Isoquinoline Alkaloids

Alkaloids Derived from Phenylalanine and Tyrosine

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ISOQUINOLINE ALKALOIDS1- IPECACUANHA ALKALOIDS

Occurrence:

Ipecac is the dried roots and rhizomes of Cephalis ipecacuanha (Brazilian ipecacuanha) or Cephalis acuminata (Cartagena or Panama ipecacuanha) Fam. Rubiaceae.

It contains several alkaloids (2 –2.5 %), mainly emetine (50- 70 % of total alkaloids), with cephaline and psychotrine.

N

MeO

RO

N

OMeOMe

HH

R = Me EmetineR = H Cephaline

N

MeO

HO

N

OMeOMe

H

Psychotrine

2

Emetine: white amorphous powder, non-phenolic, soluble in alcohol, ether and

CHCl3, sparingly soluble in H2O

Cephaline: colorless needles, being phenolic (soluble in alkalis), insoluble in H2O,

soluble in CHCl3 or alcohol, on methylation with methyl-sulphate is converted to

emetine

Psychotrine: yellow prisms, being phenolic, sparingly soluble in H2O, ether, soluble

in ethanol and CHCl3, on reduction is converted

N

N

OCH 3

OCH 3

H3CO

H3COH

HHO

H3CO

OCH 3

OCH 3

N

N

HHO

H3CO

OCH 3

OCH 3

N

N

EmetineMethylationReduction and

methylation

Reduction

H2

Psychotrine Cephaline

3

4

Cephaline

Emetine

With Dragendorf’s reagentWith J/CHCl3

reagent

With J/CHCl3 reagent

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BisbenzyltetrahydroisoquinolinesCurare alkaloids• dried extract from the bark and stems of Strychnos species e.g. S. castelnaei,

S. toxifera, S. crevauxii (Fam. Loganiaceae) and from Chondodendron species (Fam. Menispermaceae) used as arrow poison by certain native tribes of the Amazon regions of South America.

• Curare contains several alkaloids (4-7%), the most important is d-tubocurarine(quaternary ammonium structure with two ether bridges)

• the other alkaloids are tertiary bases : (-) curine, (+) - isochondrodendrine and (+) chondrocurine.

6

7

Properties: d-tubocurarine (4ary alkaloid) is freely soluble in H2O. It is a phenolic

dextrorotatory alkaloid. It is a bis-benzyltetrahydroisoquinoline alkaloid.

Tests: Saturated aqueous solution + FeCl3 faint green color green color.

Solution of the alkaloidal HC1 + Na2CO 3 yellow brown precipitate.

Uses: Tubocurarine chloride is mainly used by i.m. or i.v. routes as

skeletal muscle relaxant.

It is used to control and reduce convulsions of strychnine poisoning and of tetanus.

It is used as a diagnostic aid in myasthenia gravis. 8

- (+)-tubocurarine- a white or yellowish white to grayish white, odorless, derived from tube curare and isolated in 1898, soluble in water and in alcohol, insoluble in acetone, chloroform and ether., - it is a non-depolarizing neuromuscularblocking agent , employed i. m or i. v. as a skeletal muscle relaxant to secure muscle relaxation in surgical procedures. - Its use was discontinued about ten years ago. -A semisynthetic derivative of C-toxiferine is used N, N-diallylnortoxiferinium dichloride (=alcuronium), which is used i. v. as adjunct in anesthesia.

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CH3N

O

RO

HO

1

23

4

5

6

7

8

9

10

11

12

1314

15 16

R = H : MorphineR = CH3 : Codeine

1615

1413

12

11

10

9

8

7

6

5

4

32

1

CH3O

O

N CH3

CH3O

H H

Thebaine

Crude Opium Milky exudate obtained by incising the unripe capsules of Papaver somniferum

(Papaveraceae) The active principles are represented by 10 to 20% alkaloids More than 25 alkaloids of different types have been obtained The most important type is the morphinane type e.g. morphine, codeine, Thebaine Opium alkaloids occur naturally combined with specific acid (meconic acid).Occurs only in opium

Chemical tests: by directly adding ferric chloride to the aqueous extract red color develops (characteristic of meconic acid).

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OPIUM POPPY

Papaver somniferum

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CLASSIFICATION Natural opiates: are alkaloids contained in the latex of opium as morphine, codeine, and thebaine.

Semi-synthetic opioids: created from the natural opiates, such as heroin, oxycodone, and hydrocodone are derived from morphine, codeine, and thebaine.

Fully synthetic opioids: such as pethidine, methadone, tramadol.

Endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.

Opium alkaloids are subclassified into 3 groups:

Benzylisoquinoline alk.

Phenylethylamine alk.

Phenanthrene alk.

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BENZYLISOQUINOLINE:Papaverine

Properties:

It is a weak base and is optically inactive.

Tests for identification

Warren's test (specific for papaverine):

Papaverine + crushed crystal of KMnO4

+ Marqui's reagent green color blue.

Uses:

Papaverine possesses smooth muscle relaxant activity. It is used as antispasmodic for GIT spasms, clots and in bronchial asthma in a dose up to 600 mg of papaverine HCl daily.

Noscapine

Used as antitussive medicine without pain killing effect

Phenylalkylamines:Narceine

Properties:

It is a tertiary Alkaloids. Narceine is an amphoteric alkaloid since it contain a carboxylic group.

N

O

O

C O

CH3

CH3

COOH

OCH3

OCH3

OCH3

PHENANTHEREN GROUP:Morphine:

Properties:Morphine is levorotatory, insoluble in water, sparingly soluble in ethanol (1:250) and chloroform (1:1500), practically insoluble in ether and benzene.

It contains 2 OH groups, one is a phenolic at C-3 (gives a soluble phenate with alkali) and the other is a 2ry alcoholic at C-6.

RO

HO

NCH3H

O

R= H MorphineR= CH3 Codeine

A

B

C

DE

3

6

TESTS FOR IDENTIFICATION:Tests due to phenolic properties: 1- Morphine gives a blue color with FeCl3.

2- Nitrous acid test: solution of morphine in dilute HCl + NaN02 + NaOH red color.

3- Morphine + dil H2SO4 + HI→ I2 give violet colour when dissolve in CHCl3

Tests with alkaloidal color reagents:1- Liebermann' s reagent black color.

2- Mandalin's reagent bluish-gray color.

3- Marquis' reagent violet color.

4- HNO3 → red colour convert to yellow on heating.

USES:Morphine act as a narcotic analgesic (reduce pain & induce sleep) in a dose of 5-20 mg of morphine hydrochloride, sulfate or tartrate, administered orally or parentrally, every 4 hours.

Used before and after surgical operations and to terminally ill cancer patients.

Suppress peristaltic movement so stops diarrhea.

Adverse Effects:Two major problems are associated to morphine use:

Addiction and Tolerance.

Morphine

O

HOH

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Morphine (Astramorph)

HO- Group is needed for activity

HO- Group not important to activity

Codeine:

Properties:

It is soluble in H2O, boiling H2O, ethanol, CHCl3 and ether, (c.f. morphine).

Codeine is non Phenolic.

Test: Codeine + concentrated H2SO4 + FeCl3, warm in water bath bluish violet color + HNO3 Red color.

Uses:

It has less narcotic analgesic than morphine.

It is mainly used as antitussive.

RO

HO

NCH3H

O

R= H MorphineR= CH3 Codeine

A

B

C

DE

3

6

Codeine

O

HOH

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Morphine (Astramorph)

HO- Group is needed for activity

HO- Group not important to activity

O

HOH

NH

CH3

CH3O

Codeine (5X LESS potent than morphine)

Inefficiently converted to HO group in the liver

Thebaine

Thebaine (paramorphine) is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but produces stimulatory, with strychnine-like convulsions, rather than depressant effects. Thebaine is not used therapeutically, but is converted industrially into a variety of compounds including oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and etorphine.

O

CH3O

NH

CH3

CH3O

SEMI-SYNTHETIC DERIVATIVES OF MORPHINE:

Heroin

It is the diacetyl derivative of morphine. It has no any medical applications but it is one of the most dangerous abused substance.

Morphine is easily acetylated to diacetylmorphine using acetic anhydride.

CH3

CO

CCH3

O O

morphine

Heroin is more potent than morphine (it takes less for the same effect), lasts longer, and is more addicting.

Apomorphine

Obtained by heating morphine with coc. HCl in sealed vials. During this reaction rearrangement and elimination of water takes place. Apomorphine is used in the treatment of Parkinson’s disease and erectile dysfunction.

+ HCl, Δmorphine

Ether bridge opening (ring E):

Resulted in group of compounds called morphinans. Synthetic morphinans are racemic compounds. Only the levo isomers have analgesic activity. Levorphanol is 8 times as active as morphine. The dextro isomers as dextromethorphane lack the CNS and analgesic effects, however, they are used as cough suppressants.

RO

NCH3H

R= H (-) Levorphanol RP=8R= CH3 (+) Dextromethorphan

RO

HO

NCH3H

O

R= H MorphineR= CH3 Codeine

A

B

C

DE

3

6

The C-6 Hydroxyl group and ring c modifications:Removal or derivitization of the alcoholic hydroxyl group at C-6 increase

lipophilicity and consequently the analgesic activity.

Reduction of the 7,8 double bond, oxidation of C-6 hydroxyl and addition of OH group at C-14 all increase the activity.

HO

R

NCH3H

O

HO

NCH3R

O

HO

HO

NCH3H

O

O

R=H Hydromorphone RP=5-6R=OH Oxymorphone RP=10Dihydromorphine

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R=H 6-Deoxymorphine RP=10R=OCH3 6-Methoxymorphine RP=5R=OC2H5 6-Ethoxymorphine RP=2.5R=OCOCH3 6-MAM RP=4.2

The C-3 Hydroxyl group:

Etherification of this phenolic OH decrease the analgesic activity and the compounds are used mainly as antitussive e.g. Codeine and Pholcodine.

C2H4O

HO

NCH3H

O

NO

Pholcodine

29

30

31

32

CodeineMorphine

Papverine

Noscapine

Marquis reagent

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Phenylalkylamine Alkaloids

Alkaloids Derived from phenylalanineAlkaloids with Exocyclic Nitrogen

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 Phenylalkylamine group

1.1. Benzylamine type 1.2. Phenylethylamine type

1.3. 2-Aminophenylpropan type

N

R R RR

N

RR

N

2

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Ephedra Alkaloids

Various Ephedra species, e.g. E. sinica (Ephedraceae) Ephedra used as remedy for Asthma in Chinese medicine Contains 2% alkaloids e.g. ephedrine, Pseudoephedrine, norpseudoephedrine.

HO-C-H

CH3-NH-C-H

CH3 CH3

H-C-NH-CH3

HO-C-H

CH3

H-C-NH2

HO-C-HR RR

S RR

L-Ephedrine D-Pseudoephedrine D-Norpseudoephedrine

S

C = O

H2N-C-H

CH3

L-Cathinone

(-)-Ephedrine is the major Alkaloid in Ephedra.

Ephedrine is a phenylalkylamine with N atom in the side chain

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E. sinica

37

• Ephedrine is similar to adrenaline in structures.• Advantages of Ephedrine over adrenaline:

1- Orally active. 2- Prolonged action

CH CH CH3

NHOH CH3

Ephedrine

CH CH2

NHOH CH3

HO

HO

Adrenaline

* *

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Pharmacology: ephedrine is an indirect sympathomimetic, close to adrenalineUses: in asthma, allergic drugs, bronchodilator, nasal congestion and in cough mixtures

Chen’s test: Ephedrine HCl in water + 0.1 ml CuSO4 + 1ml NaOH → Violet

colour, shake with Ether →

Ether layer → purpleAqueous layer → blue

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2- Capsicum

Ripe fruit of Capsicum annum (Solanaceae) Contains 1.5% Capsainoids (amides of vanillylamines with satrurated or unsaturated C8-C13 fatty acids)

NR

H

HO

H3CO Capsaicine R =

O

O

Dihydrocapsaicine R =O

Nordihydrocapsaicine R =

Uses: as carminative, counterirritant in the form of tincture or plaster in the treatment of rheumatism and neuralgic painsTest: 1- solution of capsaicine + FeCl3 green color 2- Capsaicine + H2SO4 + small amount of sugar violet color after period of 1 h

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Capsicum annum Capsicum frutesence

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3- Khat

Leaves of Catha edulis (Celastraceae) in fresh leaves cathinone, in the dried cathine Pharmacology: 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.

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Khat

3- Peyote Alkaloids

NH2

H3CO

H3CO

OCH3

Mescaline

• Source: Lophophora williamsii ( is a small, spineless cactus)

• Hallucinogenic • Major alkaloid

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Tropolone Alkaloids

Alkaloids Derived from Phenylalanine and Tyrosine

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Colchicum Alkaloidsdried, ripe seed and corm of Colchicum autumnale (Liliaceae) Up to 1.2 %, the chief constituent is colchicine Colchicine possesses a tropolone structure and being non- basic or weak-basic in character, soluble in H2O, aq. alcohols and CHCl3, occurs as pale yellow needles, may be extracted from both acid and alkaline solutions by shaking with CHCl3

Tests for colchicine: 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.Pharmacology: Colchicine possesses an anti-mitotic and anti-inflammatory activity. It is useful for treating of the acute attack of gout .

H3CO

H3CO

OCH3

OCH3

O

NH-CO-CH3

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Imiazole Alkaloids

Alkaloids Derived from histidine

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Imidazole Alkaloids Pilocarpus Alkaloids

• Source: Jaborandi leaves (Pilocarpus jaborandi).• Constituents: (+)-Pilocarpine.• Properties: 1- Oily liquid miscible with water.

2- Non-volatile liquid alkaloid.3- Lactone function.

• Test:Helche’s test: Alkaloid + Dil acid + K2CrO7 → violet colour

(Pilocarpine dichromate)• Uses:

1- Miotic. 2- Diaphoretic.3- Hair preparations.

N

N O

CH3

O

Pilocarpine is a cholinergic agent causing

constriction of the pupil (Antagonistic to Atropine).

Pilocarpine salts are valuable in ophthalmic practice

and are used in eye drops as miotics and for the

treatment of glaucoma.

Pilocarpine gives relief for dryness of the mouth that

results in patients undergoing radiotherapy for mouth

and throat cancers.

Effects/Uses:

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52

Chemical tests:1- Helch’s test (H2SO4 + H2O2 + KCr2O7) gives violet color

2- Ekkert’s test (Na-nitroprusside + NaOH) leave for a period in HCl-solution, it gives red

color