine.

N

C6H5 COC2H5

CH3

O

Fentanyl( 芬太尼 )

Structural modification of the 4-phenylpiperidines has led to discovery of the 4-anilidopiperidine or the fentanyl group of analgesics.

Fentanyl and its derivatives are μ agonists, and they produce typical morphine-like analgesia and side effects.

NCH2CH2C6H5

NCOC2H5C6H5

N

C6H5 OCOC2H5

CH3

CH3

Structural variations of fentanyl

Structural variations of fentanyl that have yielded active compounds are substitution of an isosteric ring of the phenyl group, addition of a small oxygen-containing group at the 4-position of the piperidine ring.

Newer drugs that illustrate some of these structural changes are alfentanil （阿芬他尼） and sulfentanil （舒芬太尼） .

Both of these drugs have higher safety margins ( 安全范围 ) than other μ agonists. They have more rapid onset and shorter duration of action than morphine.

Sulfentanil( 舒芬太尼 )

NCH2CH2

NCOC2H5C6H5

CH2OCH3

S

BioisosterismBioisosterism

Alfentanil( 阿芬太尼 )

NCH2CH2

NCOC2H5C6H5

CH2OCH3

N

N N

N

OCH2CH3

BioisosterismBioisosterism

Refentanil( 瑞芬太尼 )

N

CH2CH2COOCH3

NCOC2H5C6H5

CO2CH3

N

CH2CH2R1

NCOC2H5C6H5

R

N

CH2CH2COOH

NCOC2H5C6H5

R

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R1=±½»ù£¬ R2=H ·ÒÌ« ÄáR1=±½»ù£¬ R2=COOCH3¿¨ ·ÒÌ« Äá

N

NCOC2H5C6H5

C6H5

·ÒÌ« Äá(Fentanyl)

OhmefentanylOhmefentanyl （羟甲芬太尼）（羟甲芬太尼）

ôǼ׷ÒÌ« Äᣨ Ohmefentanyl£©

N

NCOC2H5C6H5

C6H5

OH

CH3

60006000

88

1300013000

Pethidine Hydrochloride (Dolantin)

1-methyl-4-phenyl-4-piperidinecarboxylic ethyl ester hydrochloride

. HCl

N

C6H5 COOC2H5

CH3

Synthesis of pethidineCH2CN

+ CH3N(CH2CH2Cl)2NaNH2

NC

N CH3

H2SO4

HOOC

N CH3

C2H5OH

C2H5OOC

N CH3

. HCl

C2H5OOC

N CH3

II I III

HCl

Physical-chemical properties

NH3C CO2C2H5

. HCl + Na2CO3

white crystalline power

NH3C CO2C2H5

oil solid mp 30~31¡æ

Hydrolysis

NH3C CO2C2H5

H+

short time

Identifying reaction

YellowMp 188~191℃

OH

NO2O2N

NO2

+

N

C6H5 CO2C2H5

CH3

OH

NO2ON2

NO2

N

C6H5 CO2C2H5

CH3

.

Metabolism of pethidine

N

C6H5 CO2C2H5

CH3

N

C6H5 CO2H

CH3

N

C6H5 CO2-Glu

CH3

NH

C6H5 CO2C2H5

NH

C6H5 CO2H

NH

C6H5 CO2-Glu

Pethidine acid

Norpethide(no activity,toxity)

Norpethidinic acid

liver

no activity

Pharmacologic activity (1)

Pethidine is a μ agonist with about 1/10 the potency of morphine after intramuscular dose.

主要用于创伤、手术后或癌症晚期的疼痛。Pethidine produces the analgesia, dependence,

respiratory depression, and euphoria caused by other μ agonists, but it causes less constipation, and it does not inhibit cough.

When given orally, pethidine has 40~60% bioavailability as a result of significant first-pass metabolism.

Pharmacologic activity (2)

Pethidine has received extensive use in obstetrics( 产科学 ) because of its rapid onset, short duration of action.

Prolonged dosage of pethidine may cause an accumulation of the metabolite normeperidine. Normeperidine has only weak analgesic activity, but it causes CNS excitation.

Pethidine has a strong adverse reaction when given to the patients receiving a monoamine oxidase (MAO) inhibitor.

Fentanyl Citrate ( 枸橼酸芬太尼 )

N-Phenyl-N-[1-(2-phenylethyl)-4-piperidinyl] propanamide citrate

N CH2CH2C6H5CH3CH2CO - N

C6H5

HO - C COOH

CH2COOH

CH2COOH

Design of synthesis routine

N CH2CH2C6H5CH3CH2CO - N

C6H5

HO - C COOH

CH2COOH

CH2COOH

III II I IV

Synthesis of Fentanyl Citrate (1)

CH2CH2NH2

CH2=CHCO2CH3

CH2CH2NCH2CH2CO2CH3

CH2CH2CO2CH3

CH3ONa CH2CH2N O

CO2CH3

HCl

CH2CH2N OPh-NH2

piperidine

CH2CH2N N

H2/NiCH2CH2N N

H

CH2CH2N N

COCH2CH3

(CH3CH2CO)2O

HO - C COOH

CH2COOH

CH2COOH

citric acidCH2CH2N N

COCH2CH3

Synthesis of Fentanyl Citrate (2)

Pharmacologic activity

Fentanyl is a μ agonist with about 80 times the poyency of morphine.

The advantages of fentanyl over morphine for anesthetic procedures are its short duration of action (1to 2 hours).

A fentenyl patch has been released for the treatment of severe chronic pain. Fentanyl’s short duration of action after parenteral dosing is due to redistribution, rather than to metabolism or excreceion. Repeated doses of fentanyl can result in accumulation and toxicities. Elderly patients are usually more sensitive to fentanyl and require lower doses.

Sulfentanil Citrate( 枸橼酸舒芬太尼 )

NCH2CH2

NCOC2H5C6H5

CH2OCH3

S

HO - C COOH

CH2COOH

CH2COOH

Addition of the 4-methoxymethyl group and bioisosteric replacement of the phenyl with a thiophenyl on the fentenyl structure results in a 10-fold increase in μ opioid activity.

Pharmacologic activity

Sufentanil is 600 to 800 times more potent than morphine.

Despite its greater sedative and analgesic potency, sufentanil produces less respiratory depression at effective anesthetic doses.

Sufentanil is available in an intravenous dosage form, and it is used for anesthetic procedures. It has a faster onset and shorter duration of action than fentenyl. The shorter duration of action is due to redistribution from brain tissues.

D. Phenylpropylamine

German scientists synthesized another series of open chain compounds as potential antispasmodics( 解痉药 ).

Methadone was the major drug to come from this series of compounds.

(+)-Methadone

NCH3

H3CC2H5O

H3C

Methadone is especially useful for its oral activity and its long duration of action. These properties make methadone useful for maintenance therapy of opioid addicts and for pain suppression in the terminally ill (e.g., hospice 临终关怀医院 programs).

Methadone

It has moderate dependence liability and constipating( 便秘 ) effects. Methadone is a respiratory depressant and cough suppressant.

The withdrawal syndrome is slower in onset, more protracted( 延长 ), and less severe than that seen with heroin. Accordingly, it is used to detoxify dependent subjects.

Because of its relatively mild sedative and euphoric effects, it is also used for maintenance during rehabilitation ( 康复 ).

The configuration of Methadone

NH3C

CH3 O

C2H5

A

¦Ä+:

H3C

NH3C A

D

COOC2H5

pethidine

CH3N

OHO OH

H

morphine

AB

C

D

E

Dextropropoxyphene ( 右丙氧芬 )

N OCH3

H3CCOCH2CH3

H3CCH2

Propoxyphene is an open chain compound that was discovered by structural variation of methadone.

Propoxyphene is a weak μopioid agonist, having only one-fifteen the activity of morphine. The active (+)-isomer has (2S,3R) absolute configuration.

Methadone Hydrochloride

6-(dimethylamino)-4,4-diphenyl-3-heptanone hydrochloride

N

CH3H3C C2H5O

H3C

HCl .4

675

3

Synthesis of methadone

CN

+

H3CN(CH3)2

Cl

NaNH2C

N

H3CN(CH3)2

CN

N(CH3)2

CH3

(1) C2H5MgBr

(2) H+

H3CN(CH3)2

C

N(CH3)2

CH3

H3C

+

+

methadone isomethadone

O

H3C

O

Reduction reaction

N

CH3H3C C2H5O

H3C. (i-PrO)3Al

or Na-Hg

Identification of methadone (1)

N

CH3H3C C2H5O

H3CNH2NHCONH2

Identification of methadone (2)

NCH3H3C C2H5O

H3C

+

N NHO3S N(CH3)2

NCH3H3C C2H5O

H3C N NHO3S N(CH3)2.

¼×»ù³È

yellow

The metabolism of methadone

The elimination of methadone depends on liver function and urinary pH.

The typical half-life is 19 hours, but if urinary pH is raised from normal values of 5.2 to 7.8, the half-life becomes 42 hours. At the higher pH, a lower percentage of methadone exists in the ionized form, and there is more renal reabsorption of the drug.

Enzyme inducer (e.g., phenytoin, rifampin) can lead to withdrawal in patients using methadone for maintenance of addiction.

Toxic doses can build up in patients with liver disease or in geriatric patients （老年病人） who have a decreased oxidative metabolism capacity.

Metabolism of methadone in the liver

CH3

N

CH3

CH3

OCH3

N

CH3

H

ON

CH3

CH3

CH3

N

CH3

CH3

HOCH3

NH

CH3

HOCH3

NH2

HO

CPY-450

CPY-450

CPY-450

Methadol Normethadol Dinormethadolactivity activity activity

alcohol dehydrogenaseno activity

greater oral potency and longer duration of action

Pharmacologic activity （ 1 ）

Methadone is a synthetic agent with about the same μ opioid potency as morphine.

The drug is used as a racemic mixture, but nearly all of the activity is due to the (-)-isomer.

Methadone’s usefulness is a result of its greater oral potency and longer duration of action compared with other μ agonists.

Pharmacologic activity （ 2 ）

Methadone is an excellent analgic ( 无痛感的 ) for use in cancer patients, and it is often used in hospice programs.

Oral doses of 40mg are commonly used for 24 hour suppression of withdrawal symptoms (addiction maintainence) in opioid addicts. Methadone requires once-a-day dosing, usually at a clinic, to suppress withdrawal symptoms.

α－ Methadol （ LAAM ）

Although methadone is a good drug for maintenance of addiction, it is not deal. Methadone requires once-a-day dosing, usually at a clinic, to suppress withdrawal symptoms. Once-a-day dosing is expensive and sometimes logistically difficult to achieve.

LAAM is available and is used in some treatment programs to overcome the problems of methadone.

LAAM is more potent than methadone, and it has a longer duration of action. A single oral dose of this agent can suppress abstinence withdraw for up to 3 days.

E. Aminotetralin( 氨基四氢萘 )

Aminotetralins represent A, B ring analogs of morphine.

A number of active compounds in this class have been described, but only dezocine (地左辛 ), a mixed agonist/antagonist, has been marketed.

Dezocine (地左辛 )

Dezocine possess agonist/antagonist effects (antagonist analgesics), and has less dependence liability.

HOH3C

NH2

A B

CH3N

OHO OH

H

morphine

AB

C

D

E

Tramadol(曲马朵 )

Tramadol is weak μ receptor agonist.对呼吸抑制作用小，短时间应用时成瘾性小，用

于中重度疼痛的止痛。

OHCH2N(CH3)2CH3O

A

C

CH3N

OHO OH

H

morphine

AB

C

D

E

(4)High potent μagonists

Etorphine(埃托啡）Dihydroetorphine （二氢埃托啡）

Etorphine(埃托啡）

Etorphine is about 1000 times more potent than morphine as μ agonist.

Etorphine has a low therapeutic index in humans, and its respiratory depressant action is difficult to reverse with an opioid antagonists; thus, the compound is not useful in medical practice.

N

HO O OCH3

CH3

CH3

HOC3H7-n

Dihydroetorphine （二氢埃托啡）N

HO O OCH3

CH3

CH3

HOC3H7-n

二氢埃托啡的镇痛作用强于埃托啡，动物实验结果显示戒断症状及精神依赖性均明显轻于吗啡。

二氢埃托啡 1991 年上市，开始作为非麻醉品用于临床，但在使用中发现有较强的精神依赖性和躯体依赖性，耐受性形成很快，成瘾性强，滥用潜力大， 1992 年开始按麻醉药品管理。

Section 2 Opioid Antagonists and agonist / antagonist

If the N-methyl of rigid opioid analgesics (such as morphine, morphinans and benzomorphans) is substited by allyl, cyclopropylmethyl (CPM) or cyclobutylmethyl (CBM), these analgesics become μ antagonists, but they are also agonists of other opioid receptor subtype, such as κ receptor.

(1) Opioid Antagonists

Nalorphine ( 烯丙吗啡 ), naloxone ( 纳洛酮 ) and naltrexone ( 纳曲酮 ) are clinically used to detoxify opioid analgesics.

Nalorphine( 烯丙吗啡 )

N

HO O OH

CH2CH=CH2

Nalorphine is an opioid agonists/antagonists.It is a μ antagonist and κ receptor agonist.严重的焦虑、致幻等精神症状，不能作为镇痛药。

Naloxone( 纳洛酮 )

N

HO O

CH2CH=CH2

OH

O

Naloxone is a “pure” opioid antagonist.因有首过效应，纳洛酮须非肠道给药。

Naltrexone （纳曲酮）

N

HO O

CH2

OH

O

Naltrexone is a “pure” opioid antagonist.纳曲酮与纳洛酮比较，作用强，口服，维持时间长。

(2) Opoid agonists/antagonists

喷他佐新于 1976 年进入临床，成为第一个拮抗性镇痛药。

其他有布托啡诺、丁丙诺啡和地左辛。

Pentazocine （喷他佐辛）

(2α, 6α,11R)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6- methano-3-benzazocin-8-ol, Talwin

喷他佐辛属于苯吗喃类，为混合的激动 -拮抗剂，即为 μ 受体弱拮抗剂（纳洛酮的 1/30 ）， κ 受体激动剂（镇痛作用是吗啡的 1/6 ），不良反应较小，成瘾性小，为非麻醉药品。

喷他佐辛口服有首过效应，临床用于减轻中度至重度疼痛。

CH2CH=C(CH3)2N

HO

CH3

CH3

1

11102

3

45

678

9

Butophanol （布托啡诺）

Butorphanol is a μ antagonist (about 1/6 the potency of naloxone) and strong κ agonist (5 times more potent than morphine). The mixed agonist / antagonist has less dependence liability.

缺点：首过效应， 镇静、焦虑等 κ 受体激动剂副作用，心血管副作用。

临床用于中度至重度疼痛止痛和辅助麻醉。

CH2N

HO

OH

Nalbuphine hydrochloride ( 盐酸纳布啡 )

Nalbuphine is a μ antagonist (about 1/4 the potency of naloxone) and strong κ agonist (about the same potency as morphine). The antagonist analgesic has less dependence liability.

缺点：首过效应， κ 受体激动剂副作用。临床用于中度至重度疼痛止痛和辅助麻醉。

N

HO O OH

CH2

OH

.HCl

Buprenorphine Hydrochloride( 盐酸丁丙诺啡 )

盐酸丁丙诺啡为 μ 受体强的部分激动剂， κ受体部分激动剂和 δ受体拮抗剂。对阿片受体有高亲脂性，镇痛作用强于吗啡 (20~50 倍 ) ，但不能被纳洛酮拮抗。

呼吸抑制副作用轻，单独用耐受性和成瘾性小，临床用于中度至重度疼痛止痛和海洛因戒毒。

N

HO O OCH3

CH2

CH3

OH

C(CH3)3

. HCl

Dezocine (地左辛 )

Dezocine possess agonist/antagonist effects (antagonist analgesics), and has less dependence liability.

HOH3C

NH2

A B

Section 3 Endogenous opioid peptides

1973 年 Simon, Snyder and Terenius证实鼠脑内存在立体特异性的阿片样镇痛药的结合位点，这些位点存在于包括人和所有脊椎动物的中枢神经系统及一些外周平滑肌系统的神经组织中。

体内既然存在阿片受体，必然有尚未鉴定的内源性配体存在。

Endogenous opioid peptides

1. 1975 年 Hughes and Kosterlitz等从猪脑内提取、分离、纯化、鉴定得到两个吗啡样镇痛作用多肽： Enkephalin(脑啡肽 )：

A. methionine enkephalin (Tyr-Gly-Gly-Phe-Met) ( 甲硫氨酸脑啡肽 , Met-E)

B. leucine enkephalin (亮氨酸脑啡肽 , Leu-E) (Tyr-Gly-Gly-Phe-Leu) 。

All these peptides are called endorphin( 内啡肽 ) or opioid peptides( 内源性阿片样肽类 )

2.β-endorphin (β-内啡肽 , 31peptides): Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu.

dynorphin 1-17 (强啡肽 , 17 peptides ): Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Aps-Asn-Gln.

α-neoendorphin(α- 新内啡肽 ,10 peptides ): Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys.

β-neoendorphin(β- 新内啡肽 ,9 peptides ):Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro.

Section 4 Structure-Activity Relationships of Opioid Analgesics

μ Receptor Agonistsκ Receptor Agonistsδ Receptor Agonists

1.Structure-Activity Relationships of μ Receptor Agonists

1. 吗啡为 μ 受体选择性激动剂，左旋体有活性。2. μ 受体激动剂结构中均有 A 环和碱性叔胺 N原子，是镇痛作用必需的。 在生理 pH 条件下，叔胺 N原子形成正离子。

3. A 环与碱性 N原子或者通过 2个碳原子的碳链（相当于 B环的 9 、 10位）或者通过 3个碳原子的碳链（经过哌啶环的一边）相连接。

4. 刚性结构μ受体激动剂 3- 酚羟基使活性显著增强。5. 叔胺 N原子上取代基的大小对具有激动或拮抗活性有重要影响。

6. 哌啶类和氨基酮类柔性结构和吗啡等刚性结构具有共同的药效构象。

柔性结构和刚性结构具有共同的药效构象

N

HOHHH

H3CH

O

OHA

EB

CD

N

HH

H3C

OHA

B

D CN

H3CCH3 O

C2H5

A

¦Ä+:

H3C

NH3C

A

D C£ O£ C2H5

ON+

HH

OHA

B

D

2. Structure-Activity Relationships of κ Receptor Agonists

All of the market κ agonists have structures related to the rigid opioids and N-ally, N-CPM, or N-CBM substitutions. The compounds are all μ receptor antagonists and κ receptor agonists.

吗啡类、吗啡喃类和苯吗喃类等刚性结构中的 N上被 allyl 、 CPM 或 CBM 取代，这些化合物具有激动和拮抗双重活性。

The κ agonist activity is enhanced if there is an oxygen group placed at the 8-position (e.g., ethylketazocine, 乙基酮佐新 ). The oxygen group in an N- substituent also enhances κ activity.

Ethylketazocine （乙基酮佐新）

N

HOCH3

CH3

O

8

在 6 ， 7- 苯并吗啡烷环上引入含氧基团可使 κ 阿片受体激动活性增强。

Bremazocine （布马佐新）

N

HOCH3

CH3

CH3

OH

在 6 ， 7- 苯并吗啡烷环 N- 取代基上引入含氧基团可使 κ 阿片受体激动活性增强。

3. Structure-Activity Relationships of δ Receptor Agonists

Structure-activity relationships for δ receptor agonists are the least developed among the opioid compounds.

Nonpeptide δ selective agonists are just beginning to be discovered.

Peptides with high selectivity for δ receptors are known. The SARs for some of these peptides are discussed in the following.

4.Structure-Activity Relationships of Endogenous Opioid Derivatives

1. All of the endogenous peptides have Leu- or Met-enkephalin as their first amino acid residues.

2. The tyrosine at the first amino acid residue position of all the endogenous opioid peptides is essential for activity. Removal of the phenolic hydroxyl group or the basic nitrogen abolishes activity. The Tyr1 free amino group may be alkylated (methyl or ally groups to gives agonists and antagonists), but it must retain its basic character. The structure resemblance between morphine and the Tyr1 group of opioid peptides is especially obvious.

3.The next most important moiety in the enkephalin structure is phenyl group of Phe4. Removal of this group or changing its instance from Try1 can result in full of substantial loss in activity.

4. The replacement of the natural L-amino acids with unnatural D-amino acids can make the peptides resistant to the actions of several peptidases that generally rapidly degrade the natural endorphins. The placement of bulky groups into the structure (e.g., the addition of N-Me to Phe4) also slows the action of peptidases. Conversion of the terminal carboxyl group into an alcohol or an amide protects the compound from carboxy peptidases.

5. Structural changes that highly restrict the formational mobility of the peptides (e.g., substitution of proline for Gly2 or cyclization of the peptide) have been especially useful for the discovery of receptor selective opioid peptides.

脑啡肽分子内形成氢键

O

NH

HN

NN

CH3

H

NH H

O

O

O

O

COOH

CH3

H

H

5. Models of the Opioid Receptor

根据吗啡和合成镇痛药的共同的药效构象， 1954年， Beckett 和 Casy 提出的阿片受体模型。

Beckett 和 Casy 提出的阿片受体模型

－

氢键接受部位

适合芳环的平坦区

凹槽

负离子部位N

HOHHH

H3CH

O

OH

三点论

μ 阿片受体激动剂具有以下结构

具有一个碱性中心 ;具有一个平面芳环结构 , 碱性中心与芳环几乎共平面 ;

烃基链部分凸出于平面。

埃托啡及其衍生物与 μ 阿片受体结合图形

氢键接受部位

适合芳环的平坦区

凹槽

负离子部位

－

A

HO O

N+

CH3

H

OCH3

OH

H3C

四点论

刚性结构和柔性结构的吗啡样化合物 N- 取代基和芳环部分可能结合在受体不同亚部位

Portoghese 注意到刚性结构的吗啡、吗啡喃或苯吗喃类，当 N-取代基的改变时，镇痛作用相应改变，说明刚性结构的吗啡样化合物以相同的方式与受体结合呈现镇痛活性。

柔性结构哌替啶等， N-取代基的改变，不能产生刚性结构的吗啡样化合物那样相应的活性改变。因此认为刚性的和非刚性的阿片样镇痛药结构中 N-取代基部分，分别结合在受体的不同表面上，而呈现不同的镇痛性。

后来发现刚性的吗啡等镇痛药，当芳环上有 3-OH取代，活性增强，而在非刚性系列，例如哌替啶衍生物烯丙基罗定，当其结构中的间位被 OH取代，镇痛作用消失。因此认为，这两个系列中的芳环结构部分，分别结合在受体表面分离的不同亚部位。

Allyprodine( 烯丙基罗定 )

N

OCOC2H5

CH3

R

N

HOHHH

H3CH

O

OH

morphine

脑啡肽与 μ 阿片受体相互作用

NH

N

M

O

N

OR

O

N+

OH G

O

P

A

T

Tyr-Gly-Gly-Phe

吗啡与 μ 阿片受体相互作用

PA

T

N+

OH G

H3O

H

O

OH

哌替啶衍生物与 μ 阿片受体相互作用

CH3N+

H

OCH3

OR

P ， 疏水性

A

T

东罂粟碱与 μ 阿片受体相互作用

P

A

T

NH+

OHOH3CO

H3C

H3C

OH

N

HO O OCH3

CH3

CH3

HO

Summary

1. The classifying of synthesis analgesicsPiperidines: Pethidine, Fentanyl;Phenylpropylamines: Methadone;Morphinans: Levorphanol;Benzomorphans: Pentazocine;Aminotetralins: Dezocine Cyclohexane derivatives: Tramadol.

2. Opioid anatagonists and antagonist analgesics

Opioid anatagonists(Nalorphine, Naloxone and Naltrexone) : pharmacologic action and chemical structure characteristics.

Antagonist analgesics(pentazocine): pharmacologic action and chemical structure characteristics.

3. Structure-activity relationships of μreceptor agonists

μ激动剂化学结构中均有 A 环和碱性氮原子。A 环与碱性氮原子或者通过 2个碳原子的碳链（相当于 B 环的 9 、 10位）或者通过 3个碳原子的碳链（经过哌啶环的一边）相连接。

3- 酚羟基使活性显著增强。叔胺结构对镇痛作用是必需的， N原子上取代基的大小对具有激动或拮抗活性有重要影响。

4. Models of the opoid receptor

μ 阿片受体激动剂的结构特点： 具有一个碱性中心 ; 具有一个平面芳环结构 ; 碱性中心与芳环几乎共平面 ; 烃基链部分凸出于平面。

5. Clinically available agents

Morphine Hydrochloride: chemical structure characteristics, physical-chemical properties and pharmacologic action.

Pethidine Hydrochloride: chemical structure characteristics and pharmacologic action.

Methadone Hydrochloride: chemical structure characteristics and pharmacologic action.

Fentanyl Citrate: chemical structure characteristics, pharmacologic action and synthesis routine.