Opioid Analgesics

Introduction
The correct term is analgetic, but the
word analgesic is more popular and
universally used.
An analgesic is defined as a substance
bringing about insensibility to pain
without loss of consciousness.

2
 What are opiate/opioid analgesics?
Analgesics, or pain killers, that bind to opioid receptors which are found
principally in the:
◉ CNS
◉ Gastrointestinal tract
There are a number of broad classes of opioids:
◉ Natural opiates
Alkaloids contained in the resin of the opium poppy including
morphine, codeine and thebaine
◉ Semi-synthetic opiates
Created from the natural opioids such as hydromorphone,
oxycodone and diacetylmorphine (heroin)
◉ Fully synthetic opioids
Fentanyl, methadone and tramadol
◉ Endogenous opioid peptides
Produced naturally in the body, such as endorphins,
enkephalins, dynorphins and endomorphins
 Types of Pain
• Physiological
• Pain associated with touching a hot object or with a cut.
• Inflammatory
• Pain from infection and tissue injury
• Neuropathic
• Pain due to injury to the peripheral NS or CNS

Within these classes there are different levels of pain.

• Acute
• Chronic
• Cancer
• Arthropathy (e.g. arthritis)
• Visceral
• Neuropathic
• Diabetic
4
 Major Classes of Analgesics
• Opioids
• Non-steroidal anti-inflammatory drugs
(NSAID’s)
• Acetaminophen
• Analgesic adjuvants

5
 Enkephalins and Endorphins
• Hughes discovered the presence of an endogenous factor
from pig brain that possessed opiate-like properties.
• It was given the name enkephalin and found to consist of
two pentapeptides- methionine or Met enkephalin and
leucine or Leu enkephalin (previous slide).
• These are also found to be present in all animals including
humans.
• They exist as segments of a pituitary hormone, the 91-
amino acid β-lipotropin, that is cleaved to release various
segments with specific function.
• Segment 61 to 65 is Met enkepalin, 61 to 76 is α-endorphin,
61-77 is γ-endorphin, and 61 to 91 is β-endorphin.
• The endorphins (short for endogenous morphines) have 20
times the analgesic activity of morphine when injected into
rat brain. They also produce tolerance and dependence.
6
Enkephalins

7
 Opioid receptors
• In 1970s researchers were able to label opioid receptors with reversible
radioactive ligands that allowed the pharmacological actions of specific
receptors and their locations to be identified.
• Opioid receptors are distributed throughout the brain, spinal chord and
peripheral tissues.
• Genes for the four major opioid receptor subtypes have been cloned
• The MOP = μ receptor (mu for morphine)
• The KOP = κ receptor (kappa for ketocyclazocine)
• The DOP = δ receptor (delta for deferens, because it was originally
discovered in the mouse vas deferens)
• The NOP = nociceptive/orphanal FQ receptor (named as an orphan
receptor because the endogenous/exogenous ligand was unknown
at the time of discovery)

8
 Opioid receptors
• The opioid receptors belong to the G-protein coupled
receptors (GPCRs)
• The 4 opioid receptors share extensive homology in the TMs
with most of the variation in the loop regions.
• Activation of the receptor causes inhibition of adenylate
cyclase, a decrease in cAMP which regulates many cellular
processes.
• One process that is inhibited is the opening of voltage-gated
calcium channels on nociceptive C-fibers.
• This results in hyperpolarization of the nerve cell.

9
Opioid receptor

10
 Ligand binding site
• There is no X-ray structure of any opioid receptor.
• The binding site has been inferred from homology
modeling, molecular dynamics, site-directed mutagenesis,
chimeric receptors, and SAR studies.
• Though there is no definitive model, the binding site is
believed to be formed by conserved residues on TM3,
TM4, TM5, TM6 and TM7.
• There is some evidence that the N-terminal may also be
an important determinant of ligand binding affinity.
• The ligands are thought to bind toward the bottom of the
cavity via interactions with a conserved Asp from TM3
and a His from TM6.

11
• Molecular modeling shows the phenolic OH of Tyr1
of opioid peptides or the ring A OH of nonpeptide
opioids forms a H-bond with the conserved His on
TM6.
• The Tyr1 charged nitrogen or the N+ of nonpeptide
agonists forms an ionic bond with the conserved
Asp of TM3.
• Antagonists are thought to bind deeper in the
binding pocket, but retain the ionic bond with Asp
of TM3.
• The bulky substituent on the charged nitrogen of
antagonists is believed to insert between TM3 and
TM6 preventing the shifts required for activation.
• Antagonists prevent the necessary movement of
TM3 and TM6 resulting in functional antagonism. 12
Endogenous and Exogenous opioid peptides

13
 The μ-receptor
• Found primarily in the brainstem and medial thalamus.
• Endogenous peptides include endomorphin-1,
endomorphin-2, β-endorphin.
• Exogenous agonists are 4,5-epoxymorphinan, morphinan,
benzomorphan, 4-phenyl/4-piperidinyl piperidines and the
diphenylheptanes.
• Exogenous peptides such as dermorphin isolated from the
skin of South American frogs.
• In general, agonists at the μ-receptor produce analgesia,
respiratory depression, decreased g.i motility, euphoria,
feeding and the release of hormones.

14
 δ-receptor

• Endogenous peptides – Met and Leu enkephalin

• Synthetic peptides DADLE, DSLET, and DPDPE (modified enkephalins)
• Amino acids that distinguish δ-receptor ligand specificity – Tyr284,
Val296, Val297 in EC3 that connects TM6 and TM7 are crucial to
selective δ-ligand binding. Besides, Tyr129 in TM3 and Tyr308 in
TM7.
• Some selective δ-receptor ligands are shown in the next slide.
• Transgenic mice lacking the δ-receptor display increased levels of
anxiety.
• δ-receptor agonists show antidepressant activity in rat models.
• This suggests that ligands targeting this receptor could be used for
treatment of schizophrenia, bipolar disorders, and depression.

15
 κ-receptor

• Found in the limbic, brain stem and spinal chord.

• Shows less structural homology to the μ-receptor than to
the δ-receptor.
• This receptor does not bind the enkephalins.
• This receptor shows a clear preference for binding Arg at
pos. 6 as seen in the dynorphin peptides.
• The structures of some κ-agonists and antagonists are
shown in the next slide.
• Spiradoline was developed with the premise that a selective
κ-agonist would be an analgesic without the μ-opioid
problems of addiction and respiratory depression.

16
 Selectivity
• The natural opiates and related synthetic
opioids are predominantly μ agonists.
• Morphine and some of its analogs have
10-20 times selectivity over other
receptors.
• Drugs that bind to κ receptors have high
analgesic activity, lack many of the opioid
side effects but have dysphoric and
hallucinogenic effects.
• No useful drugs have been developed that
are selective for the δ receptors 17
Opium Poppy-Papaver
somniferum
 History of Opium
Opium contains a complex mixture of 40 alkaloids, principle one
being morphine
› Responsible for analgesic activity
Because of morphine’s poor oral bioavailability, it was infrequently
used in medicine until the hypodermic syringe was invented in
1853
Morphine was used during the American Civil War and the Franco-
Prussian war.
› Due to poor understanding about:
● Safe dose levels
● Effects of long-term use
● And increased risks of addiction, tolerance and
respiratory depression
› Many casualties were either killed by overdoses or became
addicted to the drug
 Basic Structures
2 major rings systems are seen in the opium alkaloids
• Phenanthrene as present in morphine

• Benzylisoquinoline as seen in papaverine

20
 Diverse pharmacology
The 2 groups have different pharmacological effect.
• The morphine group acts principally on the CNS as
depressant and stimulant.
• The depressant action is responsible for increased
tolerance to pain, sleepiness, lower perception to
external stimuli and euphoria.
• Respiratory depression and addiction are some side effects.
• The stimulant action is illustrated by the convulsions
produced by some members of this group e.g.
thebaine
• The papaverine group has little action on the CNS -
antispasmodic action on the smooth muscle.

21
 History of Opium
Opioids have been the mainstay of pain treatment for
thousand of years, and they remain so today
The opiates are perhaps the oldest drugs known to humanity
◉ The first undisputed reference to opium is found in the
writings of Theophrastus in the third century B.C.
◉ The use of opium was recorded in China over 2000 years
ago, and was known in Mesopotamia before that
Its use in medicine is quoted in a twelfth-century prescription:

Take opium ,mandragora, and henbane in equal parts and

mix with water. When you want to saw or cut a man, dip a
rag in this and put it to his nostrils. He will sleep so deep
that you may do what you wish.
 History of Opium
Morphine named after the Greek God of Dreams –
Morpheus

Isolated by Serturner in 1806 and named by him.

Total synthesis reported but less efficient than

extraction and isolation

Mammalian neuroblastoma cells shown to

biosynthesize morphine!!!!!
 Properties of Morphine
◉ Good for treating dull, constant pain rather than
sharp, periodic pain
◉ Also has a large number of side effects including:
◉ Depression of the respiratory centre
◉ Constipation
◉ Excitation
◉ Euphoria
◉ Nausea
◉ Pupil constriction
◉ Tolerance and dependence
◉ ADDICTION
 Withdrawal symptoms
associated with morphine
◉ Anorexia
◉ Weight loss
◉ Pupil dilation
◉ Chills
◉ Excessive sweating
◉ Abdominal cramps
◉ Muscle spasms
◉ Hyperirritability
◉ Lacrimation
◉ Tremor
◉ Increased heart rate
◉ Increased blood
pressure
 Opioids of Abuse-
Heroin
Heroin Morphine
History of Heroin
⦿ First synthesized in 1874
by an English chemist but
only became popular
more than 20 years later
⦿ From 1898 through 1910,
under the name heroin,
diacetylmorphine was
marketed as a non-
addictive morphine
substitute and cough
suppressant
Morphine Fentanyl
5R,6S,9R,13S,14R
 Modifications prior to 1929
• Before 1929, compounds made were esters of the phenolic/alcoholic
groups and ethers of the phenolic group e.g. codeine
• This gave compounds some of which had greater activity than
morphine but were more toxic and had greater addiction potential.

31
 Work of Small and Eddy in 1929
• They thought that it might be possible
to separate chemically the addictive
properties of morphine from its
analgesic activity,
• To find synthetic molecules without this
undesirable property.

32
39
 SAR Conclusions

• All of the compounds made had the same addiction potential as

morphine.
• In fact, these studies showed that any modification that increased
analgesic activity caused a concomitant increase in addiction liability.

40
 Second Phase - Modification

• In the second phase, the various ring structures in morphine - the

phenanthrene, dibenzofuran, and carbazole were modified.

41
Structure of morphine
 Morphine modifications by Grewe, 1946
• In 1946, Grewe synthesized N-methylmorphinan, which has high
degree of analgesic activity. This shows that the ether bridge in
morphine is not essential for activity

• The 3-hydroxy derivative (racemorphan) has an intensity and duration

of action greater than morphine.
• The levo form of racemorphan is more active and is marketed as
levorphanol.
• The dextro form is a cough suppressant (dextrorphan).
• The ethers and acyl derivatives of racemorphan have also considerable
activity.
43
 Dextromethorphan
Racemorphan

Levorphanol
Dextrorphan
 N-Aralkyl morphinans

• N-Phenylethyl and N-p-aminophenylethyl analogs of

levorphanol are 3 and 18 times more active than the parent.
• The N-furylethyl analog is 30 times more active than
levorphanol and 160 times more than morphine.
• The N-acetophenone analog (levophenacylmorphinan) is 5
times more active than morphine.
• The N-cyclopropylmethyl derivative (cyclorphan) is about 20
times stronger than morphine as an analgesic, however, it
has hallucinatory side effect. It is also reported to be a
morphine antagonist.
• The N-cyclobutylmethyl derivative (butorphanol) has mixed
agonist-antagonist properties and has been marketed as an
analgesic. 45
Benzomorphan derivatives (Benzazocines)

• R1= R2= CH3 (I) is more potent than R1= H, R2= CH3
• The phenethyl (R2) derivative is 20 times more potent than
(I)
• The most potent compound is R1= CH3 and R2= CH2CH2Ph
(Phenazocine). Levo isomer is more active.
• Antagonist at Mu type analgesics :
▪ R1 → CH3 , R2 → -CH2 CH=C(CH3 ) 2 (pentazocine); agonist at kappa
▪ R1 → CH3 , R2 → -CH2 -cyclopropyl (cyclazocine)
• In 1938 Eisleb and Schaumann discovered meperidine (a simple
piperidine compound) with ⅕ the analgesic activity of morphine

• The demonstration that compounds with analgesic activity exist that

are distantly related to morphine, spurred the efforts of various
research groups.
 SAR of meperidine

Meperidine act = 1
Name R1 R2 R3 C3 Act

Meperidine CH3 H COOC 2 H5 H 1.0

Bemidone CH3 m-OH COOC 2 H5 H 1.5

Ketobemidone CH3 m-OH COC2 H5 H 6.2

Alphaprodine CH3 H OCOC 2 H5 CH3 (trans) 5.0

Phe is axial, reverse ester is equ
(see later morphine receptor)
Betaprodine CH3 H OCOC 2 H5 CH3 (cis) 14.0

Pheneridine CH2 CH2 Ph H COOC 2 H5 H 2.6

Anileridine CH2 CH2 Ph-NH2 H COOC 2 H5 H 3.5

Diphenoxylate CH2 CH2 C(CN)Ph2 H COOC 2 H5 H None

Loperamide CH2 CH2 C[CON(CH3 )2 ]Ph2 p-Cl OH H None

Fentanyl On N1 we have CH2 CH2 Ph On C4 we have N(C6 H5 )COC 2 H5 940

48
Modifications on meperidine

• Replacement of the 4-phenyl group by H, alkyl, other aryl, aralkyl or heteroaromatic

groups reduce activity.
• The 4-phenyl and the 4-ester give optimal activity.
• m-Hydroxy group on the phenyl ring (bemidone) increases activity. It is in the same
position as in morphine.
• The “reverse ester” (OCOC2 H5 ) is more active.
• At the C3 position, with a methyl group, the trans form (alphaprodine) is less active than
the cis (betaprodine).
• With the 3-allyl and 3-propyl substituents, the α-trans forms are more potent than
the cis, indicating that a 3-carbon chain is tolerated in the axial pos. The 3-ethyl
isomers (cis and trans) are equal in activity.
• At N of the piperidine ring, it was believed that Me was optimal, however, an aralkyl
group can markedly increase activity e.g. pheneridine and anileridine.
• Diphenoxylate and loperamide lack analgesic activity and are intestinal spasmolytics used
to treat diarrhea.

49
 Fentanyl

• An unusual modification in meperidine is fentanyl, where the phenyl

and the acyl groups are separated from the piperidine ring by a
nitrogen.
• It is a powerful analgesic, 50 times stronger than morphine with
minimal side effects.

50
 Ring opened compounds

• Bochmuehl and Erhart prepared compounds of the type shown in

next table (first entry in table) that possessed both analgesic and
spasmolytic activity.
• The Hoechst labs. prepared the ketone derivatives some of them
with very good activity. One of them was methadone.
• Introduction of m-OH groups in the phenyl ring markedly decreased
activity.
• The levo isomer of both methadone and isomethadone is more
active than the racemic.
• All structural derivatives of methadone give more potent
compounds than isomethadone. At the same time they are also
more toxic.
• Replacing the R3 group by H, OH or acetoxy decreases activity.
• The amide analogs are more active e.g. racemoramide (dextro
active).
51
Name R1 R2 R3 R4 Analgesic
Activity
Methadone
=1
- Ph Ph COO-alkyl CH2CH2N(C2H5)2 0.15
Methadone Ph Ph COC2H5 CH2C*H(CH3)N(C 2H5)2 1.0
Isomethadone Ph Ph COC2H5 C*H(CH3)CH 2N(C2H5)2 0.65
Dipanone Ph Ph COC2H5 CH2CH(CH3)-Npiperidinyl 0.8
Phenadoxone Ph Ph COC2H5 CH2CH(CH3)-Nmorpholinyl 1.4
Alphacetylmethadol Ph Ph CH(C2H5)OCOCH3 CH2CH(CH3)N(CH3)2 1.3
Betacetylmethadol Ph Ph CH(CH3)CH 2OCOCH 3 CH2CH(CH3)N(CH3)2 2.3
Racemoramide Ph Ph CO-Npyrrolidine CH(CH3) CH 2Nmorpholinyl 3.6
Propoxyphene Ph CH2Ph OCOC2H5 CH(CH3) CH 2N(CH 3)2 0.21

53
 SAR
All morphine like analgesics possess the
following features (Braenden et. al.)
4
1. A tertiary nitrogen (N17) with one of the 1
groups being small in size.
2. A central carbon atom (C13) which is
quarternary.
3
3. A phenyl group (C1-C4, C11, C12) or its
isostere connected to the central carbon
atom. 2

4. A 2C chain (C15, C16) separating the

central carbon from the nitrogen.

55
 Beckett and Casy hypothesis of the morphine receptor
Besides the chemical features discussed
under SAR, the size and shape of the
molecule are also important.
Beckett and Casey put forth their
hypothesis relating stereochemical
features and activity, this was based not
only on morphine but also on N-
methylmorphinan A
• An anionic site in the receptor that can
interact with the basic center ( ).
• A pocket that can interact with the flat
aromatic group (A) coplanar with the basic
center by van der Waals interaction.
• A cavity that can accommodate a
projecting hydrocarbon group (shown
enclosed by the oval) that forms a 3D • Beckett and Casy complementary morphine
geometric pattern with the aromatic receptor site
center and the basic nitrogen. • Fundamental to the proposal is that the
• A H-bonding site for the phenolic OH
receptor is essentially inflexible, and that a
group on ring A.
lock-and-key type situation existed.

• See Slide No. 51

56
 Parallelism and non-parallelism
• Portoghese noted that in certain series (methadone,
meperidines, prodines), when identical changes in the N-
substituent were made, there was parallelism in the
direction of the activity, whereas in others there appeared
to be non-parallelism.
• Parallelism and non-parallelism is due to similar and
dissimilar binding modes. This is shown in the following
figure. Meperidine
Methadone

Methadol

+ is the protonated nitrogen, is the nitrogen substituent

57
• If two different analgesiophores (the analgesic molecule
minus the N-substituent) bearing identical N-substituent are
positioned on the receptor surface such that the N-
substituent occupies the same position in the receptor, a
similar pharmacological activity may be anticipated.
• As one proceeds from one N-substituent to another, the
response should likewise change resulting in the parallelism
effect.
• On the other hand, if two analgesiophores are bound to the
receptor such that the N-substituents are not arranged
identically, one may anticipate non-identical responses to
changing the N-substituents – i.e. non-parallelism

58
Enkephalins

61
 Multiple receptors

• Martin has named these receptors based on the response

to probe molecules
• μ (mu)-receptors for morphine specific effects
• δ (delta) for cyclazocine
• κ (kappa) for ketocyclazocine

• Based on pharmacological criteria these receptors are

named OP3, OP1 and OP2 respectively
• Various combinations of these receptors in different tissues
could be responsible for the varying effects observed.

* E. Coutinho -Opioid Analgesics 62

 Products

1. Morphine
• Serturmer is credited with isolation of morphine in 1803.
• Structure determined in 1925 by Gulland and Robinson and the
total synthesis accomplished by Gates and Tschudi in 1952.
• It is obtained only from the opium poppy, Papaver Somniferum,
from the resin obtained by lancing the unripe pod or from poppy
straw.
• Morphine is present to the extent of 5 to 20% in opium.
• It is isolated by various methods, but the final step is ppt. from an
acidic solution by conc. ammonia. It is recrystallized from boiling
alcohol.
• It is generally available as the hydrochoride or sulfate salts.

* E. Coutinho -Opioid Analgesics 63

Atom numbers and ring labels for morphine

* E. Coutinho -Opioid Analgesics 64

 Morphine

• Prototype ligand for the μ-receptor

• Numbering and ring letters are shown in previous slide
• Morphine has 5 chiral centers C5, C6, C9, C13 and C14.
• However, the no. of stereoisomers is 16 and not 32 because
of the restriction of the C9 to C13 ethanamino bridge.
• The naturally occurring form has the stereochemistry 5R, 6S,
9R, 13S and 14R.
• The X-ray structure is T-shaped with the A, B and E rings
forming the vertical portion and the C and D rings forming
the horizontal line (top of the T).

* E. Coutinho -Opioid Analgesics 65

Structure of Morphine

D
C
B E

* E. Coutinho -Opioid Analgesics 66

Morphine and its isomer

* E. Coutinho -Opioid Analgesics 67

 Codeine
2. Codeine
• Occurs to a very small extent in opium.
• Most of the codeine is produced by methylating
the phenolic group (3-OH) in morphine with
diazomethane or dimethyl sulfate or methyl
iodide.
• Codeine is less effective as an analgesic than
morphine, with the same side effects as
morphine.
• Is metabolized in the liver to morphine, then
exerts its analgesic effect. (3-OH grp is imp. for
activity)
• Codeine has been used as an antitussive,
depressing the cough reflex and is present in
many cough preparations.
• Available as the phosphate and sulfate salts.

* E. Coutinho -Opioid Analgesics 68

 Heroin
3. Diacetylmorphine hydrochloride (heroin hydrochloride)
• 2 to 3 times more potent than morphine as an analgesic, very high addiction
liability.
• Highly abused narcotic.
• Heroin has two polar groups which are masked and is therefore the most
efficient compound of the three to cross the blood-brain barrier.
• However, before it can act at the receptor, the acetyl group on the phenolic
group has to be removed by esterases in the brain.
• Therefore, it is more powerful than morphine because it enters the brain more
easily, but is less powerful than 6-acetylmorphine because the 3-acetyl group
has to be removed before it can act.

* E. Coutinho -Opioid Analgesics 69

Metabolism of morphine and codeine

* E. Coutinho -Opioid Analgesics 70

Metabolism of morphine, codeine and heroin

* E. Coutinho -Opioid Analgesics 71

 Hydromorphone
4. Hydromorphone or dihydromorphinone
(1926)
• Obtained by catalytic reduction
(hydrogenation) of the 7,8 double bond and
oxidation (dehydrogenation) of the 6-OH
group.
• 5 times more potent than morphine, equal
addicting properties and a shorter duration
of action.
• Also a potent antitussive.
• Available both as the free base and the
hydrochloride salt.

Morphine
* E. Coutinho -Opioid Analgesics 72
 Hydrocodone
5. Hydrocodone bitartrate,
dihydrocodeinone bitartrate.
• Prepared by catalytic reduction of the 7-8
d.b. in codeine and oxidation of the 6-OH
group or from thebaine.
• Pharmacological activity midway between
codeine and morphine.
• Lower frequency of side effects compared
to codeine.
• More effective than codeine as an
antitussive.

Thebaine
* E. Coutinho -Opioid Analgesics 73
 Oxymorphone
6. Oxymorphone hydrochloride
14-hydroxydihydromorphinone hydrochloride
(1959)
• Used for the same purposes as morphine.
• Effective as morphine in ⅛ to ⅟₁₀ the dosage.
• High addiction liability.

Morphine
* E. Coutinho -Opioid Analgesics 74
 Oxycodone
7. Oxycodone hydrochloride
Dihydrohydroxycodeinone

• Prepared by catalytic reduction (7-8 d.b.

) of hydroxycodeinone, itself prepared
by hydrogen peroxide (in acetic acid)
reaction of thebaine.
• Used as sedative, an analgesic and a
narcotic.

Thebaine
* E. Coutinho -Opioid Analgesics 75
 Tramadol
8. Tramadol hydrochloride
(±)-cis-2[(dimethylamino)methyl]-1-(m-
methoxyphenyl)cylcohexanol hydrochloride
• Resembles part of the codeine structure
consisting of the phenyl and the cyclohexane
rings.
• Activity is attributed to the O-demethyl
metabolite, which is 6-times more active than
the parent.

Codeine
* E. Coutinho -Opioid Analgesics 76
 Apomorphine
9. Apomorphine hydrochloride.
When morphine or its hydrochloride salt is
heated at 140oC under pressure in
presence of 35% HCl, apomorphine is
obtained.
• Used as an emetic, administered s.c.
• "Orphan drug" for use in Parkinson’s
disease.

Morphin
* E. Coutinho -Opioid Analgesics
e 77
 10.Meperidine
Meperidine hydrochloride
Ethyl 1-methyl-4-phenyl-4-
piperidinecarboxylate hydrochloride
(Piperidine 4-carboxylic acid is also called
isonipecotate)
• Synthesized as a spasmolytic but found
to have far greater analgesic character.
• Analgesic effect lies between morphine
and codeine
• Especially useful to relieve pain due to
spastic conditions of intestine, uterus,
bladder, etc.
• Possesses addiction liability.

* E. Coutinho -Opioid Analgesics 78

 11.Alphaprodine
Alphaprodine hydrochloride
(±)-1,3-dimethyl-4-phenyl-4-piperdinol
propionate hydrochloride
• Effective analgesic, similar to meperidine
• Special value in obstetric analgesia.

* E. Coutinho -Opioid Analgesics 79

 12.Anilieridine
Anilieridine
Ethyl 1-(p-aminophenylethyl)-4-
phenylisonipecotate

• More active than meperidine

• Same use and same limitations as
meperidine.
• Less dependence and better substitute
for meperidine
• Also available as the hydrochloride salt.

* E. Coutinho -Opioid Analgesics 80

 13.Diphenoxylate
Diphenoxylate hydrochloride
Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-
phenylisonipecotate monohydrochloride

• Although strongly related structurally to the

meperidines, it has very little analgesic
activity.
• It inhibits excessive gastrointestinal motility,
like the constipating effect of morphine.
• Used in treatment of diarrhea

* E. Coutinho -Opioid Analgesics 81

 14.Loperamide
Loperamide hydrochloride
4-(4-chlorophenyl)-4-hydroxy-N,N-
dimethyl-α,α-diphenyl-1-
piperidinebutanamide hydrochloride

• Molecule is a hybrid of methadone-like

and meperidine-like, but related to
diphenoxylate.
• More potent, more specific and longer
acting than diphenoxylate.

* E. Coutinho -Opioid Analgesics 82

 15.Ethoheptazine
Ethoheptazine citrate
Ethyl hexahydro-1-methyl-4-
phenyl-1H-azepine-4-carboxylate

• Effective orally against moderate pain

• Minimal side effects
• No addiction liability

* E. Coutinho -Opioid Analgesics 83

 16.Fentanyl
Fentanyl citrate
N-(1-phenylethyl-4-
piperidyl)propionanilide citrate

• Analgesic activity 50 times that of

morphine in humans.
• Side effects similar to other potent
analgesics
• Has dependence liability

* E. Coutinho -Opioid Analgesics 84

 17.Alfentanil
Alfentanil hydrochloride
N-[1-[2-(4-ethyl-5-oxo-4,5-dihyro-1H-
tetrazolin-1-yl)ethyl]]-4-(methoxymethyl)-4-
piperidyl]propionanilide hydrochloride

• Alfentanil was discovered at Janssen

Pharmaceutica in 1976.
• Same properties and side effects as
fentanyl.

* E. Coutinho -Opioid Analgesics 85

18.Methadone
Methadone hydrochloride
6-(Dimethylamino)-4,4-diphenyl-3-
heptanone hydrochloride

• The (-) form [levanone] has the morphine-

like properties.
• Toxicity of methadone is 3-10 times that
of morphine, but its analgesic effect is
twice that of morphine and 10 times that
of meperidine.
• High addiction liability.

* E. Coutinho -Opioid Analgesics 86

19.Propoxyphene
Propoxyphene hydrochloride
(napsylate)
(2S, 3R)-(+)-4-(Dimethylamino)-3-
methyl-1,2-diphenyl-2-butanol propionate
hydrochloride
• α(+) is 2S,3R and α(-) is 2R,3S
• β(+) is 2S, 3S and β(-) is 2R, 3R
• It is the α-(+) isomer which is active which is
also called dextropropoxyphene.
• The α-(-) and β-diastereomers are less
potent as analgesics
• The α-(-) isomer, levopropoxyphene, is an
effective antitussive.
• As an analgesic equal in activity to codeine.
• No antidiarrheal, antitussive or antipyretic
effect like the other related analgesics.
* E. Coutinho -Opioid Analgesics 87
20.Levorphanol
Levorphanol tartrate
(-)-3-hydroxy-N-
methylmorphinan
• Schnider and Graüssner
synthesized the
hydroxymorphinans including
the 3-hydroxy derivative.
• The (±) form is called
racemorphan, which is resolved
to give levorphanol.
• 6 to 8 times more potent than
morphine and similar in uses
and liability to morphine.

* E. Coutinho -Opioid Analgesics 88

21.Butorphanol
Butorphanol tartrate
17-
(cylcobutylmethyl)morphinan-3,14-
diol D-(-)tartrate

• Cyclobutyl analog of 14-OH

levorphanol
• As potent an analgesic as levorphanol
• Has some antagonistic activity

* E. Coutinho -Opioid Analgesics 89

22.Pentazocine
Pentazocine
Cis-2-(3,3-dimethylallyl-)-5,9-
dimethyl-2’-hydroxy-6,7-benzomorphan

• Analgesic activity possibly resides in the

(-) isomer
• 25 mg equivalent to 10 mg morphine
• Both hydrochloride and lactate salts are
available.

* E. Coutinho -Opioid Analgesics 90

23.Mixed agonist-antagonist
Nalbuphine hydrochloride
17-(cylcobutylmethyl)-4,5-
epoxymorphinan-3,6α,14-triol
hydrochloride

• Combination of the oxymorphine

nucleus and the nitrogen substituent of
butorphanol
• Potent analgesic of the mixed agonist-
antagonist class.
• Similar to morphine in potency.

* E. Coutinho -Opioid Analgesics 91

24. Narcotic Antagonists
Nalorphine hydrochloride
N-allylnormorphine hydrochloride

• Direct antagonist effect against

morphine, meperidine, methadone
and levorphanol
• Strong analgesic effect, but not used
as an analgesic because of high
incidence of undesirable psychotic
effects.

* E. Coutinho -Opioid Analgesics 92

25.Naloxone
Naloxone hydrochloride
4,5-epoxy-3,14-dihydroxy-17-(2-
propenyl)morphinan-6-one
hydrochloride

• 7 times more active than nalorphine in

antagonizing the effects of morphine
(given to addicts in a detox program).
• No agonist effect, no analgesic activity.

* E. Coutinho -Opioid Analgesics 93

 26.Naltrexone
Naltrexone
17-cyclopropylmethyl-4,5α-epoxy-3,14-
dihydroxymorphinan-6-one

• Preferred agent for treating opiate addicts.

* E. Coutinho -Opioid Analgesics 94

26.Levallorphan
Levallorphan tartrate
17-(2-propenyl)morphinan-3-ol
tartrate

• Resembles nalorphine in its

pharmacological action and is about 5
times more effective as a narcotic
antagonist.

* E. Coutinho -Opioid Analgesics 95

 27.Cyclazocine
Cyclazocine
Cis-2-cylcopropylmethyl-5,9-
dimethyl-2’-hydroxy-6,7-benzomorphan.

• Potent narcotic antagonist, with analgesic

activity (with hallucinogenic activity)

* E. Coutinho -Opioid Analgesics 96

 Narcotic antagonists
• Replacement of N-methyl group by larger alkyl groups lowers analgesic
activity and counteracts the effects of morphine.
• The reversal of activity increases from ethyl, to propyl, to allyl
(nalorphine), reaching maximum with cyclopropylmethyl.
• It was thought that N-allyl type derivatives were antagonists and devoid
of analgesic activity.
• Lasagna and Beecher discovered that nalorphine (N-allylnormorphine)
was mg for mg as potent an analgesic as morphine.
• Nalorphine was the first antagonist to be marketed but was taken out
because of side effects.
• The discovery of nalorphine led to the development of related
derivatives such as pentazocine (adding the ′allyl ′ group to the
benzazocine nucleus).
• Pentazocine is useful as an analgesic, has low addiction potential, but
is not free from the other side effects of morphine.

* E. Coutinho -Opioid Analgesics 97

 Narcotic antagonists

• The N-allyl and N-cyclopropylmethyl derivatives are the most

potent antagonists, but also possess psychomimetic activity,
whereas the weak antagonists (mixed agonist-antagonist) do
not.
• The weaker antagonists pentazocine, butorphanol and
nalbuphine are more useful analgesics with butorphanol
and nalbuphine having the N-cyclobutylmethyl group.
• Levallorphan (N-allyl), naloxone (N-allyl), naltrexone (N-
cyclopropylmethyl) are the three marketed antagonists (all
derived from the morphine structure).
• These drugs are used to prevent, diminish, or abolish many of
the actions or the side effects of narcotic analgesics, like
addiction, respiratory and circulatory depression, euphoria,
depression, nausea, drowsiness, analgesia and hyperglycemia.

* E. Coutinho -Opioid Analgesics 98

• Narcotic antagonists are used to treat narcotic addiction.
• These will block the euphoric effects of heroin, thereby aiding
rehabilitation of an addict.

* E. Coutinho -Opioid Analgesics 99

 Portoghese hypothesis

• Induced fit mechanism

• Since several configurationally unrelated molecules can bind, means
that there is more than one mode of binding.

X and Y are H-bonding sites

100
Thiambutene analogs

Diethylthiambutene
(N,N-Diethyl-1-methyl-3,3-di-2-thienylallylamine)

Dimethylthiambutene
(N,N,1-Trimethyl-3,3-di-2-thienylallylamine)

Ethylmethylthiambutene
(N-Ethyl-N,1-dimethyl-3,3-di-2-thienylallylamine)

101
Morphine binding to μ-receptor

* E. Coutinho -Opioid Analgesics 102

 Anomalies in Beckett and Casy hypothesis
• Several active compounds are not related configurationally
to R-alanine, e.g. α-methadol, the carbethoxy analog of
methadone (see str. below) and diampromide & its analogs
(next slide).

• To be in tune with the receptor model, in the piperidine

series, the 4-phenyl group must occupy the axial position.
• However, the compound below has the phenyl group in
the equatorial position, but nevertheless is as potent as
morphine.

103
R-Alanine, R-Methadone and S-Methadol

104