Alkaloids

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 yearsPlant Material

Acid solution

EtOAc: neutral/weakly basic alkaloids

1) Methanol2) Concentrate3) Partition EtOAc/2% acid

Petroleum ether extracts non-polar fats and waxes

Residue: polar material

Wash with petroleum ether

Basic aqueous solution of quaternary alkaloids

1) Ammonia2) Partition with EtOAcEtOAc: basic 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 MORPHINE - - A TYPICAL ALKALOIDA TYPICAL ALKALOID

O

N CH3

OHMeO

..contains nitrogenbasic due to the

unshared pair

heterocyclic ring

Found only in the Opium Poppy - papaver somniferum

Plant source.Most alkaloidsare found inplants.

….. not ubiquitous.

There are three main types of alkaloids :

Terpenoids or purines

colchicine

HOW ARE ALKALOIDS CLASSIFIED ?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 SYSTEMSHETEROCYCLIC RING SYSTEMS

N

H

N

H

pyrrolidine pyrrole

N

H

N

piperidine pyridine

NN N

H

quinoline isoquinoline indole

N

Hdihydroindole

HETEROCYCLIC RING SYSTEMSHETEROCYCLIC RING SYSTEMS (cont)

N N

NH

N

quinolizidine pyrrolizidine tropane

benzylisoquinoline

N

N N

N

H

purine

C C N

-phenylethylamine

Some Examples of Classification

NH

N

OMe

OMeMeO

MeO

emetine

N

ON

CH3

CH3 CH3PO OH

O

H

psilocybin

-

+

N

N

CH3H

nicotine

BY RING TYPEBY RING TYPE

N

N N

N

O

O

CH3

CH3

CH3

caffeine

Amino Acid Precursors

N

N

CH3

nicotine

from ornithine NH2

OCH3

H3CO

H3CO

mescaline

fromtyrosine

NH3C

CO2CH3

O Ph

Ococaine

from ornithine

N

O

N

O

strychnine

from tryptophan

O

HO

NCH3

HO

morphine

fromtyrosine N

NH

HO2C CH3

lysergic acid

from tryptophan NH

N

HO

H3CO

H

from tryptophan

NH

N

HO

MeO2C

NMeO

N

OH

CO2CH3

O

O

R

R= -CH3 vinblastineR= -CHO vincristine

from tryptophan

N OH

H3C

Lycopodine

from lysine

NH

OH

Histrionicotoxin

Some Examples of ClassificationBY PLANT FAMILY BY PLANT FAMILY ::

N

O

O

OH

OH

N

H

MeO

MeO

MeO

O

OH

N CH3

MeOO

O

N CH3

O

H

H

OH

MeO

These alkaloids are found in Amaryllidaceae

daffodilsnarcissuslilliesetc

belladine

lycorine

tazettine

galanthamine

The other threeare biochemicallyderived frombelladine.

“Amaryllis” Alkaloids

THE PURPOSE OF ALKALOIDS IN PLANTS THE PURPOSE OF ALKALOIDS IN PLANTS ((??))

The spectacular pharmacological properties of many of thealkaloids keeps asking about their purpose in plants.

Many ideas have been advanced:

What seems most likely is that there are many reasons why plantselaborate alkaloids, and in many cases the purpose of the alkaloidmay be unique to a given plant.

Defense Mechanisms Insect Repellants Herbivore Attractants

Nitrogen Storage Growth Regulation

Vestiges of Old Metabolic Experiments

Metal ion transport (chelates) Competitive Herbicides

Anti-fungals

Insect Attractants

Alkaloids derived from lysine and ornithine (arginine)

HO2C

HN NH2

NH2

NH2

arginine

H2O

HO2CNH2

NH2pyridoxal

phosphate

H2NNH2

ornithine putrescine

HO2C NH2

NH2pyridoxal

phosphateH2N NH2

lysine cadaverine

- CO2

- CO2

Alkaloids derived from ornithine: Biosynthesis of Cocaine

H2NNH2

putrescineNH

NH2SAM H3C

pyridoxalphosphate

NH

OH3C

H

-H2O

N

CH3

O2C

O

SCoA

N

CH3

O

SCoA- CO2

O2C

O

SCoA

- CO2

N

CH3

O

SCoA

O P450

N

CH3

O

SCoA

O

HO

-H2O

N

CH3

O

SCoA

OH

NH3C

O

SCoA

O

Biosynthesis of Cocaine

NH3C

O

SCoA

O

NH3C

O

OH

O-H2O

SAMN

H3C

O

OCH3

O

NH3C

OH

OCH3

ONADPH

NH3C

O

OCH3

O

Ph

OCocaine

Alkaloids derived from tyrosine. Morphine Biosynthesis

NH2

HO

H

OHO

-CO2

-CO2

CO2H

NH2HO

CO2H

OHO

PAL

PAL

thiamin

hydroxylation

Tyramine

NHHO

HO

HO

NH2

HO

HO

Dopamine

+NH

HO

HO

HO

2 SAMN

HO

H3CO

HO

CH3

Norcoclaurine

NHO

H3CO

HO

CH3

1) hydroxylation2) SAM

NHO

H3CO

H3CO

CH3

HO

Reticuline

NHO

H3CO

H3CO

CH3

HO

HO

H3CO

N

CH3

OH

H3CO

epimerization

"- 2 H•"

•O

H3CO

N

CH3

O •

H3CO

O

H3CO

N

CH3

O

H3CO

HO

H3CO

N

CH3

O

H3CO

••

HO

H3CO

N

CH3

O

H3CO

NADPHHO

H3CO

N

CH3

OH

H3CO

O

H3CO

N

CH3H3CO

1) P4502) isomerization3) NADPH

O

H3CO

N

CH3HO

O

HO

N

CH3

HO

Codeine Morphine

P450

Alkaloids derived from tryptophan. Physostigmine

biosynthesis

NH

NH2

CO2H PAL

NH

NH2

tryptophan tryptamine

SH3C

asenosyl

R

NH

NH2

CH3

NH

CH3

NH

N

CH3

N

CH3 CH3

OO

NHH3C

physostigmine

COOH CO2

R-CHNH2 R-CH2NH2 -H2O RN=CHR’ RNH-CH-R’ CH2R’’

Schiff Base Alkaloid COOH Transamination R’-CHO R’-CHNH2 -CO2

Alkaloid Biosynthesis

Mannich Condensation

+H-C-H R”carbonion

Amino Acids Schiff Base 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

7. Histidine Derived Alkaloids

8. Amination Reacrion Derived Alkaloids

9. Purine Alkaloids

Based on Amino Acid from which

they were derived

1-Ornithine Derived Alkaloids1. Pyrrolidine and Tropane Alkaloids (Hyoscymine, Hyoscine, Atropine)

2. Pyrrolizidine Alkaloids

2-Lysine Derived Alkaloids1. Piperidine Alkaloids (Lobelia)

2. Quinolizidine Alkaloids

3. Indolizidine Alkaloids

3-Nicotinic Acid Derived Alkaloids1. Pyridine Alkaloids (Nicotinic Acid)

4-Tyrosine Derived Alkaloids1. Phenylethylamin and simple tetrahydroisoquinoline Alkaloids (curarine)

2. Modified Benzyltetrahydroisoquinoline Alkaloids (Opium Alkaloids)

3. Phenethylisoquinoline Alkaloids (Colchicine)

4. Terpenoid Tetrahydroisoquinoline Alkaloids ( Emetine)

5-Tryptophan Derived Alkaloids1. 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 Alkaloids1. Quinazoline Alkaloids

2. Quinoline and Acridine Alkaloids

7-Histidine Derived Alkaloids1. Imidazole Alkaloids (Pilocarpine)

8-Amination Reaction Derived Alkaloids1. Acetate Derived Alkaloids

2. Phenylalanine derived alkaloids (Ephedrine)

3. Terpenoid Alkaloids

4. Steroid Alkaloids

9-Purine Derived AlkaloidsCaffeine, theobromine, theophylline

1-Ornithine Derived Alkaloids

Tropane alkaloid• There are two important types of tropane

alkaloids:

Tropane Alkaloids

1-Ornithine Derived 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

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 or Hyoscyamine

Scopolamineor Hyoscine

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

• 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• 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

• Tropicamide is an amide of tropic acid, though a pyridine nitrogen is used to mimic that of the tropane.

• Cyclopentolate is an ester of a tropic acid-like system, but uses a non-quaternized amino alcohol resembling choline.

• 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 premedicant to dry bronchial and salivary secretions.

• 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.

• The potent bronchodilator ipratropium bromide is thus synthesized from noratropine by successive isopropyl and methyl alkylations whilst oxitropium bromide is produced from norhyoscine by N-ethylation and then N-

methylation. Both drugs are used in inhalers for the treatment of chronic bronchitis.

• Benzatropine (benztropine) 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.

Structure Activity Relationship

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

A, B = Bulky Groups

C = H,OH -C - Chain

AB

CN

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.

AnisodamineAnisodamine

Cocaine

Aneasthetic EffectBetter local aneasthetic were discovered

CNS Stimulant:Brompton’s cocktail Drug of Abuse The free base is used for

inhalation

1.B. Cocaine

Structure Activity Relationship

Aryl group connected to carboxylic acid ester

Lipophilic hydrocarbon chain

Basic amino group

-C- O - Chain

O║

Aryl N

Erythroxylum Coca

http://en.wikipedia.org/wiki/Image:Erythroxylum_coca.jpg

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-termeffects 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.

• 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-termeffects 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

• 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.

LidocaineLidocaine (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.

2-Lysine Derived Alkaloids

Piperidine Alkaloids

As the next homologue to ornithine, lysine and its associated compounds give rise to a number of alkaloids, some of which are analogous to the ornithine group.

Lysine Derived Alkaloids

• LOBELIA

• Lobelia BHP; BP 1988 (Lobelia Herb, Indian Tobacco) consists of the dried aerial parts of Lobelia inflata (Campanulaceae), an annual herb indigenous to the eastern USA and Canada. It is cultivated in the USA and Holland.

Lobelia inflataCampanulaceae

Constituents: Lobelia contains about 0.24-0.4% of alkaloids (BP 1988, not less than 0.25% as determined by a standard stas-Otto procedure) the most important of which is lobeline.Uses:

Minor alkaloids identified include closely related structures, e.g. lobelanine . The North American Indians employed lobelia as an alternative or substitute for tobacco (Nicotiana tabacum; Solanaceae), and it is found that lobeline stimulates nicotinic receptor sites in a similar way to nicotine, but

with a weaker effect .Lobeline has been employed in preparationsintended as smoking deterrents. The crude plant drug has also long been used to relieve asthma and bronchitis, though in large doses it can be quite toxic.

Biosynthesis of lobeline

PomegranataThe barks, fruit-rind and seeds of the pomegranate, Punica granatum (Punicaceae) all find medicinal use.Both stem and root barks are used and occur in curved or channeled pieces about 5-10cm long and 1-3cm wide.Constituents: They contain about 0.5-0.9% of volatile liquid alkaloids, the chief of which are pelletierine and pseudopelletierine, together with about 22% of tannin. Uses: anthelminthic, Tapeworms, Astringent.Seed extract for use in the treatment of diarrhea, (Antidiarrhoea).

Punica granatumPunicaceae

Chemical composition

PELLETIERINE

Piper nigrum

• The pungency of the fruits of black pepper• (Piper nigrum; Piperaceae), a widely used• condiment, is mainly due to the piperidine

alkaloid• Piperine. In this structure, the piperidine

ring forms part of a tertiary amide structure, and is incorporated via piperidine itself, the reduction product of Δ1-piperideine