Pharmacognosy -2 PHG 322 - PSAU · Alkaloids of Phenylalkylamine Classes of phenylalkylamine a. Bezylamine type Drug Name: Fructus Capsici Plant Source: Capsicum annua, Capsicum frutescens

Prof. Dr. Amani S. Awaad

Professor of PharmacognosyPharmacognosy Department,

College of Pharmacy Salman Bin Abdulaziz

University,

Al-Kharj. KSA.

Email: [email protected]

Pharmacognosy -2

PHG 322

Atypical/non- heterocyclic alkaloids

*Physical & chemical properties

Alkaloids of

Phenylalkylamine

Tropolone

Terpenoids

4-Chemical classification

i. Atypical/non- heterocyclic alkaloids (proto alkaloids or biological amines)

Alkaloids cont…

Alkaloids Classification

Terpenoids(Steroids, Aconite)

Tropolone(Colchicine)

phenylalkylamine(Mescaline, ephedrine, hordenine, capsaicinoids, cathinone )

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Alkaloids of Phenylalkylamine TropoloneTerpenoids

Terpenoids


Alkaloids of Phenylalkylamine

It derived from Phenylalanine amino acid


Biosynthetic Source:

Distribution :This group of alkaloids occurs in many plants and can be

classified into the followings:

a. Bezylamine type (e.g. the capsaicinoids)

b. Phenylethylamine Type (e.g. mescaline)

c. 2-aminophenylpropane type (e.g. ephedrine,

cathinone)

N

R R

Benzylamine type

NN

R R

Phenylethylamine-type

RR

2-Aminophenylpropane-type

2

Alkaloid-like amines. Have no nitrogen as part of the heterocyclic ring.


Classes of phenylalkylamine

a. Bezylamine type

Drug Name: Fructus Capsici

Plant Source: Capsicum annua, Capsicum frutescens

Other Names: Capsicum, grains of paradise, Red pepper, Chili.

Habitat: The plant is indigenous to Mexico and Central America and is cultivated today

in warmer regions of the globe

Family: Solanaceae

1) The capsaicinoids

Constituents:Capsaicinoids

(amides of the vanillyl amine with C8-C13- fatty acids)

Chief components:capsaicin (vanillamide of 8 methyl-on-E-6-enoic acid) (32-38%) ,dihydrocapsaicin (18-52%)& Nordehydrocapsaicin (responsible for the pungency of the paprika).

Carotenoids , Flavonoids, Volatile oils, Steroid Saponins.



a. Bezylamine type

1) The capsaicinoidsBiological Effects:

1-Pain modulation effect ( The most important active ingredient in the herb is capsaicin, which exert hyperemic effects. It exhibits TRPV1 agonistic activity.)

-Cutaneous nociceptors are also known as peripheral sensory neurons of primary sensory neurons activated by noxious stimuli. -Peripheral fibers produce a local response consisting of edema, redness and vasodilation, while afferent fibers relay nociseptive information to the central nervous system resulting in the perception of pain and burning. -Long-term desensitization of the fibers occurs after repeated exposure to capsaicin, and results in a subsequent loss of pain sensation.Capsaicin binds to the C-type vanilloid receptor (VR1) and opens a cationic channel allowing the influx of Calcium.

- The calcium influx is an excitatory response, which initiates release of neuropeptides (substance P).- the neuropeptides are responsible for chemogenic pain, thermoregulation and neurogenic inflammation.- By blocking the calcium channel, there will be a depletion of substance P in the sensory nerves and loss of pain.



a. Bezylamine type


Biological Effects cont….:

2-Antimicrobial effect- Capsaicin and dihydrocapsaicin have antimicrobial effects against Bacillus cereus, Bacillus subtilis,

Clostridium sporogenes, Clostridium tetany, and Streptococcus pyogenes.

- Capsaicin has shown bactericidal activity against H. pylori and therefore, could have a protective

effect against H. pylori-associated gastroduodenal disease

3-AntineoplasticDetoxification/ Gastroprotective/Thrombolytic Effect

- Capsaicin and dihydrocapsaicin have detoxification activity with pharmacologically active substances by interacting irreversibly with hepatic drug metabolizing enzymes.- Capsaicin has a gastroprotective effect against gastric mucosal injury caused by aspirin.- Capsicum has been found to induce increased fibrinolytic activity and simultaneously cause hypocoagulability of blood.



a. Bezylamine type


Indications and UsageApproved by Commission E:- Muscular tensions & Rheumatism

Precautions and Adverse Reactions:

General: there has not yet been a final determination of possible health hazards or side effects in conjunction with the proper administration of designated therapeutic dosages. Internal administration may increase gastrointestinal peristalsis resulting in diarrhea, intestinal and gallstone colics. External applications can lead to blister and ulcer formation.

Hematologic Effects: induced increase fibrinolytic activity and simultaneously cause hypocoagulability.Hypersensitivity: Anaphylaxis and rhinoconjuctivities symptomsRespiratory Effects: Alveobronchiolitis and fibrotic changes.

Warning: use should be limited to 2 days and should only be used again after 2 weeks. Keep away from eyes!



a. Bezylamine type


Drug Interactions:

Aspirin and salicylic acid compounds-

the bioavailability of aspirin (acetylsalicylic acid) and of salicylic acid were reduced when given concomitantly with Capsicum annum extract.

Overdosage:

Toxic dosages lead to life-threatening hypothermia by affecting the thermo

receptors.

High doses of drugs ( or the herb) administered over extended period can

cause chronic gastritis, kidney damage, liver damage, and neurotoxic

effects. The treatment of poisoning proceeds symptomatically.



a. Bezylamine type


Alcohol solution of capsaicin+FeCl3

leads to bluish green colour.

Capsiacin+H2SO4+small amount of sugar

leads violet colour after period of (1

hour)

Test of identity:



b. Phenylethylamine

mescalineOil in nature ; hallucinating drugs

Plant Source: Lophophora williamsii, Echinopsis pachanoi & Echinopsis peruviana

Habitat: From earliest recorded time, peyote has been used by natives in northern Mexico and the

southwestern United States

Family: Fabaceae

medical usage: Mescaline has a wide array of suggested medical usage, including treatment of alcoholism and depression.

However, its status as a Schedule I controlled substance in the Convention on Psychotropic Substances limits availability of

the drug to researchers..

Side effects of mescaline:Side effects of mescaline use may include: anxiety, racing heart beat (tachycardia), dizziness, diarrhea,

vomiting and headache

mescaline



c) 2-aminophenylpropane type

Plant Source :

Various species of Ephedra (Ephedraceae)

Chinese species Ephedra sinica, E. equisetina

and the Indian and Pakistani E. intermedia and E. gerardiana

1-Ephedrine & pseudoephedrine

It may be also prepared by chemical synthesis

COCOCH3

+ NH2CH3

2 H2/ Pt NHCH3

OH





The drug contains about 2% alkaloids.

Ephedrine was isolated in 1887. Its use in modern medicine began in 1923

The chief constituents is almost always- (-) ephedrine (=(1R,2S)-1-phenyl-2-

methylaminopropan-1-ol) represent 40 - 90% of the total alkaloids

. It also occurs as (+)-pseudoephedrine (which has the 1S, 2S configuration)

and the corresponding norephedrine andnorpseudoephedrine.

Constituents:

(-) (+)

(+)

- The drug also contains traces of cyclic compounds

5-phenyloxazolidines andephedroxane (3,4-dimethyl-5-phenyloxazolidone)

Alkaloids of Phenylalkylamine Classes of phenylalkylamine


1-Ephedrine & pseudoephedrinePharmacological Action:

- ephedrine is an indirect sympathomimetic, structurally very close to adrenaline. It produces release of endogenous

catecholamines from the postganglionic sympathetic fibers.

- It accelerates respiration and increases its intensity it is bronchodilator.

- It decreases the contractility of the bladder.

- It is not metabolized much, can be used orally and its duration of action is longer than that of adrenaline.

- It is well resorbed and highly lipophilic. It crosses blood-brain barrier and by releasing mediators

- centrally, has a stimulating psychic effect. (stimulation of the attention and of the ability to concentrate and decrease in the

sensation of fatigue and the need for sleep).

- Ephedrine is also ingredient of syrups and other formulations designed for the treatment of non-productive coughs

- Ephedrine HCl is used for its vasoconstrictive properties, (as an ingredient of nasal sprays and nasal drops), for antiseptic and vasoconstictive (treatment of congestion of rhinitis, sinusitis, and rhinopharyngitis).

- Ephedrine HCl alone or in combination with antihistamine, is an ingredient of drugs designed for the symptomatic treatment of nasal congestion (rhinorrhea and nasal obstruction).- In addition, ephedrine HCl has been used to treat the acute attack of asthma.





2. Dissolve ephedrine in CHCl3 and leave it for 12 h, then allow chloroform to evaporate, crystals of ephedrine hydrochloride separate out.

3. In a small porcelain dish triturate ephedrine with crystals of potassium ferric cyanide K[Fe3(CN)6] and few drops of water and heat, odor of benzaldehyde is produced.

4. Ephedrine doesn't give positive Mayer's test.

Identification of ephedrine

Chen’s test:

Ephedrine HCl in water + 0.1 ml CuSO4 + 1ml NaOH

→ Violet colour, shake with Ether →

Ether layer → purple

Aqueous layer → blue

1. Dissolve ephedrine in 1 ml water with few drops of diluted HCl. Add 2 drops of copper sulfate solution and

then and sodium hydroxide solution, a reddish color is produced by adding 2 ml of ether and shaking, 2 layers

are separated, the ether layers becomes while the aqueous layer turn blue.

Alkaloids of Phenylalkylamine Classes of phenylalkylamine


2- Cathinone

Drug name: KhatPlant source : Catha edulis (Celastraceae) - is a shrub with indeciduous leaves. It is of the modest size in arid areas (1-2m), but can reach 10 m in the tropics. - It is native to the horn of Africa.- It is cultivated in the south east of the Arabian peninsula (Yemen), in Somalia, and Ethiopia. - It is widely employed in these countries for chewing.

ConstituentsIn the fresh and young leaves, the chief constituent is Cathinone [(S)-α-aminopropiophenone]. - In the dried drug and in older leaves, cathinone has been converted to norpseudoephedrine (Cathine) and norephedrine. - In addition, the leaf contains complex polyesters of polyhydroxylated dihydrofurans(cathedulines) and arylalkylamines (Khatamines), which participate in the responsibility for the activity of drug.- Cathinone possesses pharmacological properties analogous to those of D-amphetamine.- It causes anorexia, hyperthermia, respiratory stimulation, mydriasis, arrhythmia- and hypertension.- It induces the release of catecholamines from storage

(norpseudoephedrine)


Tropolone

Tropolone Alkaloids

Colchicum seed is the dried, ripe seed of Colchicum autumnale (Fam. Liliaceae). Colchicum corm is the dried corm of the same species.

The genus name is from Cholchis on the Black Sea, where the plant flourishes autumnal refers to the season when the plant blooms.

The plant is cultivated in England, central and southern the Europe and northern Africa.

The plant is known to the Greek for its toxicity, was used in the Byzantine empire since the fifth century to treat gout.

The concentration of total alkaloids is very variablefrom 0.3 to 1.2%. The chief constituent is colchicines(0.6%).

Tropolone AlkaloidsSource: Colchicum autumnale .

Constituents: Colchicine & Colchamine.

1-Colchicines can be extracted in water. 2-Colchicine is extracted by a hydroalcoholic solution; 3-back extraction with chloroform after removal of alcohol separates colchicoside (which remains in the aqueous phase) and the alkaloids (dissolved in chloroform). 4-Colchicines can be crystallized from chloroform solution after washing with alkaline solutions. Other alkaloids include democolcine, colchicilline and its demethylated derivative

Properties:

Amorphous, yellow-white alkaloid (darkens on exposure to light).

Gives a strong yellow coloration with strong mineral acids.

Dissolves readily in water, alcohol and chloroform, but only slightly in ether or petroleum spirit.

It is a Weak base

It is sensitive to light and photoisomerized to lumicolchicine(pharmacologically inactive) upon exposure to UV radiation

Extraction

Tropolone Alkaloids

Test:1- with few drops of mineral acids, gives yellow color

2- with conc HNO3, dirty violet color is produced, which changes through

brown to yellow.

.

Uses:1- Treatment of Gout.

2- Anticancer in vitro.

3- Treatment of Mediterranean Sea fever.

Colchicine possesses an anti-mitotic, anti-inflammatory activity.Therefore it is used for treating the microcrystalline arthritis caused by sodium urate crystals.

It is useful for treating of the acute attack of gout. Agricultural research sometimes uses colchicines to create polyploidy strains.

Colchicines is prescribed orally and indicated in the treatment of gout. It is efficacious in over 95% of cases 3 mg on the first day (in three single doses) 2 mg in two doses on the second and the third day.1 mg on the following days up to a maximum dose of 10 mg.


Terpenoidal alkaloids

Terpenoids

• Aconites, commonly called wolfsbane or monkshood, are species of Aconitum (Ranunculaceae).

• valued ornamental herbaceous plants, grown for their showy blue or purple flowers, which are shaped like a monk’s cowl.

• Their alkaloid content, mainly in the roots, makes them some of the most toxic plants commonly encountered. The dried roots of Aconitum napellus were once used, mainly externally for relief of pain, e.g. in rheumatism.

• The toxic alkaloids (0.3–1.5%) are complex diterpene-derived esters. Aconitine is the principal component (about 30%) and is a diester of aconine with acetic and benzoic acids.

• These alkaloids appear to behave as neurotoxins by acting on sodium channels. All species of Aconitum and Delphinium are potentially toxic to man and animals and must be treated with caution.

Terpenoidal Alkaloids

alkaloids solely based on mono-, sesqui-, di-, and tri-terpenoid skeletons have been isolated and

characterized. Most of them present in Aconite.


Terpenoidal alkaloids based on a C30 terpen skeleton A few typical examples of

the Terpenoidal alkaloids are, namely:

aconine and actinitine, which shall be discussed in the sections that follow:

Biological Source:

Aconine is the hydrolyzed product of aconitine which is obtained from

the dried roots of Aconitum napellus Linn. (Ranunculaceae) and other

aconites. A. napellus in also known as aconite, blue

rocket and monkshood. Usually it contains up to 0.6% of the total alkaloids

of aconite, of which approximately one third is the alkaloid aconitine.

A. Aconine

Uses :

1. It is used in the treatment of neuralgia, rheumatism and

inflammation.

2. It is employed occasionally as analgesic and cardiac depressant

Terpenoidal alkaloids can be either contain terpen (C30) only or steroidal (C-27) nucleus

I-Terpenoidal nucleus

hydrolyzed

28


B. Aconitine

Biological Source

The botanical source is the same as Aconine

Uses1. It is exclusively used in producing heart arrythmia in

experimental animals.

2. It has also been used topically in neuralgia

The aconitine and mesaconitine compounds have a special ester group

(special ordering of elements) that is available to bind to other areas.

This ester group is what helps to give both aconitine and mesaconitine

their poisonous capabilities as a neurotoxin, because this is what

provides compounds with the ability to bind to the Na+ protein channel

and throw off the entire nervous pathway of an animal

About 3mg of the plant for an adult is considered a deadly dose

can case poising to human.

Side effects

I-Terpenoidal nucleus

29


II- Steroidal nucleus

In general, the steroidal alkaloids represent an important

class of alkaloids that essentially afford a close structural

relationship to sterols . these group of alkaloids

invariably occur in the plant kingdom as glycosidal

combination with carbohydrate moieties.

The steroidal alkaloids may be broadly

classified into two major groups, namely:

(a)Solanum Alkaloids

(b) Veratrum Alkaloids



Many plants in the Solanaceae accumulate. Steroidal alkaloids based on a C27 cholestane skeleton, e.g. solasodine,

tomatidine & solanidine.

(a) Solanum Alkaloids

1. Solasodine

Isolation: It is obtained by the hydrolysis of solasonine

which yields solasodine, L-rhamnose, Dgalactose and D-

glucose respectively.

Biological Sources : It is obtained from the fruits of Capsicum

annuum L. (Chili, Sweet Peppers); shoots and berries of S.

dulcamara L. (Bittersweet, Bitter Nightshade,); leaves of S.

nigrum L. (Wonder berry).All from F. Solanaceae

Uses : It is invariably used as a starting material for

steroidal drugs.



2. Tomatidine

Biological Source: It is obtained from the roots of Rutgers tomato plant

[Lycopersicon esculentum Mill., cultivar. “Rutgers”] (Solanaceae)

(Tomato).

Isolation: It is obtained by the hydrolysis of tomatine to yield a molecule

of tomatidine along with 2 moles of D-glucose, 1-mole of D-xylose and 1-mole of D-

galactose




3. Solanidine

Biological Source The plant of Capsicum annuum L.

(Solanaceae) (Chili, Peppers, Paprika) contains solanidine

Isolation It is obtained by the hydrolysis of solanine which yields

one mole each of L-Rhamnose, D-Galactose, and D-Glucose




The Veratrum alkaloids represent the most important and medicinally

significant class of steroidal alkaloids. that the basic ring systems present in

the Veratrum alkaloids are not quite the same as seen in the usual steroidal

nucleus, as present either in the cholesterol


Structure :In the structures of Veratrum alkaloids the ring ‘C’ is a five

membered ring while ring ‘D’ is a six-membered ring (B) which apparently

is just the reverse of the pattern in the regular steroidal nucleus.

In general, the majority of Veratrum alkaloids may be classified

into two categories solely based on their characteristic structural

features, namely:

(i) Cevaratrum alkaloids

(ii) Jeveratrum alkaloids

Veratrum alkaloidssteroidal nucleus

Terpenoidal AlkaloidsII- Steroidal nucleus


(i) Cevaratrum alkaloids

Ceveratrum Alkaloids The important alkaloids belonging to this group of alkaloids are,

namely: Protoveratrines; Veratridine, Cevadine, Germine etc.,

1. ProtoveratrinesBiological Sources: It is obtained from the rhizome of Veratrum album

L. (Liliaceae) and Veratrum viride Ait. (Liliaceae) (American Hellebore).

2. Veratridine

Biological Sources: It is obtained from the seeds

of Schoenocaulon officinale (Schelecht. And Cham.) A. Gray

and also from the rhizome of Veratrum album L. (Liliaceae).

Uses: 1. It is used as an antihypertensive agent which exerts its action

2. It also possesses emetic action.

3. It is used in the treatment of toxemia of pregnancy




The Jeveratrum group of alkaloids is usually represented by the structure

of veratramine, jervine and pseudojervine etc., which essentially have the following

salient features showing the points of difference in comparison to the Ceveratrum

alkaloids:

(ii) Jeveratrum alkaloids

1.Veratramine

Biological Sources It is obtained in the rhizomes

of Viratrum viride Ait. (Liliaceae) .

Chemical Structure: The chemical structure of

veratramine has also been referred to as

azasteroid, wherein the N-atom is present is in

one or more side chains.

Thank you for attention!

Documents

Pharmacognosy -2 PHG 322 - PSAU · Alkaloids of Phenylalkylamine Classes of phenylalkylamine a. Bezylamine type Drug Name: Fructus Capsici Plant Source: Capsicum annua, Capsicum frutescens