‫بسم هللا الرحمن الرحيم‬
PHG 322
PHARMACOGONSY II
LECTURE 3
PRESENTED BY
ASSISTANT PROF. DR. EBTESAM ALSHEDDI
III. Alkaloids of the Isoquinoline group
Ipeca
Opium
Curare
Raw opium
• Raw opium: is the air dried latex obtained by
the incisions from the unripe capsules of
Papaver somniferum .)eaecarevapaP(
• Opium is the source of many alkaloids, including
morphine, thebaine, codeine, papaverine, and
noscapine.
• Morphine is the predominant one.
CALIFORNIA POPPIES
Papaver spp
Do not contain morphine or codeine,
but like all poppies have papaverine
(the “poppy alkaloid”).
OPIUM POPPY
Papaver
somniferum
Opium alkaloids occur naturally combined with specific acid (meconic acid).
Occurs only in opium
Specific test:
Meconic acid + FeCl3 gives purplish red colour
Not destroyed by dilute HCl (c.f. from ferric acetate and formate)
Unaffected by addition of HgCl2 (c.f. from thiocyanate)
CLASSIFICATION
Natural opiates: are alkaloids contained in the latex of opium as
morphine, codeine, and thebaine.
Semi-synthetic opioids: created from the natural opiates, such as heroin,
oxycodone, and hydrocodone are derived from morphine, codeine, and
thebaine.
Fully synthetic opioids: such as pethidine, methadone, tramadol.
Endogenous opioid peptides, produced naturally in the body, such as
endorphins, enkephalins, dynorphins, and endomorphins.

Opium alkaloids are subclassified into 3 groups:
Phenylethylamine
alk.
Phenanthrene alk.
8
Benzylisoquinoline
alk.

BENZYLISOQUINOLINE:
Papaverine
Properties:
It is a weak base and is optically inactive.
OCH3
OCH3
Tests for identification
Warren's test (specific for papaverine):
H3CO
N
Papaverine + crushed crystal of KMnO4
H3CO
+ Marqui's reagent  green color  blue.
Uses:
Papaverine possesses smooth muscle relaxant activity. It is
used as antispasmodic for GIT spasms, clots and in bronchial asthma
in a dose up to 600 mg of papaverine HCl daily.
Phenylalkylamines:
Narceine
Properties:
It is a tertiary Alkaloids. Narceine is an amphoteric
alkaloid since it contain a carboxylic group.
O
N
O
OCH3
CH3
CH3
C O
COOH
OCH3
OCH3
 PHENANTHEREN GROUP:
Morphine:
Properties:
Morphine is levorotatory, insoluble in water, sparingly soluble in
ethanol (1:250) and chloroform (1:1500), practically insoluble in ether
and benzene.
It contains 2 OH groups, one is a phenolic at C-3 (gives a soluble
phenate with alkali) and the other is a 2ry alcoholic at C-6.
RO
3
A
B
O E
D
C
HO
H
NCH3
6
R= H Morphine
R= CH3 Codeine
TESTS FOR IDENTIFICATION:
Tests due to phenolic properties:
1- Morphine gives a blue color with FeCl3.
2- Nitrous acid test: solution of morphine in dilute HCl +
NaN02 + NaOH  red color.
3- Morphine + dil H2SO4 + HI→ I2 give violet colour when
dissolve in CHCl3
Tests with alkaloidal color reagents:
1- Liebermann' s reagent  black color.
2- Mandalin's reagent  bluish-gray color.
3- Marquis' reagent  violet color.
4- HNO3 → red colour convert to yellow on heating.
USES:
Morphine act as a narcotic analgesic (reduce pain & induce sleep) in a
dose of 5-20 mg of morphine hydrochloride, sulfate or tartrate,
administered orally or parentrally, every 4 hours.
Used before and after surgical operations and to terminally ill cancer
patients.
Suppress peristaltic movement so stops diarrhea.
Adverse Effects:
Two major problems are associated to morphine use:
Addiction and Tolerance.
Morphine
HO- Group is needed for activity
2
HO
3
1
11
4
O
13
5
HO
10
15
12
9
14
H
8
6
16
H
N
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
Codeine:
Properties:
It is soluble in H2O, boiling H2O, ethanol, CHCl3 and ether, (c.f.
morphine).
Codeine is non Phenolic.
Test:
Codeine + concentrated H2SO4 + FeCl3, warm in water
RObath 
bluish violet color + HNO3  Red color.
3
A
B
Uses:
O E
C
It has less narcotic analgesic than morphine.
It is mainly used as antitussive.
D
HO
H
NCH3
6
R= H Morphine
R= CH3 Codeine
Codeine
HO- Group is needed for activity
Inefficiently converted to HO group in the liver
2
HO
3
11
4
13
5
10
15
12
O
HO
CH3O
1
O
9
14
H
8
6
16
H
N
H
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
H
N
CH3
HO
Codeine (5X LESS potent than morphine)
Thebaine
CH3O
O
H
N
CH3
CH3O
Thebaine (paramorphine) is an opiate alkaloid. A minor constituent of opium,
thebaine is chemically similar to both morphine and codeine, but produces
stimulatory, with strychnine-like convulsions, rather than depressant effects.
Thebaine is not used therapeutically, but is converted industrially into a
variety of compounds including oxycodone, oxymorphone, nalbuphine,
naloxone, naltrexone, buprenorphine and etorphine.
SEMI-SYNTHETIC DERIVATIVES OF
MORPHINE:
Heroin
It is the diacetyl derivative of morphine. It has no any medical
applications but it is one of the most dangerous abused substance.
Morphine is easily acetylated to diacetylmorphine using acetic
anhydride.
O
O
morphine
H3C
C
O
C
CH3
Heroin is more potent than morphine (it takes less for the same
effect), lasts longer, and is more addicting.
Apomorphine
Obtained by heating morphine with coc. HCl in sealed vials. During this
reaction rearrangement and elimination of water takes place.
Apomorphine is used in the treatment of Parkinson’s disease and erectile
dysfunction.
morphine
+ HCl, Δ
Ether bridge opening (ring E):
Resulted in group of compounds called morphinans. Synthetic
morphinans are racemic compounds. Only the levo isomers have
analgesic activity. Levorphanol is 8 times as active as morphine. The
dextro isomers as dextromethorphane lack the CNS and analgesic
effects, however, they are used as cough suppressants.
RO
RO
3
A
B
O E
H
NCH3
R= H
(-) Levorphanol RP=8
R= CH3 (+) Dextromethorphan
D
C
HO
H
NCH3
6
R= H Morphine
R= CH3 Codeine
The C-6 Hydroxyl group and ring c modifications:
Removal or derivitization of the alcoholic hydroxyl group at C-6 increase
lipophilicity and consequently the analgesic activity.
Reduction of the 7,8 double bond, oxidation of C-6 hydroxyl and addition
of OH group at C-14 all increase the activity.
HO
HO
HO
O
O
H
NCH3
R
R=H
6-Deoxymorphine
RP=10
R=OCH3
6-Methoxymorphine RP=5
R=OC2H5
6-Ethoxymorphine
RP=2.5
R=OCOCH3 6-MAM
RP=4.2
O
H
14
NCH3
R
NCH3
O
HO
Dihydromorphine
R=H Hydromorphone RP=5-6
R=OH Oxymorphone RP=10
The C-3 Hydroxyl group:
Etherification of this phenolic OH decrease the analgesic activity
and the compounds are used mainly as antitussive e.g. Codeine and
Pholcodine.
O
N
C2H4O
O
H
HO
Pholcodine
NCH3
Similar synthetic manipulations make
hydrocodone more potent than codeine
2
CH3O
3
1
11
4
12
O
13
5
O
10
15
9
14
H
8
6
16
H
N
CH3
7
Hydrocodone
(much more potent than codeine)
Hydrocodone or dihydrocodeinone (marketed as Vicodin, Anexsia,
Dicodid, Hycodan, Hycomine, Lorcet, Lortab (or Loritab), Norco,
Novahistex, Hydroco, Tussionex, Vicoprofen, Xodol) is a semisynthetic opioid derived from two of the naturally occurring opiates,
codeine and thebaine. Hydrocodone is an orally active narcotic analgesic
and antitussive. Sales and production of this drug have increased
significantly in recent years, as have diversion and illicit use. Hydrocodone
is commonly available in tablet, capsule and syrup form.
Oxycodone
HO- Group is needed for activity
CH3O
2
HO
3
1
11
4
12
O
13
5
HO
CH3 group reduces potency
10
15
oxidized OH
9
14
H
8
6
O
16
H
N
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
H
OH
N
CH3
O
Reduced C=C
Oxycodone (Percocet) -OH group increases potency
(equal to morphine
in potency)
Oxycodone
• Oxycodone is a potent and potentially addictive
opioid analgesic medication synthesized from
thebaine. Its name is derived from codeine - the
chemical structures are very similar.
• It is effective orally and is marketed in
combination with aspirin (Percodan, Endodan,
Roxiprin) or paracetamol/acetaminophen
(Percocet, Endocet, Roxicet, Tylox) for the
relief of pain. More recently, ibuprofen has been
added to oxycodone (Combunox).
N atom substitution:
Methyl group in nitrogen resulted in compounds with analgesic effects. Ethyl
morphine is also analgesic. Compounds with 3- 5 carbons alkyl group on nitrogen
are antagonists. More than 5 carbons the compounds again are analgesic.
2
HO
3
1
3
2
HO
1
3
1
11
4
13
5
10
15
12
O
HO
2
HO
9
14
H
8
6
H
H
C
N
C
H2
7
8
6
16
12
O
9
14
CH2
O
Nalorphine
13
5
10
15
12
O
11
4
11
4
16
H
OH
H
C
N
7
Naloxone
C
H2
13
5
CH2
O
10
15
9
14
8
6
16
H
OH
N
C
H2
7
Naltrexone
3- CURARE ALKALOIDS
Occurrence:
Curare or South American arrow poison is the dried crude extract,
obtained mainly from Chondrodendron tomentosum (Menispermaceae)
and certain Strychnos species, (Loganiaceae).
Curare contains several alkaloids (4-7%), the most important is d-tubocurarine.
MeO
N
Me
OH H
O
O
Me
Me
H
N+
OH
OMe
Properties:
d-tubocurarine (4ary alkaloid) is freely soluble in H2O. It is a phenolic
dextrorotatory alkaloid. It is a bis-benzyltetrahydroisoquinoline
alkaloid.
Tests:

Saturated aqueous solution + FeCl3  faint green color  green
color.

Solution of the alkaloidal HC1 + Na2CO 3  yellow brown
precipitate.
Uses:

Tubocurarine chloride is mainly used by i.m. or i.v. routes as
skeletal muscle relaxant.

It is used to control and reduce convulsions of strychnine
poisoning and of tetanus.

It is used as a diagnostic aid in myasthenia gravis.