1. 1. Isoquinoline Alkaloids
Alkaloids Derived from Phenylalanine and Tyrosine
1. Isoquinoline Alkaloids
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

2. 1. Isoquinoline Alkaloids
More than 800 alkaloids belong to this group.
They have been derived from isoquinoline, 1,2,3,4-tetrahydro- or 3,4-dihydro-
derivatives.
It is important to take in consideration that the basic nucleus (Isoquinoline)
could be opened or enlarged.
Nine types of isoquinoline alkaloids have pharmacognostical interest such as:
1- Benzylisoquinoline type (e.g. papaverine)
2- Bisbenzylisoquinoline type (e.g. tubocurarine)
3- Phthalidisoquinoline type (e.g. Noscapine, Hydrastine)
4- Protoberberine type (e.g. berberine)
5- Aporphine type (e.g. boldine)
6- Protopine type (Diisoquinolin) (e.g. protopine)
7- Morphinane type (Phenanthrene) (e.g. morphine, codeine, thebaine)
8- Benzophenanthridine (e.g. chelidonine, sanguinarine)
9- Emetine- (Monoterpenoid isoquinoline-) type (e.g. emetine)
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

3. Drugs containing isoquinoline alkaloids 1- Emetine- (Monoterpenoid isoquinoline-) type (Ipecac Alkaloids)
Ipecac is the dried roots and rhizomes of Cephalis ipecacuanha (Brazilian ipecacuanha) or Cephalis acuminata (Cartagena or Panama ipecacuanha) (Fam. Rubiaceae).
It contains several alkaloids (2 –2.5 %), mainly emetine ( % of total alkaloids), with cephaline and psychotrine.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

4. Physicochemical properties
Emetine: white amorphous powder, non-phenolic, soluble in alcohol,
ether and CHCl3, sparingly soluble in H2O
Cephaline: colorless needles, being phenolic (soluble in alkalis),
insoluble in H2O, soluble in CHCl3 or alcohol, on methylation with
methyl-sulphate is converted to emetine
Psychotrine: yellow prisms, being phenolic, sparingly soluble in H2O,
ether, soluble in ethanol and CHCl3, on reduction is converted to cephaline.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

5. Pharmacology of Ipecac alkaloids:
Ipecac preparations, when administered orally at low doses, are
emetics.
Cepheline is the main alkaloid responsible for the emetic activity.
Emetine is an amebicide, inhibits protein synthesis in animals and
in protozoa, kills viruses, but it is not antibacterial.
Emetine is toxic for humans (Arrhythmia, hypotension, muscular
weakness, and gastrointestinal distress).
It is no longer used in therapeutics (It has been replaced by a
synthetic derivatives, dehydroemetine).
Dehydroemetine is used for treating acute intestinal amebiasis,
hepatic amebiasis and bilharziasis.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

6. 2. Bisbenzyltetrahydroisoquinoline alkaloids
Curare alkaloids
dried extract from the bark and stems of Strychnos species e.g. S. castelnaei, S. toxifera, S. crevauxii (Fam. Loganiaceae) and from Chondodendron species (Fam. Menispermaceae) used as arrow poison by certain native tribes of the Amazon regions of South America.
Curare contains several alkaloids (4-7%), the most important is d-tubocurarine (quaternary ammonium structure with two ether bridges)
the other alkaloids are tertiary bases : (-) curine, (+) - isochondrodendrine and (+) chondrocurine.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

7. Properties: Tests: Uses:
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 HCl + Na2CO3  yellow brown precipitate.
Uses:
It is a non-depolarizing neuromuscularblocking agent , employed i. m or i. v. as a skeletal muscle relaxant to secure muscle relaxation in surgical procedures.
It is used to control and reduce convulsions of strychnine poisoning and of tetanus.
It is used as a diagnostic aid in myasthenia gravis.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

8. 3- Opium Alkaloids
Milky exudate obtained by incising the unripe capsules of Papaver somniferum (Fam. Papaveraceae).
The active principles are represented by 10 to 20% alkaloids
More than 25 alkaloids of different types have been obtained
The most important alkaloids are morphine, codeine and thebaine.
Opium alkaloids occur naturally combined with specific acid (meconic acid), which occurs only in opium.
Chemical tests:
by directly adding ferric chloride to the aqueous extract, a red color
develops (characteristic of meconic acid).
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

9. OPIUM POPPY Papaver somniferum Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

10. Classification of Opioids
Endogenous opioid peptides: produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.
Natural opioids : 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 which are derived from morphine, codeine, and thebaine.
Fully synthetic opioids: such as pethidine, methadone, tramadol.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

11. Classification of Opium alkaloids
Opium alkaloids are subclassified into 3 groups:
1- Benzylisoquinoline alkaloids.
2- Phenylethylamine alkaloids.
3- Phenanthrene alkaloids.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

12. Benzylisoquinoline type: Papaverine
Properties:
It is a weak base and is optically inactive.
Tests for identification
Warren's test (specific for papaverine):
Papaverine + crushed crystal of KMnO4 + 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.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

13. Used as antitussive medicine without pain killing effect.
Noscapine:
Used as antitussive medicine without pain killing effect.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

14. Phenylethylamine type: Narceine
Properties:
It is a tertiary Alkaloids.
Narceine is an amphoteric alkaloid since it contain a carboxylic group.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

15. Phenantheren type: Morphine: Properties:
Morphine is levorotatory, insoluble in water, sparingly soluble in ethanol and chloroform, practically insoluble in ether and benzene.
It contains 2 OH groups, one is a phenolic at C-3 (gives a soluble phenolate with alkali) and the other is a 2ry alcoholic at C-6.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

16. Tests for identification of morphine:
1- 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 color when dissolve in CHCl3
2- 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 color convert to yellow on heating.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

17. Uses of morphine: Adverse Effects:
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 parentally, 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.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

18. Structure-activity relationship of morphine
Esterification or etherification of the hydroxyl group at C-3
decreases the analgesic activity.
The inversion of configuration at C-9 and C-13 makes the
activity disappear.
Substituents on the N-atom are crucial, the replacement
of the methyl group by small alkyl radicals (e.g. allyl,
cyclopropylmethyl, cyclobutylmethyl) transforms the
compound into a partial or a complete opioid antagonist.
Introduction of a hydroxyl group at C-14 increases the
analgesic activity.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

19. Codeine: Test: Uses: 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 bath  bluish violet color + HNO3  Red color.
Uses:
It has less narcotic analgesic than morphine.
It is mainly used as antitussive.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

20. Thebaine 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.
It is not used therapeutically, but is converted industrially into
a variety of compounds including oxycodone, oxymorphone,
nalbuphine, naloxone, naltrexone, buprenorphine and etorphine.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

21. 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.
Heroin is more potent than morphine (it takes less for the same effect), lasts longer, and is more addicting.
morphine
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

22. Apomorphine
Obtained by heating morphine with con. 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.
+ HCl, Δ
morphine
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

23. 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.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

24. The C-6 Hydroxyl group and ring c modifications:
Removal or derivatization 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.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

25. 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.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

26. Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

27. 2. Phenylalkylamine Alkaloids
Alkaloids Derived from Phenylalanine and Tyrosine
2. Phenylalkylamine Alkaloids
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

28. Classification of Phenylalkylamine alkaloids
1. Benzylamine type
2. Phenylethylamine type
3. Aminophenylpropan type
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

29. Drugs containing Phenylalkylamine alkaloids
Ephedra Alkaloids
Various Ephedra species, e.g. E. sinica (Fam. Ephedraceae)
Ephedra used as remedy for asthma in Chinese medicine
Contains 2% alkaloids e.g. ephedrine, Pseudoephedrine, norpseudoephedrine.
(-)-Ephedrine is the major Alkaloid in Ephedra.
Ephedrine is a phenylalkylamine with N atom in the side chain.
PHG322, Alkaloids Part3
Ramzi A. Mothana, PhD

30. Ephedrine is similar to adrenaline in structures.
Advantages of Ephedrine over adrenaline:
1- Orally active. 2- Prolonged action
Pharmacology:
ephedrine is an indirect sympathomimetic, close to adrenaline.
Uses:
in asthma, allergic drugs, bronchodilator, nasal congestion
and in cough mixtures.
Identification (Chen’s test):
Ephedrine HCl in water ml CuSO4 + 1ml NaOH → Violet colour, shake with Ether → Ether layer → purple, Aqueous layer → blue
PHG322, Alkaloids Part3
Ramzi A. Mothana, PhD

31. Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

32. Drugs containing Phenylalkylamine alkaloids (contin..)
2-Capsicum
Ripe fruit of Capsicum annum (Fam. Solanaceae)
Contains 1.5% Capsaicinoids (amides of vanillylamines with saturated or
unsaturated C8-C13 fatty acids)
Uses: as carminative, counterirritant in the form of tincture or plaster in the
treatment of rheumatism and neuralgic pains.
Test: 1- solution of capsaicine + FeCl green color
2- Capsaicine + H2SO4 + small amount of sugar
violet color after period of 1 h
PHG322, Alkaloids Part3
Ramzi A. Mothana, PhD

33. PHG322, Alkaloids Part3
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34. Drugs containing Phenylalkylamine alkaloids (contin..)
3- Khat
Leaves of Catha edulis (Fam. Celastraceae)
in fresh leaves cathinone, in the dried cathine.
Pharmacology:
Cathinone possesses pharmacological properties analogous to those of
D-amphetamine.
It causes anorexia, hyperthermia, respiratory stimulation, mydriasis,
arrhythmia and hypertension.
It induces the release of catecholamines from storage.
PHG322, Alkaloids Part3
Ramzi A. Mothana, PhD

35. PHG322, Alkaloids Part3
Ramzi A. Mothana, PhD

36. Drugs containing Phenylalkylamine alkaloids (contin..)
4- Peyote Alkaloids
Source: Lophophora williamsii ( is a small, spineless cactus).
Peyote is native to Mexico and southwestern Texas and famous for its hallucinogenic effect.
It contains phenyl ethylamine alkaloids (major alkaloid is mescaline).
Mescaline has hallucinogenic effects similar to those of LSD and psilocybin.
PHG322, Alkaloids Part3
Ramzi A. Mothana, PhD

37. Alkaloids Derived from Phenylalanine and Tyrosine
3. Tropolone Alkaloids
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PHG322, Alkaloids Part3

38. Colchicum Alkaloids
dried, ripe seed and corm of Colchicum autumnale (Fam. Liliaceae)
Up to 1.2 %, the chief constituent is colchicine.
Colchicine possesses a tropolone structure and being non-basic or weak-
basic in character, soluble in H2O, aq. alcohols and CHCl3.
occurs as pale yellow needles.
Tests for colchicine:
1- with few drops of mineral acids, gives yellow color.
2- with conc HNO3, dirty violet color is produced, which changes through
brown to yellow.
Pharmacology:
Colchicine possesses an anti-mitotic and anti-inflammatory activity.
It is useful for treating of the acute attack of gout .
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

39. Alkaloids Derived from histidine
Imidazole Alkaloids
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

40. Source: Jaborandi leaves (Pilocarpus jaborandi).
Pilocarpus Alkaloids
Source: Jaborandi leaves (Pilocarpus jaborandi).
Constituents: (+)-Pilocarpine and isopilocarpine.
Pilocarpine is a tertiary base containing a lactone
group as well as an imidazole nucleus.
It is an oily syrupy liquid, easily soluble in water,
alcohol and chloroform, but almost insoluble in ether.
The lactone ring is opened by caustic alkali, which forms salts
with the resulting pilocarbic acid (unaffected by ammonia or alkali carbonates) (destroys the physiological activity).
it is demethylated and converted to pilocarpidine,
when heated with acids.
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

41. Pharmacology: Pilocarpine is a parasympathomimetic.
It induces salivary glands, gastric, and sweat hyper-secretion,
It increases intestinal motility, induces broncho-constriction,
and bradycardia.
It directly stimulates the muscarinic receptors in the eye,
causing constriction of the pupil (myosis) and contraction
of the ciliary muscle.
It used in the treatment of narrow-angle glaucoma.
Alone or in combination with beta-blocker (timolol) also
for treating intraocular pressure.
Pilocarpine can be used as a sialagogue to relieve dryness
of the mouth (for example, that due to the radiotherapy
of mouth and throat cancers).
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3

42. Chemical tests: 1- Helch’s test (H2SO4 + H2O2 + KCr2O7)
gives violet color
2- Ekkert’s test (Na-nitroprusside + NaOH)
leave for a period in HCl-solution, it gives
red color
Ramzi A. Mothana, PhD
PHG322, Alkaloids Part3