1. OPIUM ALKALOIDS
MOSTAFA MAHMOUD HEGAZY PH.D

2. OPIUM ALKALOIDS
 Opium is the air-dried milky exudate, or latex,
obtained by incising the unripe capsules of the
opium poppy Papaver somniferum
(Papaveraceae).
 the ripe capsule can contain up to 0.5% total
alkaloids
Opium represents a much concentrated form
and up to 25% of its mass is composed of
alkaloids ( more than 40 alkaloids).

3. Importance:
source economically valuable chemicals as
 1- treating medicines as
a- pain killer analgesics ex. Morphine.
b- cough suppressants ex. codeine and Noscapine.
c- smooth muscle relaxant ex. Papaverine
 2- leading compounds for semi-synthetic and
modelling of totally synthetic
a-analgesics
b- cough suppressants
 3- abused drugs.

4.  Historical overview
1- Poppy in ancient Egypt.
2- Opium wars (Opium addiction)
3- Poppy in Art.
 Poppy seed as food
 Ethiodized poppy seed oil (radio-opaque contrast agent)

6. ■ Opium alkaloids usually occur naturally combined with
a specific acid: (Meconic acid).
■ Meconic acid present only in Opium with morphine.
■ Meconic acid gives a deep purplish red-colored complex
with FeCl3
O
OH
COOH
HOOC
O

7. Classification of Opium Alkaloids

8. Opium Alkaloid of the Benzylisoquinoline gruop
 Papaverine and Narcotine (Noscapine)
properties
 1- Very different from the morphine,
codeine, thebaine group of alkaloids
(Morphinans).
 2- Very weak bases, their solutions are
neutral to litmus paper.

9.  3- The free bases can be extracted from
their acid solution [unstable salts] with
CHCl3.
 4- They are derived biosynthetically from
Tyrosine amino acid.

10. Isolation of the major opium alkaloids Principle
 1- Morphine (phenolic), codeine (water soluble)
and narceine (-COOH) are soluble in NaOH.
 2- In presence of NaOH, only codeine can be
extracted by CHCl3.
 3- Narceine dissolved in NH4OH (-COOH)
leaving morphine insoluble in NH4OH.
NMe2
O
MeO
OMe
COOH
O
O
OMe
Narceine

11.  4- Papaverine, narcotine and thebaine
are insoluble in NaOH.
 5- Thebaine acetate is water soluble
salt while papverine and narcotine
acetate salts are insoluble in water.
 6- Narcotine oxalate salt is water
soluble while papaverine oxalate salt is
insoluble in water.

13. Tests for identification:
Papaverine
 1- Warren’s test
Papaverine + crystal of KMnO4 + Marqui’s reagent (HCHO/
H2SO4)  Green color  Blue
 2- Papaverine + Conc H2SO4  Violet color on heating
Narcotine
1- Alkaloid + conc. H2SO4  violet. (This test is –ve with Morphine)
2- Alkaloid + sucrose + conc. H2SO4  green-yellow  blue-
violet

14. Uses of Papaverine
 1- GIT spasms and bronchial asthma for
spasmolytic activity.
 2-Effective for treatment of male impotence,
being administered by direct injection to
achieve erection of the penis for vasodilator
activity.
 3- no analgesic or hypnotic properties

15. Uses of Narcotine (Noscapine)
 1- Anti-tussive and cough suppressant
activity comparable to that of codeine, but
no analgesic.
 2- Its original name ‘narcotine’ was
changed to reflect this lack of narcotic
action.

16. Opium Alkaloids of the
Phenylethylamine group
Narceine
It is not used medicinally
NMe2
O
MeO
OMe
COOH
O
O
OMe
Narceine

17. Opium Alkaloid of the Phenanthrene Group
O
HO
HO
N
CH3
O
H3CO
HO
N
CH3
O
H3CO
H3CO
N
CH3
H H H
H H
Morphine Codeine Thebaine
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 16
 Thebaine is Tetrahydro-Phenanthrene type differs structurally
from morphine/codeine mainly by its possession of a
conjugated diene ring system.
 Morphine and Codeine are Hexahydro-Phenanthrene type

18. Thebaine
Solid, crystalline.
Codeine
Solid, crystalline.
Morphine
Solid, crystalline.
Insoluble in H2O, but soluble
ether, benzene, and CHCl3
Soluble in H2O, ether,
benzene, ethanol and CHCl3
Insoluble in H2O, ether,
benzene, ethanol and CHCl3
Non-phenolic or alcoholic
OH groups.
Non-phenolic but alcoholic
OH group at C-6
phenolic OH at C-3 and
alcoholic OH groups at C-6
Insoluble in ammonia.
It dissolve in NH4OH due to
formation of Codeine
NH4OH complex.
It can be precipitated from its
acid solutions by addition of
NH4Cl, or NH4OH

19. Thebaine
Codeine
Morphine
Salicylate salt is H2O
insoluble.
Salicylate salt is H2O
soluble.
Salicylate salt is H2O soluble.
Has basic N-CH3 group
Has basic N-CH3 group
 Has basic N-CH3 group and
an acidic OH group
 Dissolve in both acids and
bases (Amphoteric alkaloid)
It prepared from Morphine
by methylation of the
phenolic OH group
Methylation of the phenolic
OH group  Codeine

21. Chemical Tests:

22. Codeine
Codeine + Conc. H2SO4 + FeCl3
on Water bath
Blue color
HNO3
Red color
Thebaine
Thebaine + Conc. H2SO4 Blood red color Orange color

23. Uses of crude opium :
1- potent analgesic.
2- sleep-inducer (narcotic).
‫النوم‬ ‫ابو‬ ‫بإسم‬ ‫النبات‬ ‫تسمية‬ ‫تمت‬ ‫هنا‬ ‫ومن‬
Morphine named after Morpheus
the god of dreams (Greek
Mythology).
3- for the treatment of coughs.

24. Morphine actions
1- powerful analgesic and narcotic
2- causes nausea, vomiting and constipation,
3- induces a state of euphoria (mental
detachment) followed tolerance, and addiction.
Thebaine
 It is almost devoid of analgesic activity.
 Its main value is as substrate for the semi-
synthesis of other drugs

25. Codeine
 1- Codeine is a relatively safe
non-addictive medium analgesic.
Its action is dependent on partial
demethylation in the liver to
produce morphine
 2- Codeine also has valuable anti-
tussive action, helping to relieve
of dry cough.

26. Structure Activity Relationship
of Morphine

27. Analgesic activity of morphine can Increase by:
O
HO
HO
N
CH3
H
H
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 16
1- Acetylation  diacetylmorphine (heroin), that is
more potent than morphine at C-3 and C-6
2-Introduction of a CH3 group at C-5
3- Catalytic Reduction, methylation, oxidation or even
elimination of the C-6 -OH (alcoholic OH group).
4- Introduction of an OH group at C-14.
5- Replacement of N-CH3 group by other groups e.g.
phenylethyl "N-CH2-CH2-ph" group.

28. Analgesic activity of
morphine can decrease by:
1) Methylation of the phenolic OH group e.g.
codeine.
2) Opening of the N-containing ring.
3) Opening of 4,5-oxygen bridge.
4) Dehydration by heating with HCl 
apomorphine.
5) Demethylation, N-CH3  N-H (Nor-morphine).
6) Quaternization of the tertiary nitrogen.
O
HO
HO
N
CH3
H
H
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 16

30. REMEMBER
THE CAUSE OF DEATH DUE TO OPIOIDS OVERDOSE IS
PRIMARILY FROM RESPIRATORY DEPRESSION