This group includes: ◘ The neurohormone serotonin. ◘ The hallucinogenic alkaloids, psilocin and psilocybin. ◘ Physostigma alkaloids. ◘ Ergot alkaloids. ◘ Nux vomica alkaloids. ◘ Vinca alkaloids.

1. Alkaloids of the Indole Group
By
Dr. Mostafa Mahmoud Hegazy ( PH.D.)
Indole
N
H

2. Tryptophan
NH2
N
H
O
OH
Alkaloids of the Indole Group
L-Tryptophan amino acid
1- An essential amino acid that is necessary for normal growth in infants and for
nitrogen balance in adults.
2- It is a precursor of indole alkaloids in plants.
3- It is a precursor of serotonin (hence its use as an antidepressant and sleep aid).
4- It can be a precursor to niacin ( vit. B3) in mammals.

3. This group includes:
◘ The neurohormone serotonin.
◘ The hallucinogenic alkaloids, psilocin
and psilocybin.
◘ Physostigma alkaloids.
◘ Ergot alkaloids.
◘ Nux vomica alkaloids.
◘ Vinca alkaloids.

4. Serotonin (5-hydroxytryptamine)
Occurrence
◘ Serotonin in Human is found in the brain, blood platelets, and
throughout the gastrointestinal tract.
It acts as a biochemical mediator and its roles include
involvement in CNS neurotransmission, haemostasis, vascular
spasm, and gastrointestinal motility.
N
H
HO
NH2
Serotonin
(5-hydroxytryptamine)

5. ◘ Serotonin is a skin irritant that acts by promoting histamine
release.
◘ Serotonin was isolated from plant origin Mucuna pruiens
(Leguminosae) and stinging nettles (Urtica dioica). It occurs in
several fruits e.g. banana, tomatoes, avocado, pineapple,
which are although not noticed to have an irritating effect and in
the stings of wasps and scorpions.
◘ High concentrations of 5-OH indole acetic acid (a metabolite
of 5-OH tryptamine), indicate the presence of certain types of
intestinal tumors and are used in diagnosis.

6. Color tests:
1) Serotonin + Marqui's reagent  brown color.
2) Serotonin + Vitali's test  grayish green color  brown .
3) Serotonin + Ammonium molybdate solution  blue
color  brown.

7. serotonin Tryptophan
sources Mucuna pruiens and stinging
nettles . It occurs in several
fruits e.g. banana, tomatoes,
avocado and pineapple, and
found in the stings of wasps
and scorpions.
Natural sources more favourable than
pharmaceuticals which may cause
certain side effects due contaminants
during biotransformation.
Eggs, spirulina, milk, Sesame seed, meat,
salmon, nuts, turkey, chicken and banana
Biological roles As mentioned before As mentioned before
Crossing BBB does not cross cross
Medicinal use No use as neurohormone as weak antidepressant and sleep aid.
Dose and
combinations
------ May used with pyridoxine and ascorbic
acid, which are involved in its
metabolism to serotonin. As 500 mg
tablets.

8. Drugs that affect serotonin levels
Some antidepressants increase serotonin concentrations
1- As precursors (Oxitriptan and Tryptophan) hence its
use as an antidepressant and sleep aid.
2- By inhibiting the metabolism of monoamine oxidase
A- non-selective irreversible inhibitors of monoamine
oxidase types A and B (MAOIs)
B- selective reversible inhibitors of monoamine oxidase
type A (RIMAs)

9. 3- By inhibit the neuronal reuptake of serotonin after
release
A-tricyclic antidepressants
B- the selective serotonin reuptake inhibitors (SSRIs) such
as fluoxetine (tried in the management of premature
ejaculation)
C- selective serotonin and noradrenaline reuptake
inhibitors (SNRIs) such as Sibutramine is an SNRI used in
the management of obesity.

10. 2) Psilocin and Psilocybin
Occurrence
They occur in certain mushrooms, the red sacred
mushroom of Mexico, Psilocybe mexicana,
N
H
R
NMe2
R = OH Psilocin
R = OPO3H2 Psilocybin

11. Psilocin Psilocybin
◘ occurs as plates crystals ◘ white or colorless crystals
◘ It is insoluble in water, soluble in
alcohol and in dilute acetic acid.
◘ It is unstable especially in alkaline
solution.
◘ Soluble in water and dilute acetic acid,
◘ It is insoluble in chloroform and
benzene.
◘ Upon phosphorylation 
psilocybin.
◘ It is the only natural indole alkaloid
that contains a phosphate radical.
◘ Upon hydrolysis  psilocin +
phosphoric acid.
Properties

12. Color tests:
1) Marqui’s reagent:
+ Psilocin  greenish brown color
+ Psilocybin  orange color
2) Ammonium molybdate solution:
+ Psilocin  a greenish blue color
+ Psilocybin  gray color  blue  green yellow
Uses
Psilocin and Psilocybin are hallucinogenic and sympathomimetic
properties similar to those of LSD.It is less potent than LSD.
( Psychedelic drugs) = causing thought and visual/auditory changes.

13. Physostigma alkaloids (Calabar bean alkaloids)
Physostigmine (Eserine)
* Present in the seed of Physostigma venenosum Fam. Leguminosae.
* Eserine is a tertiary base, possessing an ester linkage
N
N
H
H3CO
CH3
CH3
C
O
HNH3C
Eserine
Uses
1- Glaucoma ( myotic drug).
2- Reversal of drug-induced CNS antimuscarinic effects, it has a cholinergic
effect and stimulates gland secretion (c.f. Atropine).

14. Properties
◘ Eserine on alkaline hydrolysis  eseroline + methylamine
+ CO2
◘ Eserine upon oxidation, in presence of trace of alkali e.g.
NaOH, or traces of metals is transformed to rubreserine (red
compound).
◘ Therefore, it could be affected by the alkalinity of glass
containers during storage.

15. N
N
H
H3CO
CH3
CH3
C
O
HNH3C
Eserine
N
N
HO
Me
Me
Me
H
Eseroline Rubreserine
oxidation
alkaline hydrolysis
N
N
O
Me
Me
Me
H
O

16. Isolation of Eserine
powdered seeds
- extracted with hot alcohol
- evaporate
Residue
Add water to remove the fatty layer
Aqueous layer
- Rendered alkali with Na2CO3
- extract with ether
Ether layer Eserine

17. Tests for identification
1) Eserine blue test:
Eserine + strong NH3 solution  yellowish red color which
on evaporation  a bluish residue that is soluble in alcohol
(eserine blue)
2) Eserine + NaOH  red color.
3) Eserine (due to its reducing characters) + potassium
ferricyanide + FeCl3  Prussian blue color.

18. Terpenoid Indole Alkaloids
Nux vomica alkaloids
Dried ripe seed of Strychnos nux vomica
(Fam. Loganiaceae).
* Strychnine and Brucine are poisonous alkaloids.

19. ◘ The major alkaloids are Strychnine and
Brucine.
◘ They are Dihydro indole and quinoline
derivatives.
N
O
H
H
H
N
H
O
H
R1
R2
R1 = R2 = H Strychnine
R1 = R2 = OCH3 Brucine

20. Properties
BrucineStrychnine
 White crystalline powder.
 More soluble in CH3OH and
C2H5OH.
 Unstable in presence of
H2SO4 and HNO3.
 Soluble in acetone and 25%
C2H5OH.
 Precipitate very slowly by K.
ferrocyanide.
 Mono-acidic base.
 It is dimethoxy strychnine
 Colorless rhombic crystals
 Less soluble in CH3OH and
C2H5OH.
 Very stable in presence of
H2SO4 and HNO3.
 Insoluble in acetone and 25%
C2H5OH.
 Precipitate quickly by K. ferrocyanide.
 It is a mono-acidic base (only the N atom,
farthest from the benzene ring forms salts,
while the other N is an amide and has no
basic characters).

21. - Mixed with Ca (OH)2.
- Water is added to make a paste that is dried at 100 o
C
- Extraction with CHCl3
CHCl3 extract
- Shake with dilute H2SO4.
- Acid extract rendered alkaline with NH4OH
Isolation of Strychnine and Brucine
powdered Nux-vomica seeds
- The precipitated alkaloids are filtered
Residue
- Extracted with 25% ethanol,
- Filter
Precipitate Filtrate
Strychnine Brucine

22. Separation of a mixture of Strychnine and
Brucine
Strychnine can be separated from brucine by
one of the following methods:
 Shaking with acetone, only brucine will dissolve.
 Shaking with 25% ethanol, only brucine will dissolve.
 Treating with k. ferrocyanide:
Strychnine precipitates quickly
Brucine precipitates slowly.
 Treating with conc. H2SO4 + HNO3, (only brucine is
destroyed)
(strychnine is more stable, this method is only used
for purification of strychnine from brucine).

23. Uses:
1- Strychnine was formerly used as bitter stomachic
(improves the appetite) and stimulant.
2- Strychnine is the main principle of many rodenticides
(used as a poison for rats) .
3- In large doses, it causes violent convulsions, involving
the respiratory muscles and death occurs due to asphyxia.
4- Brucine is less toxic than Strychnine but not present in
clinical use.

24. Chemical Tests
1) Nitric acid test:
Strychnine
HNO3
Yellow color
HNO3
Intense orange red colorBrucine
SnCl2
evaporation
Violet color
2) Tests for Strychnine:
A) Crystals of Strychnine
H2SO4
K2Cr2O7
Violet to purple color
B) Mandalin's reagent (Sulphovanadic acid)
Strychnine + Mandalin's reagent Deep violet blue color
H2O
Cherry-red color

25. Ergot Alkaloids
* Ergot is a fungal disease commonly found on many wild and cultivated
grasses, and is caused by species of Claviceps.
* The disease is eventually characterized by the formation of hard, seed-
like ‘ergots’ instead of normal seeds.
* Medicinal ergot is the dried sclerotium of the fungus Claviceps
purpurea (Clavicipitaceae) developed on the ovary of rye, Secale cereale
(Graminae/Poaceae).

26. ◘ Ergot alkaloids are N-monosubstituted amide
derivative of both:
Lysergic acid and its isomer Isolysergic acid.
◘ These acids forms with ammonia the
corresponding amide:
Lysergic acid  Ergine
Isolysergic acid  Isoergine

27. NH
H
N
CH3
O
OH
1
2
3
4
5
6
7
8
NH
H
N
CH3
O
OH
1
2
3
4
5
6
7
8
(+)-Lysergic acid (+)-Isolysergic acid
NH
H
N
CH3
O
NH2
1
2
3
4
5
6
7
8
Ergine
NH
H
N
CH3
O
NH2
1
2
3
4
5
6
7
8
Isoergine

28. * Ergot alkaloids contains 12 major alkaloids divided into 6
pairs according to their peptide moieties.
* Members related to Lysergic acid e.g. Ergotamine and
Ergometrine.
* Members related to Isolysergic acid e.g. Ergotaminine and
Ergometrinine.
1) Alkaloids of the Ergometrine group
Hydrolysis
2-amino propanol
CH3
H2N
OH
2) Alkaloids of the Ergotamine group
Hydrolysis
Pyruvic acid
O
H3C
O
OH
3) Alkaloids of the Ergotoxine group
Hydrolysis
Dimethyl Pyruvic acid
O
OO
H3C
CH3
Classification of Ergot alkaloids:

29. The simple Lysergic acid amides
* They are water soluble
* They are all amides of Lysergic acid with simple amines (2-
aminopropanol)
* e.g. Ergometrine (L-lysergic acid with 2-aminopropanol)
and Ergometrinine (D-lysergic acid with 2-aminopropanol)
NH
H
N
CH3
O
NH
OH
CH3
Ergometrine

30. The Polypeptide Alkaloids
* Contain a cyclized tripeptide fragment bonded to lysergic acid via an amide linkage.
* Based on the nature of the three amino acids, these structures can be subdivided
into three groups:
1) Ergotamine group. 2) Ergoxine group. 3) Ergotoxine group.
* The amino acids involved are (alanine, valine, leucine, isoleucine, phenylalanine,
proline, and α-aminobutyric acid.
* All contain proline in the tripeptide, and one of the amino acids is effectively
incorporated into the final structure in the form of an
α-hydroxy-α-amino acid.
* Thus, ergotamine incorporates alanine, phenylalanine, and proline residues in its
peptide portion.
* Hydrolysis  (+)-lysergic acid + proline + phenylalanine together with pyruvic
acid and ammonia.

31. N
N
O
O
H
HO
O
H3C
NH
H
N
CH3
O
HN
Ergotamine
Lysergic acid part
Pyruvic acid part
-Phenylalanine part
Proline part

32. Ergometrine
Hydrolysis
Lysergic acid + 2-aminophenol
Ergotamine
Hydrolysis Lysergic acid
+
Pyruvic acid
+
-Phenylalanine
+
D-Proline
Chemical Test:
Van-Urk's test
Solution of Ergot alkaloids + Van-Urk's test (p-dimethylaminobenzaldehyde in 15% H2SO4)
containing traces of FeCl3 Deep blue color

33. Properties
ErgotamineErgometrine
(Ergnovine)
 Insoluble in water.
Hygroscopic.
 Freely soluble in CHCl3.
 Upon Water hydrolysis 
proline + pyruvic acid +
β-phenylalanine + Lysergic
acid.
Decompose by air, heat.
 Soluble in water with blue
fluorescence.
 Soluble in alcohol.
 Insoluble in CHCl3.
 Upon Water hydrolysis 
2-amino propanol +
Lysergic acid.

34. - Extraction with dilute H2SO4.
- Add excess of BaSO4
(to precipitate the non-alkaloidal constituents)
- Excess barium is removed with CO2 and filtered.
Filtrate
- Alkalinization with ammonia
- Extraction with chloroform.
This is based on its solubility in water and is carried as follows:
The defatted powdered ergot
CHCl3 extract - Shake with dilute H2SO4.
- acid extract rendered alkaline
- extracted with ether.
recrystallized from acetone.
Ether layerErgometrine
Isolation of Ergometrine

35. - Treat with aluminum sulfate (to fix the alkaloid as double compound).
- Extract with hot benzene (to remove acid and neutral substances).
- Evaporate.
- Render the residue alkaline with ammonia (to liberate the alkaloid).
- Stir with large volume of benzene and filter.
Filtrate
This is based on that ergotamine is a water-insoluble alkaloid and is carried as follows:
The defatted powdered ergot
Isolation of ergotamine
Concentrate the filtrate under reduced pressure
Ergotamine

36. Uses of Ergometrine
 Used as an Oxytocic (Ecbolic), [causes vigorous contraction of the
uterus], in order to aid delivery or to prevent postpartum hemorrhage.
 Injected during the final stages of labour and immediately following
childbirth, especially if hemorrhage occurs.
 Bleeding is reduced because of its vasoconstrictor effects, and it is
valuable after Caesarian operations.
 Ergometrine is also orally active. It produces faster stimulation of
uterine muscle

37. Uses of Ergotamine
Treatment of acute attacks of migraine, Ergotamine is
effective orally, or by inhalation in aerosol form, and
may be combined with caffeine.

38. Vinca alkaloids (Catharanthus alkaloids)
Catharanthus or Vinca is the dried whole plant of Catharanthus roseus
(Fam. Apocyanaceae).

39. N
N
OCOCH3
OH
CH3
H3CO
R
N
H
COOCH3
N
OH
COOCH3
Vincristine (R = CHO)
Vinblastine (R = CH3)
They differ in the presence of:
N-methyl group in vinblastine.
N-formyl group in vincristine.

40. * Vinca alkaloids are Dimeric alkaloids having Indole and Dihydroindole
nuclei.
* Vincristine and Vinblastine are the major alkaloids in Vinca, they differs
only in the substitution on the N- atom of the Dihydroindole nucleus.
Uses:
Vincristine used in treatment of Leukemia in children.
Vinblastine is used for treatment of Hodgkin’s disease.