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Phytochemistry and Plant Metabolism
Intermediary Metabolism:
enzyme-mediated and carefully regulated chemical reactions (Metabolic
Pathways)
Primary Metabolism:
Biochemistry Processes resulting in primary metabolites (carbohydrate, amino
acid,..)
Secondary Metabolism:
Natural Products chemistry resulting in secondary metabolites ( Flavonoids,
alkalaoids,…). Building clocks for 2ry metabolites are derived from 1ry
metabolites, namely, acetate, mevalonate and shikimate.
Alkaloids are:
Secondary Metabolites
Alkali-Like compounds…Difficult to be defined…But,
Generally known as
“All Organic Nitrogenous Compounds With a Limited
Distribution in Nature”… “have Physiological Activity”
Not homogenous group of compounds!
Found in plants, microorganisms.
Extracted from seeds, fruits, leave, roots and barks
• Non-peptidic, non-nucleosidic nitrogen containing
cpds usually derived from an amino acid.
• Found in plants, insects, amphibians, fungi,
sponges etc.
Bitter tasting, generally white solids (exception nicotine is a brown liquid).
Alkaloids are “secondary metabolites”, they are
not involved in primary metabolism.
• Most studied group of natural products
• Many have heterocyclic rings as a part of their
structure
• Many are basic (“alkaline”, due to an unshared pair
on N)
Discovery:
Narcotine first alkaloid discovery
Coniine first alkaloid to have its structure established
and synthesized
Paclitaxel revolution in alkaloid
Naming: (ends with ine)
From plant generic name (Atropine)
From specific plant yielding it (Cocaine)
From physiological activity (emetine)
From discoverer
Chemistry:
Alkaloids may contain one or more nitrogen atoms, as 1o, 2o,
3o & 4o.
Most of them contain oxygen
Found as free or nitrogen oxides
Degree of basicity depends on the structure
Converted to their salts when treated with H+, while when
treated with OH, they give up their free amine.
Properties:
Sparingly soluble in water… salts are freely soluble in water.
Free alkaloids are soluble in ether, chloroform and non-polar
solvent…important for isolation and purification
Crystalline to amorphous or liquid when lack Oxygen
Have bitter taste
Form double salts with heavy metals reagents (I, Hg),
Wagners, Mayer, and Dragendroff reactions
Functions:
Provide Nonspecific Basic compounds (N)
•Source for their associated acids
•End products
•Part of some metabolic sequences
•Defense
N.B.
Plants which accumulate alkaloids develop even
when deprived the alkaloid
Plants which do not produce alkaloid survive when
administered alkaloid
Tests:
• Alkaloids are precipitated when treated with neutral - slightly
acidic solution of Dragendroff, Mayer, Wagner reagents.
• Precipitates are amorphous to crystalline
• Proteins can give false positive rxn
• Caffeine gives false negative rxn, and can be detected by
potssium chlorate and HCl solution and exposing the dried
residue to NH3.
•
They give a precipitate with heavy metal
iodides.
–
–
–
Most alkaloids are precipitated from neutral or
slightly acidic solution by Mayer's reagent
(potassiomercuric iodide solution). Cream coloured
precipitate.
Dragendorff's reagent (solution of potassium
bismuth iodide) gives orange coloured precipitate
with alkaloids.
Caffeine, a purine derivative, does not precipitate
like most alkaloids.
Extraction:
• Powder is moistened and treated with lime, extracted with
organic solvent and back extracted with aqueous acid
OR
• Powder is extracted with water or acidified aq. alcohol,
organic acids remove the organic material and free alkaloids
are precipitated by adding Na-bicarbonate or NH3
Isolation of Alkaloids
• Process remained unchanged >1,000 years
Wash with petroleum ether
Plant Material
Petroleum ether extracts Residue: polar material
non-polar fats and waxes
1) Methanol
EtOAc: neutral/weakly
basic alkaloids
EtOAc: basic alkaloids
2) Concentrate
3) Partition EtOAc/2% acid
Acid solution
1) Ammonia
2) Partition with EtOAc
Basic aqueous solution
of quaternary alkaloids
Purification of Alkaloids
• Gradient pH as alkaloids are basic
• Volatile alkaloids: distillation
• Crystallisation
• Fractional or acid/base pair
• Chromatography
• HPLC, GC, TLC and CC
MORPHINE - A TYPICAL ALKALOID
basic due to the
unshared pair
contains nitrogen
..
N CH3
Plant source.
Most alkaloids
are found in
plants.
heterocyclic ring
MeO
O
OH
Found only in the Opium Poppy - papaver somniferum
….. not ubiquitous.
There are three main types of
alkaloids:
colchicine
Terpenoids or
purines
HOW ARE ALKALOIDS CLASSIFIED ?
Common classification schemes use either:
• The heterocyclic ring systems found as a
part of the compound’s structure.
- in terms of their BIOLOGICAL activity,
- BIOSYNTHETIC pathway (the way they are produced in the plant).
• The plant or plant family where they originate*
* The majority of alkaloids (>90%) are found in plants therefore, we will speak mostly about plants and their
biochemistry.
HETEROCYCLIC RING SYSTEMS
N
N
N
H
H
H
pyrrole
piperidine
pyrrolidine
N
N
pyridine
N
N
H
quinoline
isoquinoline
indole
N
H
dihydroindole
HETEROCYCLIC RING SYSTEMS
H
N
N
N
tropane
pyrrolizidine
quinolizidine
N
N
N
C C N
N
N
H
benzylisoquinoline
purine
-phenylethylamine
(cont)
Some Examples of Classification
BY RING TYPE
MeO
OMe
NH
MeO
-O
OMe
O
P OH H3C
O
+ CH3
N
N
H
emetine
O
H3C
N
H
N
nicotine
CH3
O
N
N
N
N
CH3
CH3
caffeine
N
CH3
psilocybin
Amino Acid Precursors
from
ornithine
H 3CO
H3 C
NH2
N
N
CH3
N
OCH3
HO
N
O
mescaline
nicotine
N
CO2 CH 3
Ph
O
from
tyrosine
H 3CO
from
tryptophan
from
ornithine
cocaine
O
O
H
from
tyrosine
HO2 C
N
CH 3
strychnine
from
tryptophan
O
N
H
HO
N
H3 CO
CH 3
HO
NH
from
tryptophan
morphine
N
lysergic acid
HO
N
H3 C
N
from
lysine
N
O
H
Lycopodine
N
H
Histrionicotoxin
O
NH
MeO 2 C
OH
from
tryptophan
MeO
OH
N
R
R= -CH3 vinblastine
R= -CHO vincristine
O
CO 2CH3
Some Examples of Classification
BY PLANT FAMILY : “Amaryllis” Alkaloids
MeO
OH
HO
belladine
O
MeO
N
O
N
MeO
lycorine
H
The other three
are biochemically
derived from
MeO
belladine.
OH
H
galanthamine
H
N CH3
O
OH
O
O
O
MeO
tazettine
These alkaloids are found in Amaryllidaceae
daffodils
narcissus
lillies
etc
N CH3
THE PURPOSE OF ALKALOIDS IN PLANTS (?)
The spectacular pharmacological properties of many of the
alkaloids keeps asking about their purpose in plants.
Many ideas have been advanced:
Defense Mechanisms Insect Repellants Herbivore Attractants
Nitrogen Storage Growth Regulation Insect Attractants
Vestiges of Old Metabolic Experiments
Anti-fungals
Metal ion transport (chelates)
Competitive Herbicides
What seems most likely is that there are many reasons why plants
elaborate alkaloids, and in many cases the purpose of the alkaloid
may be unique to a given plant.
Alkaloids derived from lysine
and ornithine (arginine)
NH2
HO2C
H
N
NH2
pyridoxal
phosphate
NH2
H2O
NH2
HO2C
- CO2
NH2
pyridoxal
phosphate
NH2
HO2C
NH2
lysine
putrescine
ornithine
arginine
H2N
NH2
- CO2
cadaverine
H2N
NH2
Alkaloids derived from ornithine:
Biosynthesis of Cocaine
SAM
NH2
H2N
H3C
putrescine
pyridoxal
phosphate
NH2
N
H
O
H3C
N
H
O2C
-H2O
O
O
SCoA
N
H
N
- CO2
CH3
SCoA
CH3
O
O
O2C
O
O
P450
SCoA
N
- CO2
CH3
O
-H2O
N
CH3
HO
SCoA
H
N
CH3
O
H3C
O
N
SCoA
SCoA
O
O
SCoA
Biosynthesis of Cocaine
O
H3C
O
H3C
N
-H2O
SCoA
N
OH
O
O
O
H3 C
N
OCH3
SAM
NADPH
O
H3 C
N
OCH3
OH
O
O
H3C
N
OCH3
O
Cocaine
Ph
O
Alkaloids derived from tyrosine.
Morphine Biosynthesis
CO2 H
-CO 2
NH2
HO
NH2
PAL
HO
NH2
hydroxylation
HO
HO
Dopamine
Tyramine
PAL
CO2 H
HO
-CO2
O
HO
H 3 CO
HO
HO
H
thiamin
O
HO
HO
N
CH3
2 SAM
NH
HO
HO
HO
HO
Norcoclaurine
NH
+
H3 CO
H 3 CO
N
HO
CH3
1) hydroxylation
2) SAM
N
HO
CH3
epimerization
HO
H 3CO
HO
Reticuline
H 3CO
H3 CO
N
HO
"- 2 H•"
HO
CH 3
N
HO
CH3
H3CO
H3 CO
OH
H3 CO
H 3 CO
•O
O
H3 CO
N
N
CH3
H3 CO
N
CH3
H3 CO
O•
HO
•
•
CH3
H3 CO
O
O
H3CO
H3CO
NADPH
HO
H3CO
HO
O
N
N
N
CH3
CH3
CH3
H3CO
H3CO
H3CO
OH
O
HO
H3CO
1) P450
2) isomerization
3) NADPH
P450
O
O
N
N
CH3
HO
Codeine
CH3
HO
Morphine
Alkaloids derived from
tryptophan. Physostigmine
biosynthesis
asenosyl
H3C S
R
CO2H
N
H
PAL
NH2
NH2
N
H
tryptophan
tryptamine
CH3
N
H
CH3
NH2
N
H
O
H3C
CH3
O
NH
N
N
CH3
CH3
physostigmine
N
H
Alkaloid Biosynthesis
COOH
R-CHNH2
COOH
R’-CHNH2
CO2
R-CH2NH2
Transamination
-CO2
Amino Acids
R’-CHO
-H2O
RN=CHR’
Schiff Base
+
H-C-H
R”
carbonion
Schiff Base
Mannich Condensation
RNH-CH-R’ CH2R’’
Alkaloid
Alkaloid
Classification: (BioSynthetic Origin)
1. Ornithine Derived Alkaloids
2. Lysine Derived Alkaloids
3. Nicotinic Acid Derived Alkaloids
4. Tyrosine Derived Alkaloids
5. Tryptophan Derived Alkaloids
6. Anthranilic Acid Derived Alkaloids
Based on
Amino Acid
from which
they
were derived
7. Histidine Derived Alkaloids
8. Amination Reacrion Derived Alkaloids
9. Purine Alkaloids
1-Ornithine Derived Alkaloids
1. Pyrrolidine and Tropane Alkaloids (Hyoscymine, Hyoscine, Atropine)
2. Pyrrolizidine Alkaloids
2-Lysine Derived Alkaloids
1. Piperidine Alkaloids (Lobelia)
2. Quinolizidine Alkaloids
3. Indolizidine Alkaloids
3-Nicotinic Acid Derived Alkaloids
1. Pyridine Alkaloids (Nicotinic Acid)
4-Tyrosine Derived Alkaloids
1. Phenylethylamin and simple tetrahydroisoquinoline Alkaloids (curarine)
2. Modified Benzyltetrahydroisoquinoline Alkaloids (Opium Alkaloids)
3. Phenethylisoquinoline Alkaloids (Colchicine)
4. Terpenoid Tetrahydroisoquinoline Alkaloids ( Emetine)
5-Tryptophan Derived Alkaloids
1. Simple Indole Alkaloids (Psilocybin)
2. Simple Carboline Alkaloids
3. Terpenoid Indole Alkaloids (Reserpine, Deserpine, Vincristine, Vinblastine, Strychnine)
4. Quinoline Alkaloids (Quinidine, Quinine)
5. Pyrroloindoline Akaloids (Physostigmine)
6. Ergot Alkaloids (Ergotamine)
6-Anthranilic Acid Derived Alkaloids
1. Quinazoline Alkaloids
2. Quinoline and Acridine Alkaloids
7-Histidine Derived Alkaloids
1. Imidazole Alkaloids (Pilocarpine)
8-Amination Reaction Derived Alkaloids
1. Acetate Derived Alkaloids
2. Phenylalanine derived alkaloids (Ephedrine)
3. Terpenoid Alkaloids
4. Steroid Alkaloids
9-Purine Derived Alkaloids
Caffeine, theobromine, theophylline
1-Ornithine Derived Alkaloids
Tropane alkaloid
• There are two important types of tropane
alkaloids:
1-Ornithine Derived Alkaloids
Tropane Alkaloids
What do these groups have in common?
They all possess the tropane nucleus.
Bicyclic system made up of a 5-membered ring
(1, N, 5, 6, and 7) and a 6-membered ring (1, 2,
3, 4, 5, N). N is common to both. The nucleus
always carries an oxygen in position 3.
Tropane Alkaloids
•Are esters of hydroxytropanes and various acids (tropic, tiglic)
-Tropane moiety is formed from ornithine
-Acid moiety from Phenylalanine.
•Plant family contains tropane alkaloids are Solanaceae
•Alkaloids found in roots and leaves mainly.
•Vary with age, length and light intensity.
•Belladonna and Scopolia contains hyoscyamine and Datura Stronium
as dominant alkaloid
•Hyoscine is found in other spp of Datura as dominant alkaloid
•Atropine mainly is found in Atropa Belladona
•Cocaine is found Erythroxylum Coca
Tropane Alkaloids
They are ester alkaloids resulted from the coupling of •
organic acids with amino alcohol (Base).
The parent base is the “Tropane” base. •
H
N
1
2
7
6
NH
5
4
3
Tropane Alkaloids are classified into: •
1- Solanaceous Tropane Alkaloids.
2- Erythroxylon (Coca) Alkaloids.
1.A. Solanaceous alkaloids
• Solanaceous alkaloids come from the solanaceae
(tomato and potato). Some of the alkaloids they produce
are:
•
•
•
•
Atropine
Hyoscyamine
Hyoscine
Hyoscyamine is the pure optical isomer;
(+)Hyoscyamine, (-)Hyoscyamine. Atropine is
the racemic of hyoscyamine.
• Atropine = (±)Hyoscyamine.
• The 3-hydroxy derivative of tropane is known
as TROPINE.
Esterification of tropine with tropic
acid yields hyoscyamine (tropine
tropate).
Atropine & Hypscyamine
Hyoscyamine is the major natural alkaloid with •
negative optical rotation (l- form).
During extraction hyoscyamine racemizes to the •
optically inactive dl Atropine.
Both alkaloids composed of tropine base and tropic •
acid.
Tropic Acid
Me
NCH3
O
H
CH 2OH
O
*
Tropine base
N
O
Me
N
CH 2OH
O
O
OH
(-)-Hyoscyamine
O
Atropine
Hyoscine (Scopolamine)
Hyoscine is an ester of l-tropic acid with scopoline •
base.
Hyoscine is a syrupy liquid. •
Tropic Acid
O
NCH3
Scopoline base
O
O
OH
Separation of the Alkaloidal mixtures:
Alkaloids in the form of HCl salts
1- Alkalinize by NaHCO3 pH 7.5
2- Extract with Ether
Ether
Hyoscine free base
(pKa = 6.2)
Aqueous layer
Atropine & Hyoscyamine HCl
(pKa = 9.3)
Convert to oxalate salts,
Fractional Crystallization
(Acetone/ Ether)
Atropine Oxalate
Crystals
Hyoscyamine Oxalate
Solution
Chemical tests:
Vitali-Morin’s test: •
Solid alkaloid + fuming HNO3 → Evaporate to dryness,
dissolve residue in acetone, add methanolic solution of
KOH → Violet colour.
P-dimethylaminobenzaldehyde: •
Alkaloid + reagent in porcelain dish and heat on boiling water
path → Intense Red Colour → Cherry Red after cooling.
Gerrard’s test: •
Alkaloid + 2% HgCl2 in 50% Ethanol →
Red colour Atropine
Red after warming Hyoscyamine
White ppt Hyoscine
Structure Activity Relationship
A, B = Bulky Groups
C = H,OH
A
B -C C
Chain
N
Cationic Head: Positively charged Quaternary ammonium compounds
Cyclic substitution: at least one cyclic substituent, aromatic the most used
Esteratic Group: Necessary for effective binding
Hydroxyl Group: enhances the activity
Position of OH to Nitrogen in receptive area 2-3oA
Stereochemistry is of small contribution for antagonistic activity
Anticholinergics
Inhibit the
neurological
signals transmitted
by the endogenous
neurotransmitter,
acetylcholine.
Symptoms of poisoning
include mouth dryness,
dilated pupils, ataxia,
urinary retention,
hallucinations, convulsions,
coma, and death
Atropine has a stimulant
effect on the CNS and heart,
whereas scopolamine has a
sedative effect .
Hyoscyamine and Hyoscine
Atropine
or
 Hyoscyamine
Scopolamine
or
Hyoscine
Pharmacological Activity
• These alkaloids compete with
acetylcholine for the
muscarinic site of the
parasympathetic nervous
system
thus preventing the passage of
nerve impulses, and are classified
as anticholinergics.
Acetylcholine binds to two types •
of receptor site, described as
muscarinic or nicotinic,
from the specific triggering of a
response by the Amanita
muscaria alkaloid muscarine or
the tobacco alkaloid nicotine
respectively.
• The structural similarity
between acetylcholine and
muscarine can readily be
appreciated, and
hyoscyamine is able to
occupy the same receptor
site by virtue of the
spatial relationship
between the nitrogen
atom and the ester
linkage .
• The side-chain also plays a
role in the binding, explaining
the difference in activities
between the two enantiomeric
forms.
• The agonist properties of hyoscyamine and
hyoscine give rise to a number of useful
effects,
• Including:
• antispasmodic action on the gastrointestinal
tract,
• antisecretory effect controlling salivary
secretions during surgical operations,
• and as mydriatics to dilate the pupil of the eye.
• Hyoscine has a depressant action on the
central nervous system and finds
particular use as a sedative to control
motion sickness.
• One of the side-effects from oral
administration of tropane alkaloids is
dry mouth (the antisecretory effect)
but this can be much reduced by
transdermal administration.
• In motion sickness treatment,
hyoscine can be supplied via an
impregnated patch worn behind the
ear.
• Hyoscine under its synonym
scopolamine is also well known,
especially in fiction, as a ‘truth
drug’.
• This combination of sedation, lack
of will, and amnesia was first
employed in child-birth, giving what
was termed ‘twilight sleep’, and may
be compared with the mediaeval
use of stramonium.
• The mydriatic use also has a very
long history. Indeed, the specific
name belladonna for deadly
nightshade means ‘beautiful lady’ and
refers to the practice of ladies at court
who applied the juice of the fruit to the
eyes, giving widely dilated pupils and
a striking appearance, though at the
expense of blurred vision through an
inability to focus.
Atropine also has useful •
antidote action in cases of
poisoning caused by
cholinesterase inhibitors, e.g.
physostigmine and neostigmine
and organophosphate
insecticides.
• It is valuable to reiterate here that the
tropane alkaloid-producing plants are
all regarded as very toxic, and that
since the alkaloids are rapidly
absorbed into the blood stream, even
via the skin, first aid must be very
prompt. Initial toxicity symptoms
include skin flushing with raised
body temperature, mouth dryness,
dilated pupils, and blurred vision.
Semisynthetic Derivatives
1. Homatropine is a semi-synthetic ester of tropine with racemic
mandelic (2-hydroxyphenylacetic) acid and is used as a mydriatic,
as are tropicamide and cyclopentolate
2. Tropicamide is an amide of tropic acid, though a pyridine
nitrogen is used to mimic that of the tropane.
3. Cyclopentolate is an ester of a tropic acid-like system, but uses
a non-quaternized amino alcohol resembling choline.
4. Glycopyrronium has a quaternized nitrogen in a pyrrolidine
ring, with an acid moiety similar to that of cyclopentolate.
• This drug is an antimuscarinic used as a pre medicant to dry
bronchial and salivary secretions.
5. Hyoscine butylbromide is a gastro-
intestinal antispasmodic synthesized
from (−)-hyoscine by quaternization of the
amine function with butyl bromide.
• The quaternization of tropane alkaloids
by N-alkylation proceeds such that the
incoming alkyl group always approaches
from the equatorial position.
6. ipratropium bromide
7. oxitropium bromide
The potent bronchodilator ipratropium bromide is
thus synthesized from noratropine by successive
isopropyl and methyl alkylations whilst oxitropium
bromide is produced from norhyoscine by Nethylation and then N-methylation. Both
drugs
are used in inhalers for the
treatment of chronic bronchitis.
is an
ether of tropine used as an
antimuscarinic drug in the
treatment of Parkinson’s disease.
It is able to inhibit dopamine
reuptake, helping to correct the
deficiency which is characteristic of
Parkinsonism.
8. Benzatropine (benztropine)
Atropa Belladona
• Belladonna
• The deadly nightshade Atropa belladonna (Solanaceae) has a long
history as a highlypoisonous plant. The generic name is derived
from Atropos, in Greek mythology the Fatewho cut the thread of life.
• The berries are particularly dangerous, but all parts of the plant
• contain toxic alkaloids, and even handling of the plant can lead to
toxic effects since the alkaloids are readily absorbed through the
skin.
• Although humans are sensitive to the toxins,some animals, including
sheep, pigs, goats, and rabbits, are less susceptible.
• Cases are known where the consumption of rabbits or birds that
have ingested belladonna has led to human poisoning.
• Belladonna herb typically contains 0.3–0.6% of alkaloids,
mainly (−)-hyoscyamine
• Belladonna root has only slightly higher alkaloid content
at 0.4–0.8%, again mainly (−)-hyoscyamine.
• Minor alkaloids including (−)-hyoscine and cuscohygrine
• are also found in the root, though these are not usually
significant in the leaf.
• The mixed alkaloid extract from belladonna herb is still
used as a gastrointestinal sedative, usually in
combination with antacids. Root preparations can be
used for external pain relief, e.g. in belladonna plasters.
Datura Stramonium
Datura stramonium
• is commonly referred to as thornapple on account of its spikey fruit.
It is a tall bushy annual plant widely distributed in Europe and North
America, and because of its alkaloid content is potentially very toxic.
• Indeed, a further common name, Jimson or Jamestown weed,
originates from the poisoning of early settlers near
Jamestown,Virginia. At subtoxic levels, the alkaloids can provide
mild sedative action and a feeling of well-being.
• In the Middle Ages, stramonium was employed to drug victims prior
to robbing
• them. During this event, the victim appeared normal and was
cooperative, though afterwards could usually not remember what
had happened.
• For drug use, the plant is cultivated in Europe and South America.
The leaves and tops are harvested when the plant is in flower.
• Stramonium leaf usually contains 0.2–0.45% of alkaloids,
principally (−)-hyosycamine and
• (−)-hyoscine in a ratio of about 2:1. In young plants, (−)-hyoscine
can predominate
Hyoscyamus Niger
Hyoscyamus
•
•
•
•
•
•
•
•
Hyoscyamus niger (Solanaceae), or henbane, is a European native with a
long history as a medicinal plant. Its inclusion in mediaeval concoctions and
its power to induce hallucinations with visions of flight may well have
contributed to our imaginary view of witches on broomsticks.
The plant has both annual and biennial forms, and is cultivated in Europe
and
North America for drug use, the tops being collected when the plant is in
flower, and then dried rapidly.
The alkaloid content of hyoscyamus is relatively low at 0.045–0.14%, but
this can
be composed of similar proportions of (−)-hyoscine and (−)-hyosycamine.
Egyptian henbane, Hyosycamus muticus, has a much higher alkaloid
content than H. niger, and although it has mainly been collected from the
wild, especially from Egypt, it functions as a major commercial
source for alkaloid production. Some commercial cultivation occurs in
California.
The alkaloid content of the leaf is from 0.35% to 1.4%, of which about 90%
is (−)-hyoscyamine.
Duboisia Hopwoodii
Mandragora Officinarum
Scopolia Carniolica
Anisodus tanguticus var.
viridulus (C. Y. Wu & C. Chen).
• Solanaceae
• Herbs perennial, 40-80(100) cm tall. Roots
stout. Stems glabrous or
pubescent. Petiole 1-3.5
cm; leaf blade
lanceolate, oblong, or
ovate.
Anisodamine
• Anisodamine is an anticholindergic alkaloid that had been
recently been isolated from Anisodus tanguticus, an herb
found primarily in the Tibetan region.
• This compound was introduced into clinical use in China as a
synthetic drug in 1965, initially for the treatment of epidemic
meningitis. Later, anisodamine was shown to produce
favorable results in treatment of numerous serious ailments,
including shock, glomerular nephritis, rheumatoid arthritis,
hemorrhagic necrotic enteritis, eclampsia, and lung edema. The
mechanism of its actions were sought and traced to a
vasodilating action that affected the microcirculation. In China
it is believed that anisodamine possesses good and reliable
effects in the treatment of septic shock and morphine addiction.
However, this drug is not without its side effects.
Anisodamine
1.B. Cocaine
Aneasthetic Effect
Better local aneasthetic
were discovered
CNS Stimulant:
Brompton’s cocktail
Drug of Abuse
The free base is used for
inhalation
Cocaine
2- Erythroxylon (Coca) Alkaloids
Occurrence: •
Coca leaves contain about 2% total alkaloids.
O
Main Alkaloids are: •
1- Cocaine.
2- Cinnamylcocaine.
3. a- truxilline.
N
H3C
C
OH
OH
Ecogonine
The base for Coca Alakloid is called “Ecogonine” •
Cocaine
It is the major Alkaloid in Coca leaves. •
Cocaine is diester Alkaloid. •
Heating at 160 0C in conc. HCl leads to hydrolyses of •
cacaine to MeOH, Benzoic acid and Ecogonine base.
COOMe
NCH3
O
Benzoic acid
Ecgonine base
O
Production of Cocaine commercially:
The total Alkaloids are hydrolysed to obtain the free •
base.
The base is then Methylated with HCl in MeOH. •
The Methylated base is then esterified with Benzoly •
chloride.
Cinnamylcocaine
COOMe
NCH3
Ecgonine base
O
Cinnamic acid
O
Uses: •
Cocaine was used as local
anesthetic.
Cocaine has a CNS stimulant
activity so is one of the widely
abused drugs.
Structure Activity Relationship
O
║
Aryl -C- O -
Chain
N
Aryl group connected to carboxylic acid ester
Lipophilic hydrocarbon chain
Basic amino group
Erythroxylum Coca
Cocaine Addiction
Cocaine
• Coca leaves
• Coca leaves
The coca paste is dissolved in hydrochloric or
sulphuric acid. Potassium permanganate mixed
.
with water is added to the paste and acid solution
How is cocaine used?
• The principal routes of cocaine administration are
oral,
• intranasal,
• intravenous,
• and inhalation.
•
• The slang terms for these routes are, respectively,
"chewing," "snorting," "mainlining," "injecting," and
"smoking" (including freebase and crack cocaine).
Snorting is the process of inhaling cocaine powder
through the nostrils, where it is absorbed into the
bloodstream through the nasal tissues.
• Injecting releases the drug directly into the
bloodstream, and heightens the intensity
of its effects. Smoking involves the
inhalation of cocaine vapor or smoke into
the lungs, where absorption into the
bloodstream is as rapid as by injection.
The drug can also be rubbed onto mucous
tissues. Some users combine cocaine
powder or crack with heroin in a
"speedball."
• Cocaine use ranges from occasional use to
repeated or compulsive use, with a variety of
patterns between these extremes.
• There is no safe way to use cocaine.
• Any route of administration can lead to
absorption of toxic amounts of cocaine, leading
to acute cardiovascular or cerebrovascular
emergencies that could result in sudden death.
Repeated cocaine use by any route
of administration can produce
addiction and other adverse health
consequences.
How does cocaine produce its
effects?
• A great amount of research has been devoted to
understanding the way cocaine produces its
pleasurable effects, and the reasons it is so
addictive.
• One mechanism is through its effects on
structures deep in the brain. Scientists have
discovered regions within the brain that, when
stimulated, produce feelings of pleasure. One
neural system that appears to be most affected
by cocaine originates in a region, located deep
within the brain, called the ventral
tegmental area (VTA).
• Nerve cells originating in the VTA
extend to the region of the brain
known as the nucleus
accumbens, one of the brain's
key pleasure centers.
• In studies using animals, for
example, all types of pleasurable
stimuli, such as food, water, sex,
and many drugs of abuse, cause
increased activity in the nucleus
accumbens.
• Researchers have discovered that,
when a pleasurable event is occurring,
it is accompanied by a large increase in
the amounts of dopamine released in
the nucleus accumbens by neurons
originating in the VTA.
• In the normal communication process, dopamine is
released by a neuron into the synapse (the small gap
between two neurons), where it binds with specialized
proteins (called dopamine receptors) on the neighboring
neuron, thereby sending a signal to that neuron. Drugs
of abuse are able to interfere with this normal
communication process.
• For example, scientists have
discovered that cocaine blocks the
removal of dopamine from the
synapse, resulting in an
accumulation of dopamine.
• This buildup of dopamine causes
continuous stimulation of receiving
neurons, probably resulting in the
euphoria commonly reported by
cocaine abusers.
• As cocaine abuse continues,
tolerance often develops.
• This means that higher doses
and more frequent use of
cocaine are required for the brain
to register the same level of
pleasure experienced during
initial use.
• Recent studies have shown that, during
periods of abstinence from cocaine
use, the memory of the euphoria
associated with cocaine use, or
mere exposure to cues
associated with drug use,
• can trigger tremendous craving
and relapse to drug use, even
after long periods of abstinence.
What are the short-term
effects of cocaine use?
• Cocaine's effects appear almost immediately
after a single dose, and disappear within a few
minutes or hours.
• Taken in small amounts (up to 100 mg), cocaine
usually makes the user feel
•
•
•
•
euphoric,
energetic,
talkative,
and mentally alert, especially to the
sensations of sight, sound, and touch.
• It can also temporarily decrease
the need for food and sleep.
• Weight loss
• Some users find that the drug helps
them to perform simple physical and
intellectual tasks more quickly, while
others can experience the opposite
effect.
• The duration of cocaine's immediate euphoric
effects depends upon the route of
administration.
• The faster the absorption, the more
intense the high. Also, the faster the
absorption, the shorter the duration of
action. The high from snorting is
relatively slow in onset, and may last 15
to 30 minutes, while that from smoking
may last 5 to 10 minutes.
• The short-term physiological effects of cocaine
include constricted blood vessels; dilated pupils;
and increased temperature, heart rate, and
blood pressure
• Large amounts (several hundred milligrams
or more) intensify the user's high, but
may also lead to bizarre, erratic, and violent
behavior. These users may
experience tremors, vertigo,
muscle twitches, paranoia, or, with
repeated doses, a toxic reaction
closely resembling amphetamine
poisoning.
• Some users of cocaine report feelings of
restlessness, irritability, and anxiety. In
rare instances, sudden death can occur on
the first use of cocaine or unexpectedly
thereafter.
• Cocaine-related deaths are
often a result of cardiac arrest
or seizures followed by
respiratory arrest.
What are the long-term
effects of cocaine use?
Auditory hallucinations
Cocaine is a powerfully addictive
drug.
Once having tried cocaine, an individual may have
difficulty predicting or controlling the extent to which
he or she will continue to use the drug.
Cocaine's stimulant and addictive effects are
thought to be primarily a result of its ability to
inhibit the reabsorption of dopamine by nerve
cells. Dopamine is released as part of the
brain's reward system, and is either directly or
indirectly involved in the addictive properties of
every major drug of abuse.
• An appreciable tolerance to cocaine's high
may develop, with many addicts reporting
that they seek but fail to achieve as much
pleasure as they did from their first
experience.
• Some users will frequently increase their
doses to intensify and prolong the euphoric
effects. While tolerance to the high can
occur, users can also become more sensitive
(sensitization) to cocaine's anesthetic and
convulsant effects, without increasing the
dose taken.
• This increased sensitivity may explain some
deaths occurring after apparently low doses
of cocaine.
• Use of cocaine in a binge, during which
the drug is taken repeatedly and at
increasingly high doses, leads to a
state of increasing irritability,
restlessness, and paranoia.
• This may result in a full-blown paranoid
psychosis, in which the individual
loses touch with reality and
experiences auditory hallucinations.
What are the medical complications
of cocaine
• Gastrointestinal complications
• There are enormous medical complications
associated with cocaine use. Some of the most
frequent complications are cardiovascular
effects, including disturbances in heart
rhythm and heart attacks; such respiratory
effects as chest pain and respiratory failure;
neurological effects, including strokes,
seizure, and headaches; and gastrointestinal
complications, including abdominal pain and
nausea.
• Cocaine use has been linked to many
types of heart disease.
• Cocaine has been found to trigger
chaotic heart rhythms, called
ventricular fibrillation; accelerate
heartbeat and breathing; and increase
blood pressure and body temperature.
• Physical symptoms may include chest
pain, nausea, blurred vision, fever, muscle
spasms, convulsions and coma.
• Different routes of cocaine administration can
produce different adverse effects.
• Regularly snorting cocaine, for example, can
lead to loss of sense of smell, nosebleeds,
problems with swallowing, hoarseness, and
an overall irritation of the nasal septum,
which can lead to a chronically inflamed,
runny nose.
• Ingested cocaine can cause severe
bowel gangrene, due to reduced blood
flow.
• And, persons who inject cocaine have
puncture marks and "tracks," most
commonly in their forearms.
• Intravenous cocaine users may also experience
an allergic reaction, either to the drug, or to
some additive in street cocaine, which can
result, in severe cases, in death.
• Because cocaine has a tendency to decrease
food intake, many chronic cocaine users lose
their appetites and can experience
significant weight loss and
malnourishment.
• Research has revealed a potentially
dangerous interaction between cocaine
and alcohol. Taken in combination, the
two drugs are converted by the body to
cocaethylene.
• Cocaethylene has a longer duration of action
in the brain and is more toxic than either drug
alone.
• While more research needs to be done, it is
noteworthy that the mixture of cocaine and
alcohol is the most common two-drug
combination that results in drug-related
death.
Medicinal use
• Medicinally, cocaine is of value as a local anaesthetic
for topical application. It is rapidly absorbed by mucous
membranes and paralyses peripheral ends of sensory
nerves. This is achieved by blocking ion channels in
neural membranes.
• It was widely used in dentistry, but has been replaced by
safer drugs, though it still has applications in ophthalmic
and ear,
• nose, and throat surgery.
• As a constituent of Brompton’s cocktail (cocaine
and heroin in sweetened alcohol) it is available to
control pain in terminal cancer patients. It increases
the overall analgesic effect, and its additional CNS
stimulant properties counteract the sedation
normally associated with heroin
SAR
• The essential functionalities of cocaine
required for activity were eventually
assessed to be the
• aromatic carboxylic acid ester
• and the basic amino group,
• separated by a lipophilic hydrocarbon
chain. Synthetic drugs developed from the
cocaine structure have been introduced to
provide safer, less toxic local anaesthetics
Synthetic and semi synthetic
derivatives
• Benzocaine is used
topically, but has a
short duration of
action
• Procaine, though
little used now, was
the first major
analogue employed
• Tetracaine (amethocaine),
oxybuprocaine, and
proxymetacaine
• are valuable local anaesthetics employed
principally in ophthalmic work. The ester
function can be replaced by an amide, and
this gives better stability toward hydrolysis
in aqueous solution or by esterases.
Lidocaine
Lidocaine (lignocaine) is an example of an
amino amide analogue and is perhaps the
most widely used local anaesthetic, having
rapid action, effective absorption, good
stability, and may be used by injection or
topically.
• Lidocaine, although introduced as a local anaesthetic,
was subsequently found to be a potent antiarrhythmic
agent, and it now finds further use as an antiarrhythmic
drug, for treatment of ventricular arrhythmias especially
after myocardial infarction.
• Other cocaine related structures also find application in
the same way, including tocainide, procainamide, and
flecainide.
• Tocainide is a primary amine analogue of lidocaine,
whilst procainamide is an amide analogue of procaine. In
mexiletene, a congener of lidocaine, the
• amide group has been replaced by a simple ether
linkage.
Pyrrolizidine Alkaloids
• Two molecules of ornithine are utilized in
formation of the bicyclic pyrrolizidine skeleton,
the pathway proceeding via the intermediate
putrescine.
• Because plants synthesizing pyrrolizidine
alkaloids appear to lack the decarboxylase
enzyme transforming ornithine into putrescine,
ornithine is actually incorporated by
• way of arginine
• Many pyrrolizidine alkaloids are known to produce
• pronounced hepatic toxicity and there are many
recorded cases of livestock poisoning.
• Potentially toxic structures have 1,2-unsaturation in the
• pyrrolizidine ring and an ester function on the
• side-chain.
• Although themselves non-toxic, these alkaloids are
transformed by mammalian liver oxidases into reactive
pyrrole structures, which are potent alkylating agents
and react with suitable cell nucleophiles, e.g. nucleic
acids and proteins
• The tobacco alkaloids, especially nicotine, are derived
from nicotinic acid but also contain a pyrrolidine ring
system derived from ornithine as a portion of their
structure.