Faculty of pharmacy

Delta University for Science and Technology

Me
N H
COOMe

H O

Phytochemistry-2
Alkaloids
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 ALKALOIDS

Alkaloids are considered as an important group among the medicinally useful constituents
of plants. By 1806 morphine was isolated from opium by the European pharmacist Fredrich
Serturner. Since that time several hundreds of alkaloids have been isolated and
characterized from various plants.
The term "alkaloid" is a traditional and conventional name accepted for a group of
nitrogen—containing basic substances from plants with rather widely different chemical
constitutions and showing pronounced pharmacological actions.

Common features and properties of alkaloids:

There are certain common features which to a greater or lesser degree, are associated
with or possessed by the substances commonly known as alkaloids. These features may be
summarized as follows:

1. Alkaloids contain one or more nitrogen atom in the molecule, most commonly in a
heterocyclic ring. However, in a number of alkaloidal amines which are considered as
alkaloids (e.g. ephedrine and colchicine) the nitrogen is not in a ring.

2. Alkaloids are basic in reaction, due to the presence of the nitrogen in the molecule.
Consequently, alkaloids form salts with various acids. The alkaloid salts in solutions release
the free alkaloid bases when the solutions are made alkaline, most commonly with ammonia,
sodium hydroxide or calcium hydroxide. Alkaloids posses different values of pK b i.e different
strengths of basicity.
According to Lewis, "bases are compounds that could provide electron pairs". In our case:

Then the equilibrium constant, in water, is given by:

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The concentration of water being taken as constant as it is present in such large excess.
pKb = — loglO Kb , then the smaller the numerical value of pKb the stronger is the base
to which it refers.
From the above equations, it is evident that the strength of nitrogenous bases is related to
the availability of the unshared electron pair on the N. This depends on whether the nitrogen
is present as a primary ( —NH2), a secondary( =NH), a tertiary ( ΞN ) or a quaternary
ammonium group ( ΞN+—)(X- ). It depends also on the action of various groups and
substitutions in the molecule. To exemplify this, let us consider the two alkaloidal amines
ephedrine and colchicine:

The net result of the inductive and mesomeric effects, ephedrine is a strong base while
colchicine is a very weak base. In a weak acidic medium strong bases form stable salts
while weak bases remain as free bases in such medium.

3. Alkaloids are produced by plants; both vascular plants as well as certain species of fungi.
It should be pointed out that a number of amines (e.g. epinephrine) produced by animals
possess physical and chemical properties rather similar to those of alkaloids. Nevertheless,
by convention these animal amines are generally not considered as alkaloids.

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4. Most alkaloids exert some definite pharmacological action: morphine and codeine are
analgesics and narcotics; strychnine and brucine are central stimulants; atropine is
a mydriatic, physostigmine and pilocarpine are myotics ; ephedrine causes a rise in blood
pressure while reserpine produces a fall in excessive hypertension, etc.

5. Most alkaloids are derived in their biosynthesis from certain alpha-amino acids, e.g.
ornithine, lysine, phenylalanine, tyrosine and tryptophan (table).

However some other alkaloids although they are derived from amino acids, their nitrogen is
not included in a heterocyclic ring and they are called proto alkaloids such as ephedrine,
colchicines and mescaline.

Other atypical alkaloids are pseudo alkaloids that are biogenetically unrelated to amino
acids (such as purine alkaloids).

6. Alkaloid bases are much more soluble in a number of water-immiscible organic solvents
than they are in water. Meanwhile, alkaloid salts are generally soluble in water and mostly
nearly insoluble in the water-immiscible organic solvents.

Generally speaking, the alkaloidal free bases are insoluble in water, soluble in organic
solvents; while the salts are usually soluble in water but sparingly soluble in organic solvents.
Both alkaloidal bases and their salts are generally soluble in alcohol.

There are some exceptions to the above generalizations:

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  Some alkaloidal bases are very sparingly soluble in organic solvents, e.g. morphine is
insoluble in chloroform, pilocarpine is insoluble in ether.

 Some alkaloidal bases are soluble in water, e.g., caffeine, colchicine, ephedrine and
pilocarpine. It must be noticed that although these bases are soluble in water, they
are still soluble in organic solvents.

 Quaternary alkaloids and alkaloidal N-oxides are ionic compounds, so they are soluble
in water and insoluble in non polar solvents.

 Some alkaloidal salts are soluble in organic solvents, e.g. lobeline HCl and
physostigmine sulphate are soluble in chloroform.

 Some alkaloidal salts are sparingly soluble in water, e.g. quinine sulphate, while
quinine hydrochloride is very soluble in water.

Most of alkaloids are colorless, odorless, crystalline, bitter in taste and optically active. The .7
:following are some exceptions
 Colored alkaloids e.g. colchicine, berberine.
 Liquid alkaloids which can be either steam volatile, e.g. nicotine and coniine or
steam non volatile, e.g. pilocarpine and pelletierine.
 Amorphous alkaloids e.g. emetine.

8. Alkaloids occur in plants in one or more of the following forms:

 As free bases (rarely).

 As salts; i.e. associated with acids as follows:
a- Salts of special acids as meconic acid (opium alkaloids) and quinic and cinchotannic
acids (cinchona alkaloids).

b- Salts of organic acids, e.g. citric, oxalic and tannic acids.

c- Salts of inorganic acids, e.g. sulfuric and hydrochloric acids.

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  As glycosides; few exist in glycosidal combination with sugars forming
glycosidal alkaloids, e.g. solanine.
 As alkaloidal N-oxides.

9. The English names of alkaloids should end with the suffix (-ine). Latin names end with (-
ina). The names of alkaloids are derived according to various ways:

1 From the generic name of the plant, e.g. atropine (from Atropa), ephedrine (from
Ephedra ), pilocarpine (from Pilocarpus) and physostigmine (from Physostigma).
2 From the specific name of the plant, e.g. cocaine and belladonnine.
3 From the common name of the plant, e.g. ergotamine.
4 From the physiological activity, e.g. emetine, narcotine and morphine (God of
dreams).
5 After the discoverer, e.g. pelletierine after Pelletier.
6 From the physical properties, e.g. hygrine (hygroscopic).
Sometimes, a suffix is added to the name of the principal alkaloid to designate
another alkaloid from the same source, e.g. quinine and quinidine, ergometrine and
ergometrinine.

Prefixes are also useful to distinguish between individual alkaloids found in the plant,
e.g.:

a Isomers: pilocarpine and isopilocarpine; ephedrine and pseudoephedrine; emetine

and isoemetine.
b Ephedrine and nor ephedrine; nicotine and nor nicotine which means less N-
methyl group.
c Apomorphine and morphine; apoatropine and atropine which is one molecule of
water less.

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 Some amino acids as precursors of some alkaloids (contn.)

---------------------------------------------------------------------------------------------------------------------------
Amino acids Derived alkaloid group Representative alkaloids
--------------------------------------------------------------------------------------------------------------------------

Ergot alkaloids (ergotamine,

ergometrine, etc)
Catharanthus alkaloids (vincristine
and vinblastine), physostigmine ,
Rauwolfia alkaloids (rescrpine, etc.)
and strychnine.

Cinchcna alkaloids, e.g. quinine,

quinidine, etc.

7. Many alkaloids in quantities as small as l - lO µg in neutral-acidic solutions form

precipitates with certain alkaloid-precipitating reagents. Accordingly, such reagents, e.g.
Wagner's reagent (iodine-potassium iodide), Mayer's reagent (potassium mercuric iodide),
and Dragendorff's reagent (potassium iodobismuthate), are frequently used in testing the
absence (if negative response) or probable presence (if positive response) of alkaloids in
plant materials. Silicotungstic acid, tannic acid, picric acid and ammonium reineckate
reagentsare also considered as alkaloid-precipitating reagents.

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 Function of alkaloids in the plants

Much has been written about the possible function of alkaloids in the plants or the reasons
why they occur there. These approaches may be summarized as follows, although none
of which is wholly convincing:

1. Alkaloids in plants may be considered as poisonous agents protecting the plant against
insects and herbivores.
2. Alkaloids may function as end- products of detoxification reactions representing a
metabolic locking-up of compounds otherwise harmful to the plant.

3. They may act as regulatory growth factors.

4. They may serve as reserve substances capable of supply ing nitrogen to the plant when
necessary.

Spatial considerations and pharmacological activity

Most alkaloids must bind or interact with receptor sites and reactive sites of enzymes,
which have very characteristic and specific topography (surface structural features). Thus,
knowledge of molecular dimensions and interatomic distances as well as steric requirements
becomes important in understanding drug activity and in rationally designing new agents.

Molecular dimensions and interatomic distances

It is now widely accepted that the receptors that interact with drugs to produce a drug
action are mostly protein in nature. Thus, the distance between consecutive helical turns
down the polypeptide chain (5.4-5.5 Å) and the distance between consecutive peptide bonds
(3.6 Å) assume potential significance in the mechanism of drug.

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Stereochemistry:
Optical isomerism:
Optical isomers are frequently referred to as enantiomorphs or enantiomers. A racemic
modification, or a racemate, is a mixture of equal parts of enantiomers ( + and -) and is
therefore optically inactive. If a 3 - point attachment to the receptor is assumed, it can be
seen that only one enantiomer has the necessary configuration to bind all three groups to the
complementary areas) the receptor surface. Thus, the receptor site can distinguish between
the 2 isomers.

A molecule with two chiral centers can exist as four stereoisomers, that is, as two different
racemates. Such ensntiomers are referred to as diastereoisomers, which are
illustrated by the drug ephedrine.

D(-) Pseudoephedrine L(+) Pseudoephedrine

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 Since some type of binding of drugs to receptors occur, these 4 isomers do not have
equal activity quantitatively and even qualitatively with respect to pressor activity
(blood pressure elevating effect).

Pressor potency of the ephedrines

Isomer Relative activity
D-(-)-Pseudoephedrine 1
L-(+)-Pseudoephedrine 7
L-(+)-Ephedrine 11
D-(-)-Ephedrine 36

Clinically, D-(-)·ephedrine is used mainly as an antiasthmatic, whereas L-(+)-

pseudoephedrine is most widely used as a vasoconstrictor, thus indicating some qualitative
differences as well.
It is believed that "Differences in bioactivity of enantiomers is caused by one optical
isomer fitting the receptor surface much better than the other(s) or even that one isomer not
fitting the receptor at all .

Other examples include:

Drug Isomer Characteristic Relative activity

Hyoscyamine (-) Mydriatic l5-2O

(+) Mydriatic 1

Muscarine (+) Cholinergic 700

(-) Cholinergic 1

Quinidine (+) Cardiac depressant More active than

quinine.

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Quinine (-) Cardiac depressant Less active than
quinindine.

lt should be pointed out that (-) and (+) - cocaine are equipotent as a local anesthetic. A
possible explanation is that "no asymmetrical centers are involved in the drug – receptor
interaction, or that such interaction involves only one or two points of contact and not three .

Geometrical isomerism:
In the case of geometrical isomerism of the cis - trans type, the relationship is relatively
simple to understand.

In this figure:-

Geometrical isomerism

If it is assumed that both functional groups A and B must interact with their respective
complementary sites on the receptor to elicit a drug response, it is clear that only the cis
isomer can fulfill that requirement. The distance between B and B' in the trans isomer is too
far to interact.

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 Extraction and Isolation of Alkaloids

In alkaloid-bearing plant materials, the alkaloids constitute only a small percentage,

ranging from about 0.005 per cent (e.g. vinblastine in Catharanthus roseus) up to about 10
per cent (e.g. morphine in opium). In the extraction and isolation of the alkaloids from the
plant materials, there is first the problem of separating the alkaloids from the bulk of the non-
alkaloidal materials, and the problem of separation of the individual alkaloids from a mixture
of alkaloids. The procedures most commonly employed for the extraction of total alkaloids
from plant materials may be grouped into two main methods:

1. Procedures using water-immiscible organic solvent for the initial extraction.

2. Procedures using aqueous or alcoholic solvent for the initial extraction.

In both of the two methods, the plant material needs to be reduced to a moderately coarse
powder and fats or oils (if present) should be removed by preliminary extraction with light
petroleum, before any extraction is begun.

Method 1:
a) The powdered plant material is moistened with 10% ammonia or sodium carbonate
solution, and then macerated for about one hour with a suitable organic solvent (usually
ether or chloroform).

b) The mixture is then transferred to a continuous extraction apparatus and continuously

extracted with the solvent till complete extraction of alkaloids has been affected. To check
this, the last one-ml aliquot of the extract is evaporated, the residue is dissolved in 2 drops of
1 %HCl and then adding two drops of the suitable alkaloidal reagent.

c) The obtained extract is then extracted in a separatory funnel with several successive
quantities of a suitable acid solution (mineral or organic). The first quantity of the acid
solution usually extract 90% or more of the alkaloids as salts from the organic solvent into the

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aqueous acid. Thus, to obtain as close to l00% extraction as possible, 3 or 4 additional
quantities of acid solution must be used again, an aliquot of the last quantity of the acid
extract should display a negative alkaloidal test.

d) Traces of resins, coloring matter

and other non - alkaloidal impurities,
if present, may be removed from the
combined acid extract by shaking,
in a separatory funnel, with one or
two quantities of the organic solvent
used.

e) The purified aqueous acidic solution

in the separatory funnel is rendered distinctly alkaline
(test with litmus) with l0% ammonia and the liberated
alkaloid bases are extracted with several successive
quantities of the organic solvent. The combined organic
solvent extract is dehydrated by shaking it in a stoppered
flask with a suitable quantity of anhydrous sodium sulphate
(1 - 2 g for every about 70 ml of chloroform extract or
50 ml of ether extract) for about half an hour. It is
then filtered and freed from the solvent by distillation
under reduced pressure. This leaves a residue consisting
of a mixture of the alkaloidal constituents of the plant
material.

Method 2:
a) The powdered plant material is shaken with alcohol on a
mechanical shaker for several hours, and filtered.

b) The obtained extract, containing alkaloids and non-alkaloidal

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organic matter, is concentrated to a small volume. The
concentrated extract is then acidified and the alcohol
removed by distillation under reduced pressure, leaving
the aqueous acidic solution containing the alkaloid salts.

c) The obtained aqueous acidic solution is then allowed to stand in a cool place for 2 or 3
days to allow separation of resin material, then filtered.

d) The filtrate may now be treated as in steps d and e of Method 1.

Apart from the above two methods, volatile liquid alkaloids (e.g. nicotine and coniine) are
most conveniently isolated by subjecting an alkaline aqueous extract of the plant material to
steam distillation. Quaternary ammonium alkaloids are usually isolated by the ammonium
reineckate method.

Separation of an individual alkaloid from a mixture:

This is based on its physical and chemical characteristics such as its solubility in different
solvents, its pKb value, degree of ease of crystallization from different solvents, etc. In a
laboratory scale, all techniques of chromatography are quite satisfactory.

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 Classification of Alkaloids

According to the basic chemical constitution of the medicinally useful alkaloids, they are
grouped under the following classes:
l. Pyridine and piperidine alkaloids
2. Alkaloidal amines
3. Tropano alkaloids
4. Quinoline alkaloids
5. Isoquinoline alkaloids
6. lndole alkaloids
7. Steroidal alkaloids
8. lmidazole alkaloids
9. Purine alkaloids.

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 1. Pyridine and Piperidine Alkaloids

Among the alkaloids of pharmacological or therapeutic interest which contain a pyridine

ring or a reduced derivative of pyridine in the molecule are the alkaloids of Nicotiana species
and Lobelia inflata.

1.1. Nicotiana Alkaloids

Several plants belonging to genus Nicotiana , family Solanaceae, are reported to contain
nicotine as the main alkaloid in addition to nornicotine, anabasine, nicoteine, etc as minor
alkaloids (e.g. N. tabacum and N. rustica, the well known tobacco plants). In few species,
nornicotine occurs as the main alkaloid (e.g. N. glutinosa). In N. glauca anabasine occurs as
the main alkaloid.

H H
N N

CH3 H
N N

L- Nicotine L- Nornicotine

H
H
N
N
N H
N CH3

L-Anabasine Nicoteine

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Site of formation:
Nicotine is biosynthesized by the root. When shoots (scion) of tomato plant were grafted
onto the root stock of N. tabacum , the tomato shoots were found to contain nicotine.
On the other hand, very little nicotine was present in N. tabacum shoots which were grown
on tomato roots.
Isolation of nicotine:
Crude nicotine is obtained commercially by treating the leaves of tobacco (N. tabacum
and N. rustica) with an aqueous solution of sodium hydroxide and subsequent distillation with
steam.
Physical and_chemical characters of nicotine:
Nicotine, 3'-pyridyl-2-N-methyl-pyrrolidine, is a colorless liquid, b.p. 247°C , [α] 20D – 169°
and becomes discolored in the air. lt can be distilled with steam. It is miscible in all
proportions with water below 60 and above 2lO°C, but it is less miscible between these
temperatures. Nicotine functions as a monoacidic base when titrated with aqueous acids in
the presence of various indicators. On oxidation with potassium permanganate or hydrogen
peroxide it yields nicotinic acid.

Action and uses of nicotine:

Nicotine acts on the sympathetic and parasympathetic ganglia, producing transient
stimulation followed by persistent depression leading to paralysis. It is very toxic and
small quantities proved to be fatal in a few seconds. Nicotine is prepared commercially from
waste material of the tobacco industry and has long been used as an effective insecticide.

Biosynthesis of nicotine:

1. The particination_of nicotinic acid in the formation of the pyridine ring:

This has been disclosed by Dawson in l948. In his experiments H- and 14C-nicotinic acid
3

was administered to N. tabacum shoots. Nicotine was isolated and the isotopes were shown
to be incorporated in the molecule.

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2. The paricipation of glyceraldehvde and aspartic acid in the formation of nicotinic
acid:
This has been indicated by Leete and his coworkers by 1963-1965. In their experiments,
acetate - 2 - l4C and glycerol- 2- 14C were administered to N. glauca plant. Anabasine was
isolated and by permanganate oxidation, nicotinic acid was obtained. The individual carbon
atoms of the molecule were studied. It was revealed that C numbers 4, 5 and 6 were derived
from glycerol or a metabolically related compound ( e.g.glyceraldehyde – 3 - phosphate).
The Leete's postulated biogenetic scheme for nicotinic acid formation in Nicotiana plants is
illustrated as follows.

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3. The participation of ornithine in the formation of the pyrrolidine ring:
This has been dieclosed by Byerrum and coworkers l955—l959 as well as by Leete l958-
l964. Feeding ornithine – 2 - l4C to tobacco plant gave rise to nicotine which contained l4C
label in the α -atom of its pyrrolidine ring.

1.2. Lobelia Alkaloids

Lobelia or Indian tobacco consists of the dried leaves and tops of Lobelia inflata , family
Campanuleceae. The plant is an annual herb indigenous to USA and Canada. The drug
contains l4 alkaloids (O.l3-0.64 %) of which lobeline is the major. Other alkaloids include
lobelanine and lobelanidine.
O O O

C6H5 C CH2 CH2 CH C6H5 C6H5 C CH2 CH2 C C6H5

N N
OH
CH3 CH3
Lobeline Lobelanine

C6H5 C CH2 CH2 CH C6H5

N
OH OH
CH3

Lobelanidine

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 Lobeline is optically active, monoacidic tertiary base and forms a crystalline benzoyl
derivative (one free OH). On reduction (sodium amalgum/acetic acid), lobeline yields
lobelanidine.
Lobelanine is optically inactive and does not form benzoyl derivative (no OH). On
reduction (4 H), it is converted to lobelanidine.
Lobelanidine forms a dibenzoyl derivative (2 OH).

Action and uses:

Galenical preparations of lobelia are used for their expectorant properties. Lobeline is a
respiratory stimulant. Other effects resemble those of nicotine. For this reason, O.5—l.5 mg
doses of lobeline in lozenges or tablets are used to aid in breaking the tobacco habit.

l.3. Alkaloids of Areca Nut

Areca nut is the dried ripe seed of Areca catechu , family Palmae. The plant is a beautiful
tall palm extensively cultivated in India, Southeast Asia, East Africa, etc. Large quantities
have been consumed in the East from very early times in the form of a masticatory known as
betel, which consists of a mixture of areca nuts, the leaves of Piper betle, and lime. The lime
hastens the absorption by keeping arecoline in the form of the free base.

The drug contains several alkaloids which are reduced pyridine derivatives (O.35-0.45 %),
of which the principal ones are arecoline and arecaidine.

COOR2

R1

R1 R2
Arecoline CH3 CH3
Arecaidine CH3 H

Both are oily liquids, volatile with steam and miscible with water.
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Action and uses:
Arecoline has parasympathomimetic effects. The alksloid is used as an anthelmintic for
animals for treatment of tape worm or round worm infestation.

l.4. Alkaloids of Pomegranate

The stem and root barks of Punica granatum , family Punicaceae contain four alkaloids,
the principal one being pelletierine ( - 2 - piperidyl propionsldehyde). The three minor
alkaloids are isopelletierine, methylpelletierine and pseudopelletierine.

Pelletierine is a colorless liquid used as taenifuge and vermifuge.

CH2 CH2 CHO CH2 C CH3

N N

H H

Pelletierine Isopelletierine

N-CH3 O
CH2 CH2 CHO
N

CH3

Methylpelletierine Pseudopelletierine

l. 5. Other pyridine—piperidine alkaloids

Conium Alkaloids
The hemlock fruits (Conium maculatum) family Umbelliferae contains several Piperidine
alkaloids. Coniine and g-coniceine which are the major alkaloids.

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 OH

CH2 CH2 CH3 CH2 CH2 CH3 C CH2 CH3

N N N

H H

Coniine Coniceine Conhydrine

Coniine is a colorless steam volatile liquid with a mice-like odor,a sharp burning taste. and
strong basic properties. On exposure to air, it darkens in color.

Uses

Coniine salts are used externally as an ointment for treatment of purities hemorrhoids and
anal fissures, due to their local analgesic action.

Piperine

O R
Piperine R=H
N Chavicine R = OMe
O

Is a crystalline alkaloid in white and black pepper in up to 6-9%.The solid is tasteless but
its alcohol solution has a sharp taste.
2. Alkaloidal Amines

Among the medicinally useful alkaloids in which the nitrogen atom is not in a heterocyclic
ring are the alkaloids of Ephedra species and Colchicum species.

2. 1. Alkaloids of Ephedra
Several Ephedra species, family Ephedraceae, are reported to contain several alkaloids.
Among these alkaloids are D - (-)-ephedrine and L - (+) - pseudoephedrine (also known as
(+) – Ψ- ephedrine). These two medicinally important alkaloids are new produced by
chemical synthesis.

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 OH
*CH CH
* CH3 CH CH CH3
OH NH CH3 NH CH3

D-(-)- Ephedrine L-(+)-Pseudoephedrine

L-(+) - Ephedrine and D - (-) – Ψ - ephedrine have been made synthetically but have not
been found to occur in these plants.

Extraction:
The famous Chinese drug "Ma Huang", Ephedra sinica , a leafless low - growing shrub
with slender stem indigenous to China and Pakistan, contains 1 – 3 % of ephedrine.
Ephedrine and pseudoephedrine may be extracted from the plant material by general
procedures for alkaloid extraction, through successive benzene and dilute HCl extractions.
Ephedrine may be separated from pseudoephedrine by means of their oxalates; ephedrine
oxalate being much less soluble in cold water than pseudoephedrine oxalate. It should be
pointed out that chloroform is not a suitable solvent for the extraction of these alkaloids as
ephedrine in chloroform solution on evaporation yields ephedrine hydrochloride and oxidation
products (aldehydes).

Characters:
Ephedrine occurs as a low-melting solid (m.p. 38°C), [α] tD - 41° – 43°, steam volatile,
soluble in water, alcohol, ether, chloroform and oils. Its solution in water is strongly alkaline to
litmus paper. It gives no ppt with Mayer's reagent.

Pharmacological action and uses:

Ephedrine and (+)-pseudoephedrine exert sympathomimetic actions similar to
epinephrine. Unlike epinephrine, they are active orally. Their effect is indirect, being through
the action of endogenous epinephrine and norepinephrine present in the organism. Two
separate mechanisms are present:

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 HO OH

HO CH CH2

NH CH3

Epinephrine (Adrenaline)

1. Liberation of norepinephrine from storage sites (during the uptake process).

2. lntensification and prolongation of the effect of amines that are already acting.
Salts of ephedrine are widely used in symptomatic relief of asthma as bronchodilator. (+) -
Pseudoephedrine is used for the relief of nasal congestion.
Related Alkaloid
2.1. Cathe Alkaloids

OH O

CH CH CH3 C CH CH3

NH2 NH2

Cathine (d-Nor-y-ephedrine) Cathinone

Catha edulis family Celastraceae, (local vernacular name "Kat") contains the major
alkaloidal principle cathine; associated with other alkaloids, cathinone, cathidine and
cathinine. These are all primary alkaloids; having primary amino group. Cathine (d-Nor-
pseudoephedrine).

Cathine and cathinone are considered as the probable principal CNS stimulant
constituents of the plant. The fresh plant especially the leaves and twigs are the abused
organs.

Uses

Cathine has CNS stimulating effect; so, the alkaloids, as well as the plant are being used
(or even abused) for the same effect. The leaves are chewed habitually by many people in
East Africa and Yemen as a social habit, and to alleviate the sensation of fatigue.

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 2. 2. Alkaloids of Colchicum

The corm and seed of Colchicum autumnale (Liliaceae) and other species of Colchicum
contain a number of alkaloidal amines, mainly colchicine (0.05-0.6%).

Properties and reactions:

Colchicine contains a tropolone part in ring C of its molecule. Of the four methoxyl groups
in the colchicine molecule, the one at C - l0 is much more easily hydrolyzed than the other
three attached to the aromatic ring A.

Trimethycolchicinic acid

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 Colchicine is a very weak base (pKa l.7); it is neutral to litmus. lt may be extracted from
both acid and alkaline solutions by shaking with chloroform. It is soluble in H 2O, aqueous
alcohol, chloroform, but insoluble in ether or petroleum ether. lts optical activity ( [α] 20D - 425°
to - 450°) is due to the asymmetry of C-7.

Mild hydrolysis of colchicine by aqueous HCl or dilute alkali yields colchiceine. Vigorous
hydrolysis with HCl at 150 °C for six hours yields trimethyleolchicinic acid.

With ferric chloride solution, colchicine gives red colour while colchiceine, being phenolic,
gives a green colour.

Pharmacological action and uses:

Colchicum preparations have been used in gout but must be employed with caution.
Colchicine, administered orally or intravenously, can dramatically relieve pain and brings
about a decrease in the inflammatory changes of gout in 12 - 24 hours. Yet, it does not alter
the metabolism or excretion of ureates and has no generalized analgesic or anti-inflamma-
tory action. For acute episodes 1 mg initially followed by 0.5 mg every 2 hours until relief of
pain is obtained , or gastrointestinal symptoms make its further use undesirable; the total
amount given during a course of treatment should not exceed lO mg. The course should not
be repeated within three days.
Colchiceine is ineffective in gout but has been used in leukemia.
Demecolcine:
N - Desacetyl-N - methylcolchicine is a basic alkaloid occurring naturally in many species
of Colchicum , Gloriosa and Merendera , family Liliaceae. While colchicine itself has not
proved of reliable value in the treatment of cancer, demecolcine is active against chronic
myelocytic leukemia.

Demecolcine

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 3. Tropane Alkaloids

The medicinally useful tropane alkaloids are grouped into those occurring in a number of
genera of the Solanaceae family and those occurring in certain Erythroxylum species,
family Erythroxylaceae.

3. 1. Tropane Alkaloids of Solanaceae

Species of the genera Atropa, Datura, Hyoscyamus, Duboisia and Scopolia produce in
varying quantities several tropane alkaloids namely hyoscyamine, scopolamine (also known
as hyoscine), meteloidine, ditiglylteloidine, apoatropine, belladonine,etc. Of these,
hyoscyamine and scopolamine are of considerable interest as they occur in these species in
greater quantities than the other alkaloids and also as they are pharmacologically important
drugs.. s
Certain species (e.g. D tramonium, D. tatula, Atrona belladonna, A. acuminata , H .
muticus and H. niger ) always accumulate a greater proportion of hyoscyamine than
hyoscine. Other species (e.g. D. metel, D. ferox and D. innoxia) accumulate more hyoscine
than hyoscyamine.

Structure and properties:

Tropane alkaloids of family Solanaceae are all esters of organic acids such as tropic,
atropic, tiglic acids, combined with one of a series of tropane alcohols (an amino alcohol as a
base) such as tropan -3-ol (tropine), scopine, scopoline (also known as oscine), teloidine,
etc. Tropane, the parent base of the alkaloids, consists of seven membered bicyclic ring with
a nitrogenous bridge between C1 & C5.
Me

N
1 2
5
4 3 H
6 7
H

Tropane nucleus

(28)
(29)
 Important Alcohols
8 R-N
1 2 R-N 7
7 1 2
H H
8 N-R 3 O N-R 3
5 3 H
4 3 H OR1 O
OR1 7
7 6 6
6
6 5 4
OR1 H H OR1

Tropine R=CH3, R1=H Scopine R=CH3, R1+H

Important Acids
COOH COOH

C CH2OH C COOH
CH2OH
H H

(-) - Tropic acid (+) - Tropic acid Atropic acid

Important Alkaloids

Me

N
O

H
H
O OH

O
Atropine (dl (±) hyoscyamine) l (-)- Hyoscine (Scopolamine)

Hyoscyamine and scopolamine are both laevorotatory. Atropine (the racemic form of
hyoscyamine) and atroscine (the racemic form of scopolamine) normally do not occur in
the plants in more than trace quantities, if at all. But racemization often occurs during
extraction. Racemization of ( - ) - hyoscyamine and ( - ) - scopolsmine to atropine and
atroscine may be induced by addition of a small quantity of NaOH, Na 2CO3 or NH3 to their
cold alcoholic solution or by heating their chloroform solution.

(30)
 Hyoscyamine or atropine hydrolyzes by heating with acids or alkalis to tropine and tropic
acid. Scopolamine if similarly treated yields scopoline and tropic acid. Meanwhile,
scopolamine hydrolyzes slowly by pancreatic lipase (in ammonia - ammonium chloride
buffer) to scopine and tropie acid. Scopine is converted by acid or base to scopoline.

Structure - Activity Relationship, Action and Uses:

The circled portion can be interpreted as resembling acetylcholine (ACh). The distance
from the nitrogen atom to the carbonyl oxygen of the ester portion of atropine can, in the
proper conformation, approach that of ACh and thus bind to and block the muscarinic
receptors of ACh.

lf the circled segment of atropine is cut out, the so-called spasmophoric portion of the
atropine molecule is obtained (I). For easier comparison, the structure II is considered as the
spasmophoric prototype compound, and this was s starting point for designing clinically
effective anticholinergic drugs.

Structure II represents ACh if Y and X represent CH3 groups. The spasmophoric

cholinergic blocking egent differs primarily by having Y replaced by s large bulky group. Thus
the drug is similar enough to bind to the cholinergic receptors but not as comfortable as ACh;
therefore it does not elicit the response ordinarily obtained with ACh.

(31)
 Hyoscyamine, atropine and scopolamine are parasympatholytic or cholinergic - blocking
in action. Consequently, they relax bronchial and intestinal smooth muscles (antispasmodic),
inhibit contraction of the iris muscles of the eye (mydriatic), and decrease salivary and sweat
gland secretions. Scopolamine displays a sedative effect on the C.N.S.

Related synthetic drug:

Homatropine is a common synthetic substitute for atropine. lt is prepared from tropine and
mandelic acid.

Homatropine (Mandelyltropine)

3. 2. Tronane Alkaloids of Erythroxvlum

The leaves of Erythroxylum coca and E. truxillense, which are tropical (Peru and Bolivia)
trees of family Erythroxylaceae, contain about O.2 – 1 % alkaloids, 50-90 % of which is
cocaine.
Similar to the tropane alkaloids of Solanaceae, tropane alkaloids of Ervthroxylum are
esters also. The organic acids involved include benzoic acid, cinnamic acid and α - truxillic
acid. The principal tropane alcohol involved is ecgonine.
Me

N H
COOH

OH

H
Ecgonine

(32)
 Me
N H
COOMe

H O
Cocaine
Pharmacological action and uses:
Cocaine has the ability to block nerve conduction upon local application (local anaesthetic
action). The alkaloid is very toxic in its several other side actions and there is also the danger
of drug dependence development.

For local anaesthetic purposes, a number of synthetic drugs are now generally preferred.
(e.g. benzocaine, procaine, cinchocaine, lignocsine, etc.).

(33)
 4. Alkaloids of the Quinoline Group

The medicinally useful alkaloids of the quinoline group include the cinchona bark
alkaloids. Several alkaloids have been isolated from Cinchona succirubra, C. ledgeriana,
C. calisaya and C. officinalis, and of various hybrids of these species, family Rubiaceae.
However, among these alkaloids quinine, quinidine, cinchonidine and cinchonine are the
alkaloids of practical importance. The average content of these alkaloids in the above
mentioned drugs are: 5 - 7% quinine, 0.1 - 0.3% quinidine, 0.2 - 0.4% cinchonidine and
0.2 - 0.4% cinchonine.

Properties:
The four alkaloids are diacidic bases, forming with HCl or H 2SO4 acids, neutral and acidic
salts. Some of the physical data for the four alkaloids are presented in the following table:

Physical properties of cinchona alkaloids

--------------------------------------------------------------------------------------------------------------------------
Quinine Quinidine Cinchonine Cinchonidine
-------------------------------------------------------------------------------------------------------------------------
m.p. (°C) 177 175 265 210
[α]tD -169 +258 +229 -109
Fluorescence Strong Strong none none
in dil H2 SO4 blue blue

Structures:
The parent structure, ruban, of these alkaloids contains a quinoline ring attached through
a methylene group to a di-cyclic, nitrogen containing ring system "quinuclidine".
Quinine and quinidine are isomers and have the structure of 6 - methoxy-3-vinylruban -9-ol
. Cinchonine and cinchonidine are also isomers and have the structure of 3-vinylruban-9 -ol.

(34)
 Quinine & Quinidine R = OCH3 Ruban
Cinchonine & Cinchonidine R = H

Action and uses:

For 300 years, quinine was the drug of choice for the treatment of malaria. By 1959, it had
been totally superseded by synthetic antimalarials (e.g. chloroquine). However, 3 years later,
chloroquine - resistant strains of Plasmodium falciparum were reported from Colombia and
Brazil, and later from Southeast Asia. By l965, 80% of U.S. servicemen treated in Vietnam for
malaria with chloroquine showed a persisting parasitemia that could only be brought under
control with intravenous quinine. To prevent relapses, quinine therapy was combined with
use of pyrimethamine and sulfadiazine; these 3 drugs must be administered concurrently.

(35)
 Quinidine is used for cardiac arrhythmia and atrial fibrillation.

The mechanism of action of quinine is uncertain. Quinine has been observed to depress
so many enzyme systems that it has in the past been described as a "general proto-
plasmic poison".

Quinidine is a depressant of skeletal as well as cardiac muscle. Its cardiac actions include
the ability to increase the electrical potential necessary for excitation, which may explain why
the drug can abolish the generation of ectopic impulses.

(36)
 5. Isoquinoline Alkaloids

Among the alkaloids of pharmacological or therapeutic interest which belong to the

isoquinoline group are the alkaloids of Opium, Ipecacuanha and Curare.

5. 1. Alkaloids of Opium

Opium is the dried latex obtained by incising the unripe capsule of Papaver somniferum ,
family Papaveraceae. In 1806 the German pharmacist Friedrich Serturner (1783 – 1841)
isolated morphine from opium, and demonstrated for the first time that a single chemical
substance could account for the pharmacologic effects of a natural drug. Since that time,
some 25 alkaloids have been isolated from opium.

The alkaloids of opium are largely combined with meconic acid. Thus a positive test for
the presence of meconic acid indicates the probable presence of opium in a sample. With
ferric chloride, meconic acid gives a purplish red color not destroyed by dilute HCl (distinction
from formats and acetates).

OH

HOOC COOH
O

Meconic acid

Morphine

The chief opium alkaloids are classified into 2 main groups:

A. The phenanthrene group: Strong bases and highly toxic.

B. The benzylisoquinoline group: Weak bases and slightly toxic.

A. The phenanthrene opium alkaloids:

Morphine, codeine and thebaine are the major alkaloids of this group.
(37)
 Morphine Codeine Thebaine

They occur in opium to the extent of 8 – 15 % for morphine, 0.8 – 2.5 % for codeine and
0.1 – 1.0 % for thebaine. As the poppy capsule ripen, the morphine content decreases.

Morphine contains two hydroxyl groups, of which the 3 – OH is phenolic and the 6 – OH is
a secondary alcoholic group. It contains also 4, 5 – oxygen bridge and N – methyl piperidine
ring forming with ring C a reduced isoquinoline system.

Morphine molecule contains five chiral centers at the positions 5, 6, 9, 13 and 14. X-Ray
analysis and degradation of thebaine revealed that the hydrogens at C – 5, C – 6 and C – 14
are all cis, and the bridge at C – 9 and C – 13 is also cis.

Unlike other alkaloids, morphine is sparingly soluble in chloroform, and nearly insoluble in
ether or benzene. It is laevorotatory and behave as monoacidic base. When morphine or its
hydrochloride is heated at 140°C under pressure (in a sealed tube) with HCl, apomorphine is
formed.

Apomorphine

(38)
 Codeine is the methyl ether of morphine. Thus, it is no longer phenolic in chatacters. It is
soluble in water, It is monoacidic base. On treatment with HCl under heat and pressure,
codeine also yields apomorphine accompanied by other products.

Thebaine is the dehydro, dimethyl ethers of morphine.

B- The benzyl isoquinoline opium alkaloids:

C22 H23 NO7 413.4

O O
Me
NMe N
O O Me
H
MeO MeO
C=O
H
COOH
O
MeO OMe
MeO O
OMe
Noscapine (Narcotine) Narceine

The major alkaloids in this group are papaverine (0.5 – 1.5 % in opium), noscapine (4 – 8
%), and narceine (0.1 – 0.7 %). They are weal tertiary bases.
Noscapine was formerly known as narcotine (it has no narcotic action). It contains a
lactone system, thus it dissolves in hot alkali.
Narceine contains a free COOH group, thus it dissolves readily in ammonia and in cold
solutions of alkali hydroxides. In addition, it can form phenylhydrazone and oxime derivatives
(due to the presence of free C= O group).

(39)
Separation of the major alkaloids from opium

(40)
Structure - activity relationship of the narcotic opium alkaloids and
opiates:
Opposed to the valuable analgesic properties of morphine are inherent deficiencies
which may be summarized as follows:

a) Addiction potentiality.
b) Emetic actions.
c) Tendency to induce circulatory and respiratory depression.
d) Inconvenient gastrointestinal disturbances.

Codeine is produced commercially by methylation of the phenolic OH in morphine. This

relatively minor structural modification results in a marked lowering of analgesic
potency as well as dependence liability, observations that have served as a stimulus for
the numerous attempts at modification of the morphine molecule aiming at abolishing or
reducing dependence potential and respiratory-depressant action while retaining
analgesic activity.
The cumulative results of these efforts permitted certain general conclusions to be drawn:

l. When the phenolic OH in morphine or any related derivative is etherified or esterified, a

decrease in morphine-like activity is usually observed (heroin excepted).

2. If the alcoholic OH is muzzled, or oxidized to a keto - function, or replaced by

halogen or hydrogen, an increase in morphine – like effect as well as in toxicity is
noted.

3. Cleavage of the 4, 5 - oxygen bridge and substitution in the aromatic ring lower
activity, and saturation of the 6 - 7, or 7 - 8 double bonds may lead to some
improvement in activity.

4. Substitution of other groups for methyl in the nitrogen atom gave rise to a series of
compounds that were both analgesics and narcotic antagonists. (A narcotic antagorist

(41)
may be defined as an agent that will cancel or reverse most of the pharmacologic effects
of morphine-like substances including analgesia, euphoria and respiratory
depression).
5. On introducing an ethylenic bridge between positions 6 and 14 in an oripavine
molecule, and creating a new center at position 7 of the molecule, a number of very
interesting compounds known as derivatives of oripavine are produced. Some of these
compounds have analgesic potency ranging up to several thousands times that of
morphine.

To exemplify these general conclusions, the following important drugs are considered:

Levorphanol tartrate: (B. P. 1980)

lt is (-)-3-hydroxy-N – methyl - morphinan hydrogen tartrate.
It is a narcotic analgesic dose, 1.5 - 4.5 mg (dose of
morphine is 10-20mg).

Dextromethorphan hydrobromide: (B. P. 1980)

It is the hydrobromide of (+) -3-methoxy-N- methylmorphinan.
It is cough suppressant in 15-30 mg doses.

Levallorphan tartrate: (B. P. 1980)

It is ( - ) - N- allyl - 3-hydxymorphinan hydrogen tartate.
It is antagonist to narcotic analgesics in doses of 0.2-2.0 mg.

Nalorphine hydrobromide (B. P. 1980)

It is the hydrobromide of N-allyl - morphine. it is antagonist
To narcotic analgesics in dose of 5-10mg (I.V.), repeated to
a total dose not exceeding 40 mg.

(42)
Etorphine:
Etorphine is a typical example of derivatives of oripavine. It is used to control large wild
animals. An elephant or a rhinoceros is completely sedated and rendered immobile
by the injection of only 2 mg of etorphine,

Structural features essential for narcotic analgesia:

Studies of the chemical structures of the narcotic opium alkaloids and some examples of
synthetic narcotic analgesics disclosed the following structural features common to all :
1. A tertiary nitrogen, which becomes a cationic group in the biological media.
2. A short hydrocarbon chain held in a plane perpendicular to the page.
3. A flat aryl group held in the plane of the page.

(43)
The opiate receptors and mechanism of action :

Opiate receptors are widely distributed but are present in highest concentrations in areas
of the brain and spinal cord associated with the perception of pain.
A three point attachment to the opiate receptors takes place as follows: The nitrogen
cation attaches to an anionic site, the aromatic ring binds to a flat complementary area on the
receptor surface, and an aliphatic 2- C protrusion slides into a groove or cavity.

The opiates exert their effects after binding to receptor sites on the cell membrane of the
neuron, smooth muscle cell, or other effector. The binding is highly specific in that not only is
a specific molecular configuration required, but it must be the levo isomer.
The opiate agonist can be displaced from combination with the receptor by opiate
antagonists.

Action and uses:

Morphine exerts a depressant action on the C.N.S. it is used as a narcotic and analgesic
drug. Morphine and its derivatives are important addicting drugs.
Codeine is much weaker than morphine and is used as a cough supressant and weak
analgesic. Apomorphine is a very effective emetic. Papaverine relaxes smooth muscles by
direct action on them it has no narcotic or analgesic effects.

(44)
 5. 2. Alkaloids of Ipecacuanha

The drug consists of dried roots and rhizomes of Cephaelis ipecacuanha and C.
acuminata, family Rubiaceae. It contains 2 – 2.5 % total alkaloids of which emetine and
cephaeline are the majors. The minor alkaloids include psychotrine and psychotrine methyl
ether. The 4 alkaloids are closely related to one another, and emetine and psychotrine
methyl ether are non - phenolic, while cephaeline and psychotrine are phenolic.

Emetine R = CH3 Psychotrine R = H

Cephaline R = H O-Methyl psychotrine R = CH3

( e. g. Psychotrine methyl ether)

Emetine and cephaeline may be separated if present in an equeous solution by adding an

excess of NaOH solution; emetine is precipitated as the free base and can he obtained
either by filtration or by extraction with chloroform. Cephaeline being phenolic remains
dissolved in the alkaline solution as its sodium salt.
The International pharmacopoeia requires the drug to contain not less than 2 % of
alkaloids, at least 60 % of these must consist of non-phenolic alkaloids.

Uses:
Emetine hydrochloride is frequently given by injection in the treatment of amoebic dysentry.

(45)
 5. 3. Alkaloids of Curare
Curare is a crude dried aqueous extract from the bark and stems of some
Chondodendron (also spelled as Chondrodendron) species (family Menispermaceae)
together with some Strychnos species (family Loganiaceae). The drug had been used as an
arrow poison by certain tribes of the Amazon regions of South America. The drug produces a
paralyzing effect on voluntary muscles and a toxic action on blood vessels as well as a
histamine - like effect.

The drug contains several quaternary and non - quaternary alkaloids of which
(+) - tubocurarine is the only one of pharmacological and therapeutic importance.

Tubocurarine is a quaternary bis - benzyltetrahydroisoquinoline base. Like all quaternary

bases, it is soluble in water or alcohol and insoluble in ether or CHCl 3.

(-)- Curine is a companion alkaloid, differs from (+) tubocurarine in being 3ry alkaloid. It is
soluble in organic solvents, insoluble in cold water.

Action and uses:

lt is a neuromuscular blocking substance used to produce skeletal muscle relaxation during

anaesthesia.

(46)
 6. Alkaloids of the lndole group
The medicinally important alkaloids of the indole group include the alkaloids of Ergot,
Rauwolfia, Calabar Beans, Nux vomica and Catharanthus.

6. 1. Ergot Alkaloids
Ergot is the dried sclerotium (the resting stage) of the fungus Claviceps purpurea (family
Clavicipitaceae), growing as a parasite on the ovary of the rye ( ‫ ) شيلم‬Secale cereale (family
Gramineae). However, the ergot fungus is capable of growing as parasite on many other
members of the Gramineae family, such as barley, oats, wheat, etc.
Ergot contains 0.1 – 0.4 % (not less than 0.15 %) of total alkaloids. Six pairs of alkaloids
are known which fall into three groups:
a) The water - soluble or ergometrine group.
b) The ergotamine group.
c) The ergotoxine group.
The latter two groups (b and c) are water – insoluble one are often referred to as
peptide alkaloids.
Each pair contains a laevorotatory, pharmacologically active alkaloid and its
dextrorotatory isomer which is practically inactive pharmacologically. The active
members contain (+) - lysergic acid, while the inactive members contain (+) - isolysergic
acid.

(47)
a) Water - soluble alkaloids :
These constitute one pair of alkaloids : ergometrine and ergometrinine. Ergometrine,
the active member of this pair occurs as a white or faintly yellow odorless crystalline powder.
It is readily soluble in water. Ergometrine is also known as ergonovine or ergobasine. On
alkaline hydrolysis, ergometrine yields lysergic acid and (+) – 2 – aminopropanol.

(48)
b) and c) The peptide alkaloids:
These constitute five pairs of water – insoluble alkaloids:
(-) – Pharmacologically active (+) – Pharmacologically inactive
Ergotamine group Ergosine Ergosinine
Ergotamine Ergotaminine

Ergotoxine group: Ergocristine Ergocristinine

Ergocryptine Ergocryptinine
Ergocornine Ergocorninine

The Structures of these alkaloids may be demonstrated in general to be consisted of five

portions: the lysergyl (or isolysergyl) portion, the amide nitrogen linked to C-17 and the
three portions marked as a, b and c.

Hydrolysis studies by acids and alkali; showed that portion a is derived from pyruvic acid
in the ergotamine group, and from dimethylpyruvic acid in the ergotoxine group.
Portion b is derived from proline in both groups. Portion c is derived from leucine in
ergosine and ergocryptine, from phenvlalanine in ergotamine and ergocristine, and from
valine in ergocornine pairs.

(49)
 Consequently R1 and R2 as well as the products of hydrolysis other than (+) – lysergic acid
or (+) – isolysergic acid of the peptide alkaloids may be summarized as shown in the
following table :

(50)
Stability of ergot alkaloids:
Ergotamine on standing in alcoholic solution is slowly converted to its inactive (+)-isomer
ergotaminine. Generally speaking, the (-)- alkaloids are converted to their corresponding (+)-

(51)
isomers by boiling their solutions in ethanol or methanol or by the action of alcoholic alkali.
Ergometrine in solution shows mutarotation.

Under the influence of excessive exposure to light or U.V. light, ergot alkaloids in aqueous
acid solutions are converted to their corresponding lumi-alkaloids (e.g. lumi-ergotamine, etc.).
These lumi-alkaloids are yellow-brown in colour, and have an OH group at C - 10 and no
double bond at C-9 - C-l0.

Assay of ergot :
Ergot is assayed for its total alkaloidal content (not less than 0.15 %) one also for its
water-soluble alkaloidal content (not less than 0.01 %) by a colorimetric procedure involving
the use of Van Urk reagent. This reagent (p - dimethylaminobenzaldehyde in 66% sulphuric
acid containing traces of FeCl3) develops blue color with ergot alkaloids as well as lysergic
acid and its derivatives.

Pharmacological action and uses:

Ergometrine (usually as maleate) is a uterine stimulant. Because of its ready solubility in
water, this alkaloid has marked advantages over the other ergot alkaloids especially in its
ability to exert its oxytocic effect immediately after few minutes of administration.
Consequently, it is mainly used for preventing haemorrhage in child - birth as administered
after delivery of the placenta. Its derivative methylergometrine "Methergine" is used for the
same purpose.

Ergotamine also possesses oxytocic properties but it is not employed for that effect. It is
used in the treatment of migraine (by vasoconstriction of cerebral blood vessels).

Lysergide (lysergic acid diethylamide or LSD), which is not naturally occurring in ergot, is
a psychotomimetic agent used in study and treatment of some mental disorders. It is one of
the potent hallucinogens.

(52)
 6. 2. Alkaloids of Rauwolfia

The root of Rauwolfia serpentina, family Hypocynaceae, as well as various other

Rauwolfia species contain several alkaloids of which reserpine, deserpidine and
rescinnamine are the most important ones. Other alkaloids include ajmaline (the major
alkaloid), serpentine (yellow – colored quaternary base), etc.

Structures and properties:

The three most important medicinal alkaloids of Rauwolfia, reserpine, deserpidine and
rescinnamine are indole bases in which the indole nucleus is present in a β – carboline
ring. They are diesters.
In reserpine (trimethoxybenzoyl methyl reserpate), the methyl ester of reserpic acid
is linked through its OH at C - l8 by an ester linkage to trimethoxybehzoic acid.
Deserpidine (11 - desmethoxyreserpine) has the same structure as reserpine except in
that the OCH3 at C – 11in reserpine is replaced by an H in deserpidine.
ln rescinnamine (trimethoxycinnamoyl methyl reserpate) the methyl reserpate is
linked by an ester linkage to trimethoxycinnmmic acid.

Consequently, these diesters on alkaline hydrolysis yield the following:

Reserpine ----------→ reserpic acid + MeOH + trimethoxy benzoic acid.
Deserpidine --------→ deserpidic acid + MeOH + trimethoxy benzoic acid
Rescinnamine -----→ reserpic acid + MeOH + trimethoxy cinnamic acid.
The three alkaloids ere laevorotatory weak bases.

(53)
Pharmacological action and uses:

Rauwolfia and its alkaloids reserpine, deserpidine and rescinnamine are used as
tranquillizers and in the treatment of hypertension.

3. Alkaloids of Calabar Bean

Calabar bean or Ordeal seed consists of the seed of Physostigma venenosum

(Leguminosae). As a test of guilt, a suspect was made to drink a decoction of the beans. If
death resulted, the suspect was guilty. Perhaps if the decoction was drunk rapidly, because
the suspect was confident of being innocent, vomiting would occur promptly.
(54)
 The drug contains physostigmine (also known as eserine) to the extent of 0.15- 0.3 %
as the principal alkaloid.
Physostigmine is a monoacidic tertiary base, readily oxidized by oxygen in the presence
of KOH to a red compound rubreserine. On hydrolysis with KOH it yields eseroline,
methylamine and CO2 (derived from the carbamate side chain).

Physostigmine (Eserine) Eseroline

Pharmacological action and uses:

Physostigmine is a parasympathomimetic drug. It exerts its action by inhibition of
cholinestrase. Thus, it stimulates the organs innervated by cholinergic nerve fibers
producing miosis, increase the tone and peristalsis of the gastrointestinal tract, and
stimulation of secretions such as saliva, pancreatic juice and perspiration.
Eseroline which lacks the carbamate side chain, loses the above mentioned actions.
Therefore, it was concluded that the carbamate side chain is important for such physiological
activity.
Physostigmine (as its stable salicylate salt) is used as a cholinestrase inhibitor and as a
miotic.

Neostigmine bromide :

(55)
It is a synthetic drug containing a carbamate side chain and so carefully designed that the

distance between the C=O and the quaternary N equals the corresponding distance in
acetylcholine or physostigmine. It is used as cholinestrase inhibitor and in the treatment
of myasthenia gravis (unability of skeletal muscle to contract normally either due to
accumulation of curare – like drugs or excessive cholinestrase).

6.4. Nux Vomica Alkaloids

The leaf, bark and seed of some Strychnos species (Loganiaceae) are reported to contain
several alkaloids, mainly strychnine and brucine. The drug, however, consists of the dried
ripe seeds of Strychnos nux-vomica, that contains not less than 1.2 % of strychnine.
Strychnine and brucine are dihydroindole derivatives. They behave as monoacidic
bases. The two alkaloid bases can be separated from each other by 25% alcohol, which
dissolves brucine, leaving strychnine on insoluble residue.

N
R

R N

O O

Strychnine: R = H & Brucine (2,3 - dimethoxy strychnine): R = OCH3

Action and uses :
Strychnine stimulates all parts of the nervous system. It is rapidly absorbed from the
GIT and is slowly excreted, so that its action may be cumulative. Ito use as a therapeutic
agent has now been largely abandoned.

(56)
 Because of its bitter taste it has been used as a stomachic and tonic. The usual dose
by mouth is 2-8 mg (Nux vomica liquid extract contains 3 mg of strychnine in 0.2ml; or Nux
vomica tincture contains 2.5 mg of strychnine in 2 ml).
Toxic doses of strychnine produce convulsions of all voluntary (skeletal) muscles.
Death results from spasm of the respiratory muscles (fatal dose: 60-100 mg).

6. 5. Catharanthus Alkaloids
The indole alkaloids occurring in certain Gatharanthus and Vinca species (family
Apocynaceae) are generally referred to as the Vinca alkaloids.
From the tropical ornamental plant Catharanthus roseus (Vinca rosea or Lochnera rosea )
at least 60 alkaloids have new been isolated. Twenty of these alkaloids are
unsymmetrical dimeric alkaloids and having antineoplastic activity e.g. vinblastine
and vincristine. The other alkaloids are monomeric containing either in indole nucleus,
e.g. catharanthine or an indoline (dihydroindole) nucleus, e.g. vindoline which is the
major alkaloid of C. roseus.
N

N N

N H3COOC
H3COOC

*
N Catharanthine
N

H3CO N
HO
OCOCH3 *
COOCH3 H3CO N OCOCH3
Vincristine R = CHO R HO
COOCH3
CH3
Vinblastine R = CH3 Vindoline

Vinblastine is composed of the indole alkaloid catharanthine and the indoline alkaloid
vindoline. As vinblastine and vincristine occur in minute quantities in the plant (0.003%
and 0.0002%, respectively), large quantities of the plant materiel are required and

(57)
chromatographic fractionations are extensively employed in their isolation procedure.
Therefore, these alkaloids are very expensive.

Action and uses :

Vinblastine and vincristine are important cytotoxic agents used in the treatment of
neoplastic diseases.
Vinblastine is used for Hodgkin's disease (disorder of lymphoid tissue mainly in the
lymph nodes and spleen, but also in bone morrow. Cells of this tissue proliferate and the
affected nodes become enlarged. The patient may die of a chance of infection, or from
pressure on vital organs by enlarged lymph nodes).
Vincristine is used to treat leukaemia in children. These two alkaloids are considered,
in their mechanism of action, as antimitotic agents. They are administered by intravenous
injection up to 10mg weekly, in accordance with the body weight of the patient.

7. Alkaloids the Imidazole Group

Pilocarpus Alkaloids
The leaves of certain Pilocarpus species: (e.g. Pilocarpus jaborandi, P. pennatifolius, P.
microphyllus and P. racemosus) are reported to contain several alkaloids, mainly
pilocarpine(0.2 - 0.7%).

Pilocarpine & Isopilocarpine

Its stereoisomer isopilocarpine seems to constitute about one - third to one - half of the
quantity of pilocarpine. Both are water-soluble liquids and behave as monoacidic bases.
(58)
The lactone ring is opened by hot caustic alkali which forms K or Na salts with the
resulting acid. This opening of the lactone ring destroys the physiological activity of the
alkaloid.

Pharmacological action and uses :

Pilocarpine stimulates the organs innervated by post-ganglionic cholinergic fibres
to produce parasymoathomimetic effects. Thus, it possesses diaphoretic and myotic
actions and is used to reduce intra - ocular pressure in glaucoma.

8. Steroidal Alkaloids

The steroidal alkaloids of medicinal significance are found in Veratrum species , family
Liliaceae which contain the antihypertensive alkaloids protoveratrine A and protoveratrine
B: in the stem bark of Holarrhena antidysenterica, family Apocynaceae , which contains
the amoebicide alkaloid conessine : and in certain Solanum species , family Solanaceae
, which contain toxic steroidal glycoalkaloids e.e. solasonine .

Solasodine (N- analogue of Diosgenin) Diosgenin (O- analogue of solasodine)

Solasonine OH Glycosylated with----Galactose + Glucose + Rhamnose.

The alkaloidal aglycone solasodine has been investigated as potential intermediate in

corticosteroid synthesis.

9- Alkaloids of the Purine Group

(59)
 These occur principally as xanthine derivatives in :

a) Tea (prepared leaves of Thea sinensis ) which contains 1 - 5% caffeine , smaller

amounts of the theobromine.
b) Coffee (seeds of Coffea arabica ) which contains 1 - 1.3% caffeine.
c) Kola (seeds of Cola acuminata ) which contains 1 - 2.cacao5 % caffeine.
d) Cocoa (kernels of the fermented seeds of Theobroma cacao) which contains
theobrmine (0.9 – 3%) and caffeine (0.3%).

O R3
1
N
R1 N 7

O 3 N
N

R2

R1 R2 R3

Xanthine H H H

Caffeine CH3 CH3 CH3

Theophylline CH3 CH3 H

Theobromine H CH 3 CH3

Caffeine is 1, 3, 7 – trimethylxanthine. It is soluble in 60 parts of water and in 130 parts

of ethanol; it is freely soluble in chloroform. Caffeine sublimes at 180°C, and may be
extracted from tea by heating the broken leaves in a crucible covered with cold glass
plate.

Caffeine is stimulant for the C.N.S and less diuretic than theobromine.

(60)
 Theophylline is 1, 3 – dimethylxanthine. It is soluble in 120 parts of water and in 80
parts of ethanol; slightly soluble in chloroform; freely soluble in solutions of alkali hydroxides,
in ammonia and in mineral acids.

Theophylline is a powerful relaxant of involuntary (smooth) muscles.

Theobromine is 3, 7 - dimethylxanthine. It is very slightly soluble in water, in ethanol

and in chloroform; freely soluble in solutions of the alkali hydroxides and in dilute mineral
acids. Theobromine may be distinguished from caffeine by the fact that it sublimes at
220°C while caffeine sublime at 180°C; and theobromine is precipitated from dilute nitric
acid solution by silver nitrate.

Theobromine has a pronounced diuretic effect but no C.N.S stimulant effect.

(61)