ALKALOIDAL AMINES

Subject name: PHARMACOGNOSY-4 Subject code: 250006
DR. HARISHKUMAR N. KAKRANI, PRICIPAL, C. V. M INSTITUTE OF DEGREE COURSE IN PHARMACY (institute code: 272), VALLABH VIDYANAGAR 388 121

ALKALOIDS
‡ Alkaloids are a group of naturally occurring organic substances, having nitrogen in their heterocyclic ring. o ‡ Except few i.e. proto- and pseudo-alkaloids that do not have nitrogen in their structural rings.

Most alkaloids contain oxygen; those compounds are usually colorless crystals at ambient conditions. o o Oxygen-free alkaloids, such as nicotine or coniine are typically volatile, colorless, oily liquids. Some alkaloids are colored, like berberine (yellow) and sanguinarine (orange).

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Most alkaloid are weak bases, but some are amphoteric, for example theobromine and theophylline. Most alkaloids are poorly soluble in water but readily dissolve in organic solvents, such as diethyl ether, chloroform and 1,2-dichloroethane. o However, caffiene dissolves well in boiling water.

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With acids, alkaloids form salts of various strengths. o o Those salts are usually soluble in water and alcohol and poorly soluble in most organic solvents. Exceptions include scopolamine hydrobromide which is soluble in organic solvents and water-soluble quinine sulfate.

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Alkaloids occur as free bases, salts or N-oxides (N O). When the salt of an alkaloid is treated with hydroxyl ion, nitrogen gives up a hydrogen ion and the free amine is liberated.
Alkaloidal amines, Dr. Harish Kakrani, CDCP
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ALKALOIDS
‡ ‡ ‡ ‡ May be of plant or animal origin Nitrogen of alkaloids: The Nitrogen atom can either be 1Û, 2Û, 3Û or 4Û (quaternary). Alkaloids are usually bitter in taste. They are optically active. o Generally the levo rotatory isomer l (-) is pharmacologically more active than the dextro rotatory isomer d (+) of the same alkaloid. o ‡ Exception: d(+) pilocarpine, d(+) tubocurarine and d(+) quinidine are medically used.

Alkaloids are pharmacologically active even in microgram quantities. ± Plant alkaloids usually have profound physiological actions in humans even in microgramme quantity with nervous system effects being the most prominent. ± Examples of some of the more dramatic actions of alkaloids are: Mydriatics²atropine Hypotensives²reserpine Antimicrobials²berberine Miotics²pilocarpine Bronchodilator²lobeline Antileukemic²vinblastine

Analgesics/ narcotics²morphine Hypertensives²ephedrine Stimulants²strychnine ‡ BIOGENESIS OF ALKALOIDS: o

Alkaloids are produced in plants by basic substances and reactions well-known in organic chemistry.
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BIOGENESIS OFALKALOIDS
‡ True alkaloids are based on an amino acid (pre-cursor). Only a few amino acids form the precursors for all alkaloids: ornithine, lysine, phylalanine, tyrosine, tryptophan, histidine and anthranilic acid.

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OCCURRENCE & DISTRIBUTION OF ALKALOIDS

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Occur in bacteria (Pseudomonas aeruginosa) and rarely in fungi (pscilocin from hallucinogenic mushrooms).

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Some alkaloids occur in several genera from different species (caffeine), but most occur in closely related species.

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Some occur in certain families (hyoscyamine), while others occur only in a specific species (morphine).

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Rarely do plants contain more than 1 type of alkaloid. All alkaloids of one plant will have a common biogenetic origin Alkaloids occur in all plant parts, but are usually localized in one organ (e.g. the bark or seeds). Within the plant, alkaloid can vary widely from part to part ± some parts may contain no alkaloids. Occasionally, different alkaloids also form in different parts of the plant.

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CLASSIFICATION OF ALKALOIDS

ALKALOIDS

True Alkaloids

Proto-alkaloids (AMINO- ALKALOIDS)

Pseudo-alkaloids

Nitrogen in its heterocyclic ring system

Have no nitrogen as a part of their heterocyclic ring

These alkaloids have heterocyclic ring with nitrogen in it

Derived from amino acids

Derived from amino acids

But these are not derived from amino acids

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CLASSIFICATION OF TRUE ALKALOIDS
Sr. No. Class Examples Nicotine Pyridine/ piperidine Lobeline Piperine Arecoline Hyoscyamine 2 Tropane Cocaine Scopalamine Quinine 3 Quinoline Quinidine Berberine Morphine 4 Isoqinoline Chelidonine Boldine Emetine Berberis spp. Papaver somniferum Chelidonium majus Pneumus boldo Cephaelis Ipecacuanha
Alkaloidal amines, Dr. Harish Kakrani, CDCP

Species Nicotiana tabacum Lobelia inflata ‡Piper nigrum ‡P. longum Areca catechu Atropa belladonna Erythroxylon coca Datura metel Cinchona spp.

Pharmacological actions Adrenergic, CNS stimulant Expectorant, bronchodilator ‡Stimulant ‡hepatoprotective Vermicide, taenifuge Anticholinergic, Antisialagogue CNS stimulant, anaesthetic, narcotic Anticholinergic, CNS depressant Antimalarial, Antiarrhythmia Cardioactive Antimicrobial, antiprotozoal, cholagogue Sedative, analgesic, Narcotic Spasmolytic, cholagogue Spasmolytic, choleretic Emetic
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CLASSIFICATION OF TRUE ALKALOIDS
Sr. No. 5 6 Class Examples Sparteine ‡Sececionine ‡Symphytine Reserpine Ergotamine 7 Indole Strychnine Yohimbine 8 Imidazole Pilocarpine Species Sarothamnus scoparius ‡Senecio jacobeae ‡Symphytum spp. Rauwolfia serpentina Claviceps purpurea Strychnos nuxvomica Aspidosperma quebracho Pilocarpus jaborandi Pharmacological actions Oxytocic, cardiotonic, diuretic Hepatotoxin Sedative, Antihypertensive Vasoconstrictor, hypertensive CNS stimulant, deadly toxin Aphrodisiac, stimulant Miotic, cholinergic

Quinolizidine Pyrrolizidine

CLASSIFICATION OF PROTOALKALOIDS
Sr. No. Class Alkaloidal amines (protoalkaloids) Examples Colchicine 1 Ephedrine Mescaline Species Colchicum autumnale Ephedra sinica Lophophora williamsii Pharmacological actions Antimitotic, uric acid amines solvent Sympathetic stimulant, bronchodilator Hallucinogenic
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Alkaloidal amines, Dr. Harish Kakrani, CDCP

CLASSIFICATION OF PSEUDO-ALKALOIDS

Sr. No.

Class

Examples Caffeine

Species Coffea arabica Thea sinensis Paullinia cupana Solanum spp. Veratrum album Aconitum spp.

Pharmacological actions CNS and sympathetic stimulant Bronchodilator, diuretic CNS and sympathetic stimulant Steroid precursors, antiinflammatory Cardiac depressants, antihypertensives Antipyretic, analgesic, neurotoxin

1

Purine alkaloids

Theophylline Guaranine Solanine

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Steroidal alkaloids Terpenoidal alakaloids

Veratrine Aconitine

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AMINO-ALKALOIDS (PROTO-ALKALOIDS)

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AMINO ALKALOIDS
GENERAL CHARACTERISTIC FEATURES: ‡ ‡ ‡ ‡ ‡ Protoalkaloids Have no nitrogen as the part of the heterocyclic ring. Derived from amino acid like l- phenyl alanine. Physiologically active compounds Example: Ephedrine (Ephedra species) and Colchicine (Colchicum autmnale)

BIOSYNTHESIS OF AMINO ALKALOIDS: ‡ ‡ Amino alkaloids are derived from amino acid l- phenyl alanine through shikkimic acid pathway. The pathway finds its route from carbohydrates for the biosynthesis of C6- C3 units (i.e. phenyl propane derivatives) like phenyl alanine and tyrosine ‡ An important branching point arises at chorismic acid, which acts as a precursor for different amino acids.

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BIOSYNTHESIS OF AMINO ALKALOIDS

Dehydration

3- dehydro Shikimic acid

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BI

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Shikimic acid Prephenic acid
Dehydration

Phenyl pyruvic acid
Phosphoenol pyruvic acid

Shikimic acid3- phosphate

5- enolpyruvyl shikimate-3phosphate
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BIOSYNTHESIS OF AMINO ALKALOIDS

Phenyl alanine

Ephedrine (Ephedrine spp.)

Colchicine (Colchicum autumnale)
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GENERAL PHARMACOLOGICAL ACTION & USES OF AMINO- ALKALOIDS

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Cause ± ± ± Dilation of the bronchi (asthma), Increase heart rate and Peripheral vasoconstriction

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EPHEDRA

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EPHEDRA
‡ ‡ Synonym: Ma-Huang. Biological source: It consists of dried young stems of Ephedra gerardiana (wall.) Stapf, and E. nebrodensis (Tineo) Stapf. o o ‡ ‡ Family: Gnetaceae (Ephedraceae). Ephedra should contain not less than 1% of total alkaloids, calculated as ephedrine.

Geographical source: China, Pakistan, North-west parts of India, Australia, Kenya, Spain & Yugoslavia. Cultivation, Collection & preparation: o o o o o o Cultivated at an altitude of 2500- 3000 m. Annual rainfall should not exceed 50cm. Propagated by seeds or by layers or divisions of root stock. Seeds sown early in spring at a distance of 5cm, keeping distance of 1 mt between 2 rows Collected after attaining the age of 4 yrs for extraction of alkaloid Alkaloid content varies from season to season.  It is maximum in autumn o o Twigs dried in sun or even by artificial ways. Stored in dry & well closed containers
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EPHEDRA ‡ Macroscopic Characters: o General appearance: Thin cylindrical or ellipsoidal cylinder, o Size: 1±2 mm in diameter; 3.5±5.5cm in length of internode; o Color: Light green to yellow-green; o Surface: numerous parallel vertical furrows on the surface; scaly leaves at the node portion; o Leaves: 2±4 mm in length, light brown to brown in colour, usually opposite at every node, adhering at the base to form a tubular sheath around the stem. o Transverse section of the stem: appears as circle and ellipse, the outer portion greyish green to yellow-green in colour, and the centre filled with a red-purple substance or hollow. o Fracture at an internode: the outer part is fibrous and easily split vertically o Odour: slight; o Taste: slightly bitter and astringent, giving a slight sensation of numbness on the tongue .
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EPHEDRA

Macroscopical characteristics of Ephedra Stem & Leaves

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EPHEDRA
‡ Microscopic characteristics: 1. STEM: ‡ The epidermal cells of the stem covered with a moderately thick granular cuticle; the cells are polygonal or subrectangular, axially elongated, having straight anticlinal walls. ‡ The stomata are few and are of the ranunculaceous type with lignified appendages. ‡ Cortical parenchyma and pith cells contain an amorphous reddish brown substance. ‡ Non-lignified or lignified hypodermal and pericyclic fibres, which have thick walls, bear slit-like pits and blunt, slightly tapering, occasionally forked ends. ‡ The vessels of the secondary xylem of the stem are lignified with bordered pits, having rounded or oval apertures. ‡ Few, small, rounded, simple and compound starch granules with indistinct hilum are present in cortical parenchyma, pith, and medullary ray cells. ‡ Few, small prisms of calcium oxalate are present in the cortical parenchyma. 2. LEAF: ‡ The epidermis of the scaly leaf is covered with smooth (upper) or warty (lower) cuticle and consists of subrectangular to polygonal cells, having straight or sometimes slightly beaded anticlinal walls; few stomata are present resembling those of stem.
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EPHEDRA
‡ The epidermis of the apical and marginal regions of the scaly leaf shows short papillae-like outgrowths. ‡ Chlorenchymatous palisade-like cells form the outer zone of the cortex; rounded ordinary parenchymatous cells form the inner zone of the cortex. ‡ The fibres of the scaly leaf are lignified. ‡ Powder characteristics: o o Powdered herb is greyish green. The characteristics observed are as follows: ‡ Thick fragments of cutinized outer walls of epidermis ‡ Sclerenchyma fibres with extremely thickened, non-lignified to lignified walls, narrow, frequently indistinct lamina and sharp pointed ends. ‡ Fragments of vascular tissue showing spiral and pitted tracheae. ‡ Fragments of epidermis with sunken elliptical stomata

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EPHEDRA

Transverse Section of Ephedra Stem

Powder characteristics of Ephedra stem
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Alkaloidal amines, Dr. Harish Kakrani, CDCP

EPHEDRA
‡ Chemical constituents: o o Amino alkaloids: Ephedrine, nor-ephedrine, n-methyl ephedrine, pseudo-ephedrine. Chemically, ephedrine is 1-phenyl-1- hydroxy-2- methylaminopropane ‡ Soluble in water, alcohol, organic solvents and oil ‡ Odourless & colourless ‡ Deliquescent ‡ Decomposes when exposed to air. o Other constitutents: ‡ Macrocyclic alkaloids- ephedradines present in roots. ‡ Oxazolidone.

Ephedrine N-methyl ephedrine
Alkaloidal amines, Dr. Harish Kakrani, CDCP

Nor-ephedrine

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EPHEDRA
‡ Chemical Tests: o Ephedrine dissolved in water & dil. HCl Violet colored solution layer shows blue color. ‡ Uses: o Sypathomimetic effects ‡ ‡ ‡ Bronchodilator in asthma In treatment of allergic conditions like hay fever As compared to adrenaline onset of action for ephedrine is slow, but effect is much prolonged, as it is not quickly hydrolysed by mono amine oxidase in the body. o ‡ Causes peripheral contraction of arterioles, therefore used to correct the low blood pressure conditions. treat individually with Copper sulfate & NaOH if shaken with solvent ether, organic layer shows purple color & aqueous

Allied drugs: o o o o o Genus Ephedra has about 45 species About 25 species contain ephedrine. Prominent species containing ephedrine are E. equisetina & E. sinica E. intermedia, E. major, E. helryetica & E. alata: Contain from 35- 87% of ephedrine in total alkaloids. The other plants containing ephedrine are Aconitum napelles (Ranunculaceae); Sida cordifolia; and S. rhombifolia (Malvaceae); Roemeria refracta (Papaveraceae) and Taxus baccata (Taxaceae).

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COLCHICUM

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COLCHICUM
‡ ‡ Synonyms: Meadow saffron seeds, autumn crocus Botanical source : It consists of dried ripe seeds and fresh or dried sliced corms of Colchicum autumnale o ‡ Family: Liliaceae.

Geographical sources: o o Indigenous to Britain Grows in Central and Southern Europe

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Cultivation & Collection: o Colchicum propagates by repeating the life cycle with the corm, which is present as a swollen underground stem with sheathing leaves. o Towards the end of summer, the fully grown corm develops daughter corms in the axil of scaly leaf near the base. o o o These daughter corms develop parasitically on parent corm & subsequently parent corm withers away. The daughter corms develop into new corms. May also be propagated by seeds, sown 1/8 inch deep in a bed of fine soil outdoors in August or September; transplanting seedlings 3 inches apart when two years old; or by division of bulbs in August. Seedling bulbs do not flower till four or five years old.
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COLCHICUM
‡ Macroscopic characteristics: 1. Colchicum seeds: o o o o o o Very hard in nature Have a projection at hilum & from there develops strophiole, which is an outgrowth of testa. Size: 2-3mm in diameter Taste: bitter & acrid Odour: Odourless

2. Colchicum corm: o o o o o o Size: 2-3cm in diameter, 2-5mm thickness Fracture: Short Shape: sub-reniform or ovate in outline Color: yellowish brown Taste: bitter Odour: Odourless
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COLCHICUM
‡ 1. Microscopic characters: T.S of Seed: o o o o 2. Shows parenchyma & endosperm Parenchymatous cells are reddish brown with thick walls Endospermic cells show pitted walls & contain aleurone grains and fixed oils Strophiole portion of the seeds contain starch

T.S of corm: o o o o Corm has epidermis, parenchyma & vascular tissue Parenchymatous cells have abundant starch grains Epidermis has circular stomata In vascular part, the xylem vessels are spiral or annular.

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Chemical Constituents: o o o o SEED: 0.2-1% amino alkaloid , of which Colchicine is 0.8% CORMS: 0.6% Colchicine. Also contains demecolcine Both the alkaloids contain tropolone or cycloheptatrien-ol-one ring structure. Colchicine is a toxic, yellowish-white amorphour or crystalline substance that darkens on exposure to light. It is soluble in alcohol & chloroform, sparingly soluble in water.
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COLCHICUM

Powder characteristics of Colchicum seed powder
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COLCHICUM

Colchicine

Demecolcine

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COLCHICUM
‡ Chemical tests: o o ‡ Colchicine + 60 - 70% sulphuric acid or conc. HCl Alcoholic solution of colchicine + ferric chloride yellow colour is produced. red color

Uses: o o o Gout & rheumatism Also possesses anti-tumor activity Used in horticulture as a chemical agent for bringing polyploidy

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Allied drugs: o Plants bearing chemical contents similar to colchicine type of alkaloids belong to different genera such as, Dipidax, Gloriosa, Androcybium, Camptorrhiza, etc. o Other genera of same family liliaceae which contain colchicine- Androcybium, Bulbocodium, Dipidax, Littonia, Fritillaria, Ornithoglossum, etc.

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