Transcript 6-keto, 7,8

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 agents
 anesthetics (general or local)
 central nervous system (CNS) depressants
 opioid 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 enkephalins
 opioid 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 overdose
 Dependence
 Tolerance, 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
17 CH3 . HCl
N
10
9
11
D 14 8
1
B
7
A
C
2
E
6
HO 3 4 O 5 OH
. 3H2O
(-)-Morphine Hydrochloride
17 H
N
10
9
11
14 8
1
7
2
6
3
4
5
morphinan
 (5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol hydrochloride trihydrate
The Structure of (-)-Morphine
17 CH3
N
10
9
D 14 8
1 11
B
7
A
C
2
E
6
HO 3 4 O 5 OH
 Morphine is composed of five fused rings, and the
molecule has five chiral centers with absolute stereochemistry (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.
The configuration of (-)-morphine
H
H
N
H3C
D
H
H
OH
C
B
E
O
A
OH
 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.
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
O
N CH3
N CH3
N CH3
N CH3
+
HO
O
OH HO
O
OH OH O
Pseudomorphine
or Dimorphine
OH HO
O
OH
morphine N-oxide
 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
CH3
N CH3
N
HCl or H3PO4
HO
O
OH
Apomorphine
HO
OH
催吐剂
CH3
HN
I2
NaHCO3
O
O
醚层显宝石红
水层显绿色
Identification of little morphine in codeine (1)
N
N CH3
CH3
NaNO2
NO
HCl
HO
O
OH
O
OH
HO
2-nitrosomorphine
NH4OH
marron(ºì ×ØÉ«)
N CH3
NaNO2
CH3O
O
OH
HCl
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
H
H
N+ CH3
N+ CH3
first pass effect
morphine
O
HO
OH
O
RO
R=Glu or SO3-
CYP450
N-demethylation
H
H
+
N
N+ CH3
H
activity
Nomorphine
HO
OH
O
OH
HO
O
O-Glu
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 firstpass 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, dependence
 Respiratory depression, which is the cause of
death from opioid overdose.
(-)-Codeine Phosphate
CH3
N
. H3PO4 . 1.5H2O
CH3O
O
OH
 (5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17methylmorphinan-6-ol phosphate sesquihydrate
Synthesis of Codeine
N CH3
N CH3
C6H5N+(CH3)3OH-
HO
O
morphine
OH
CH3O
O
codeine
OH
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
protection from light
CH3
N
CH3O
O
OH
It is more stable than morphine.
Identification of little morphine in codeine
N CH3
N CH3
NaNO2
NO
HO
O
OH
HCl
O
OH
HO
2-nitrosomorphine
NH4OH
marron(ºì ×ØÉ«)
N CH3
NaNO2
CH3O
O
OH
HCl
Metabolism of codeine
H
H
H
N
+
CH3
N+ CH3
N+ CH3
10%
CYP450
O-Demethylation
OH
HO
O
CH3O
CYP450
Codeine
N-demethylation
OH
N
H
O
+
N
H
OH
HO
OH
R=Glu or SO3-
H
+
O
RO
CYP450
morphine N-demethylation
H
CH3O
O
O
N+ CH3
H
OH
nomorphine
HO
O
O-Glu
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
CH3
N
HO
O
H
OH
SARs for morphine derivatives
Drugs
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
Heroin（海洛因）
3,6-diOAc
10×increase
（toxicity）
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
CH3
N
AcO
O
H
OAc
 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 3acetyl 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）
CH3
N
R'
N
H
D
A
HO
O
morphine
OH
B
C
R
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.
Levophanol(左啡诺)
CH3
N
COOH
.
H
HO
C OH
C H
. 2 H2O
COOH
HO
 17-methylmorphinan-3-ol tartrate dihydrate
 Levophanol 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.
The configuration of levophanol
H
H
H3C
N
C
D
B
levophanol
A
OH
H
H
N
H3C
D
H
H
OH
C
B
E
O
A
OH
morphine
Butophanol（布托啡诺）
CH2
N
OH
HO
 Butorphanol is a μ antagonist and К agonist.
The mixed agonist / antagonist is an antagonist
analgesic and has less dependence liability.
B. Benzomorphans （苯吗喃类）
R'
N
D
R
B
A
R
HO
 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.
Pentazocine (喷他佐辛)
CH2CH=C(CH3)2
N
CH3
CH3
HO
 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.
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）
C6H5
COOC2H5
N
CH3
 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.
The conformation of pethidine
O
N
H3C
D
H
H
N
H3C
D
C£-O£-C2H5
H
H
OH
C
B
A
O
A
OH
N
H3C
E
D
A
COOC2H5
 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.
Alphaprodine（阿法罗定）
O
C6H5
COC2H5
O
C6H5
OCC2H5
CH3
N
CH3
N
CH3
 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.
Fentanyl(芬太尼)
C6H5
OCOC2H5
C6H5
N
COC2H5
CH3
N
CH3
N
CH2CH2C6H5
 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.
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)
C6H5
COC2H5
N
CH2OCH3
N
CH2CH2
Bioisosterism
S
Alfentanil(阿芬太尼)
C6H5
COC2H5
N
CH2OCH3
O
N
CH2CH2
CH2CH3
N
N
Bioisosterism
N
N
Refentanil(瑞芬太尼)
C6H5
COC2H5
N
R1=±½»ù£¬ R2=H
·ÒÌ« Äá
R1=±½»ù£¬ R2=COOCH3¿¨ ·ÒÌ« Äá
R
N
CH2CH2R1
C6H5
COC2H5
N
R
N
CH2CH2COOH
ÎÞ »î ÐỐú лÎï
Èí Ò©
Éè¼Æ
C6H5
COC2H5
N
CO2CH3
N
CH2CH2COOCH3
Èð·ÒÌ« Äá
t1/2=10~21min
²» »á Ðî»ýÖж¾£¬¼õÉÙºô Îü ÒÖÖÆ
µÄΣ ÏÕ
Ohmefentanyl（羟甲芬太尼）
C6H5
C6H5
N
COC2H5
N
COC2H5
CH3
8
N
N
C6H5
C 6 H5
·ÒÌ« Äá(Fentanyl)
OH
6000
ôǼ׷ÒÌ« Äᣨ Ohmefentanyl£©
13000
Pethidine Hydrochloride (Dolantin)
C6H5
COOC2H5
. HCl
N
CH3
 1-methyl-4-phenyl-4-piperidinecarboxylic ethyl
ester hydrochloride
Synthesis of pethidine
CH2CN
+ CH3N(CH2CH2Cl)2 NaNH2
N
CH3
NC
H2SO4
C2H5OH
N
CH3
N
HOOC
C2H5OOC
HCl
N
CH3 . HCl
C2H5OOC
II
I
III
CH3
Physical-chemical properties
N
N
H3C
CO2C2H5
H3C
CO2C2H5
. HCl + Na2CO3
white crystalline power
oil
solid
mp 30~31¡æ
Hydrolysis
N
H3C
CO2C2H5
H+
short time
Identifying reaction
OH
C6H5
CO2C2H5
O2N
NO2
C6H5
ON2
NO2
.
+
N
N
CH3
OH
CO2C2H5
NO2
CH3
NO2
Yellow
Mp 188~191℃
Metabolism of pethidine
C6H5
CO2C2H5
C6H5
CO2H
C6H5
CO2-Glu
N
N
N
CH3
CH3
CH3
Pethidine acid
C6H5
CO2C2H5
N
H
Norpethide
(no activity,toxity)
C6H5
CO2H
N
H
Norpethidinic acid
no activity
C6H5
CO2-Glu
N
H
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)
CH2COOH
CH3CH2CO - N
C6H5
N
CH2CH2C6H5
HO - C COOH
CH2COOH
 N-Phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]
propanamide citrate
Design of synthesis routine
CH2COOH
CH3CH2CO - N
N
CH2CH2C6H5
HO - C COOH
CH2COOH
C6H5
III II
I
IV
Synthesis of Fentanyl Citrate (1)
CH2=CHCO2CH3
CH2CH2NH2
CH3ONa
CH2CH2N
CH2CH2N
O
CO2CH3
CH2CH2N
O
Ph-NH2
piperidine
CH2CH2N
N
CH2CH2CO2CH3
CH2CH2CO2CH3
HCl
Synthesis of Fentanyl Citrate (2)
H2/Ni
CH2CH2N
N
H
COCH2CH3
(CH3CH2CO)2O
CH2CH2N
N
COCH2CH3
citric acid
CH2CH2N
N
CH2COOH
HO - C COOH
CH2COOH
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)
C6H5
N
COC2H5
CH2OCH3
CH2COOH
HO - C COOH
N
CH2CH2
S
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
CH3 O C2H5
H3C N
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
H3C
C2H5
CH3
N:
N
H3C
O
A
D
¦Ä+
COOC2H5
H3C
pethidine
A
CH3
N
D
H
B
C
A
E
HO
O
morphine
OH
Dextropropoxyphene (右丙氧芬)
CH3
H3C N
H3C
O
COCH2CH3
CH2
 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
H3C
CH3 O
N
HCl .
H3C
7 6
5
C2H5
3
4
 6-(dimethylamino)-4,4-diphenyl-3-heptanone
hydrochloride
Synthesis of methadone
N
C
NaNH2 N
H3C
C
+
N(CH3)2
+
Cl
H3C
O
H3C
(1) C2H5MgBr
+
(2) H+
H3C
methadone
N(CH3)2
C
CH3
N(CH3)2
isomethadone
C
CH3
N(CH3)2
O
H3C
N
N(CH3)2
Reduction reaction
CH3 O
H3C
N
H3C
C2H5
. (i-PrO)3Al
or Na-Hg
Identification of methadone (1)
CH3 O
H3C
N
H3C
C2H5
NH2NHCONH2
Identification of methadone (2)
H3C CH3O C2H5
N
H3C
H3C CH3O C2H5
N
H3C
.HO3S
N N
+
HO3S
N N
¼×»ù³È
N(CH3)2
yellow
N(CH3)2
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 CPY-450
CH3
O
CH3
N H
O
N
CH3
HO
Methadol
activity
CH3
no activity
alcohol dehydrogenase
CH3
N
CH3 CPY-450
CH3
CH3
CH3
NH
HO
Normethadol
activity
CH3
NH2
CPY-450
HO
CH3
Dinormethadol
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 oncea-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)
CH3
N
H3C
D
B
NH2
HO
A
H
C
A
B
E
HO
O
OH
morphine
 Dezocine possess agonist/antagonist effects
(antagonist analgesics), and has less dependence
liability.
Tramadol(曲马朵)
CH3
N
A
D
OH
CH2N(CH3)2
CH3O
H
B
C
A
C
E
HO
O
OH
morphine
 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。
(4)High potent μagonists
 Etorphine(埃托啡）
 Dihydroetorphine（二氢埃托啡）
Etorphine(埃托啡）
N CH3
HO
HO
O
C3H7-n
CH3
OCH3
 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.
Dihydroetorphine（二氢埃托啡）
N CH3
HO
HO
O
C3H7-n
CH3
OCH3
 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 CH2CH=CH2
HO
O
OH
 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 CH2CH=CH2
OH
HO
O
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 CH2
OH
HO
O
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）
3 CH2CH=C(CH3)2
1 N
2
11
4
CH3
5
10
9
HO
8
7
6 CH3
 (2α, 6α,11R)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3methyl-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。
Butophanol（布托啡诺）
CH2
N
OH
HO
 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。
Nalbuphine hydrochloride
(盐酸纳布啡)
N CH2
OH
.HCl
HO
O
OH
 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。
Buprenorphine Hydrochloride
(盐酸丁丙诺啡)
N CH2
. HCl
CH3
C(CH3)3
HO
O
OH
OCH3
 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。
Dezocine (地左辛)
H3C
NH2
HO
A
B
Dezocine possess agonist/antagonist effects
(antagonist analgesics), and has less
dependence liability.
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-GlyPhe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-ValThr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-TyrLys-Lys-Gly-Glu.
 dynorphin 1-17 (强啡肽, 17 peptides ): Tyr-GlyGly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-TrpAps-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 Agonists
 κ Receptor Agonists
 δ 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
H
H
N
H3C
D
H
H
OH
H3C
C
B
E
H
H
C2H5
N
H3C
C
D
CH3
O
N:
¦Ä+
B
O
A
A
H3C
OH
OH
A
H
H
N+
O
N
H3C
D
D
C£-O£-C2H5
B
A
A
OH
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）
O
N
8
CH3
HO
CH3
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）
OH
N
CH3
CH3
HO
CH3
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 Metenkephalin 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
H
O
H
N
N
H
H
H
N
O
O H
N
COOH
N
O H
CH3
CH3
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
负离子部位
－
凹槽
H
H3C
H
N
H
H
OH
O
适合芳环的平坦区
OH
氢键接受部位
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
OH
OCH3
HO
O
H3C
负离子部位
凹槽
N+
H
CH3
－
适合芳环的平坦区
氢键接受部位
A
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)
OCOC2H5
R
N
CH3
H
H3C
H
N
H
H
OH
O
OH
morphine
脑啡肽与μ阿片受体相互作用
A
O
R
G
OH
N+
N
NH
M
O
N
O
O
Tyr-Gly-Gly-Phe
P
T
吗啡与μ阿片受体相互作用
G
OH
A
P
O
H3O
N+
H
OH
T
哌替啶衍生物与μ阿片受体相互作用
A
H
N+
CH3
O
R
O
P， 疏水性
CH3
T
东罂粟碱与μ阿片受体相互作用
H3CO
H3C
P
OH
O
T
OH
H3C NH+
A
N CH3
HO
HO
O
CH3
OCH3
Summary
1. The classifying of synthesis analgesics
 Piperidines: 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.