Indole alkaloids

This group includes:

◘ The neurohormone serotonin.
◘ The hallucinogenic alkaloids, psilocin and psilocybin.
◘ Physostigma alkaloids.
◘ Ergot alkaloids.
◘ Nux vomica alkaloids.
◘ Vinca alkaloids.

1. Alkaloids of the Indole Group By Dr. Mostafa Mahmoud Hegazy ( PH.D.)

2. Alkaloids of the Indole Group L-Tryptophan amino acid 1- An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. 2- It is a precursor of indole alkaloids in plants. 3- It is a precursor of serotonin (hence its use as an antidepressant and sleep aid ). 4- It can be a precursor to niacin ( vit . B3) in mammals.

3. This group includes: ◘ The neurohormone serotonin. ◘ The hallucinogenic alkaloids, psilocin and psilocybin. ◘ Physostigma alkaloids. ◘ Ergot alkaloids. ◘ Nux vomica alkaloids. ◘ Vinca alkaloids.

4. Serotonin (5 - hydroxytryptamine ) Occurrence ◘ Serotonin in Human is found in the brain, blood platelets, and throughout the gastrointestinal tract . It acts as a biochemical mediator and its roles include involvement in CNS neurotransmission, haemostasis , vascular spasm, and gastrointestinal motility.

5. ◘ Serotonin is a skin irritant that acts by promoting histamine release . ◘ Serotonin was isolated from plant origin Mucuna pruiens ( Leguminosae ) and stinging nettles ( Urtica dioica ) . It occurs in several fruits e.g. banana, tomatoes, avocado, pineapple , which are although not noticed to have an irritating effect and in the stings of wasps and scorpions . ◘ High concentrations of 5-OH indole acetic acid ( a metabolite of 5-OH tryptamine ), indicate the presence of certain types of intestinal tumors and are used in diagnosis.

6. Color tests: 1) Serotonin + Marqui's reagent  brown color . 2) Serotonin + Vitali's test  grayish green color  brown . 3) Serotonin + Ammonium molybdate solution  blue color  brown .

7.   serotonin Tryptophan sources Mucuna pruiens and stinging nettles . It occurs in several fruits e.g. banana , tomatoes , avocado and pineapple , and found in the stings of wasps and scorpions .   Natural sources more favourable than pharmaceuticals which may cause certain side effects due contaminants during biotransformation. Eggs, spirulina , milk, Sesame seed, meat, salmon, nuts, turkey, chicken and banana   Biological roles As mentioned before As mentioned before Crossing BBB does not cross cross Medicinal use No use as neurohormone as weak antidepressant and sleep aid. Dose and combinations ------ May used with pyridoxine and ascorbic acid, which are involved in its metabolism to serotonin. As 500 mg tablets.

8. Drugs that affect serotonin levels Some antidepressants increase serotonin concentrations 1- As precursors ( Oxitriptan and Tryptophan ) hence its use as an antidepressant and sleep aid . 2- By inhibiting the metabolism of monoamine oxidase A- non-selective irreversible inhibitors of monoamine oxidase types A and B (MAOIs ) B- selective reversible inhibitors of monoamine oxidase type A (RIMAs )

9. 3- By inhibit the neuronal reuptake of serotonin after release A- tricyclic antidepressants B- the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine ( tried in the management of premature ejaculation ) C- selective serotonin and noradrenaline reuptake inhibitors (SNRIs) such as Sibutramine is an SNRI used in the management of obesity .

10. 2) Psilocin and Psilocybin Occurrence They occur in certain mushrooms , the red sacred mushroom of Mexico, Psilocybe mexicana ,

11. Psilocin Psilocybin ◘ occurs as plates crystals ◘ white or colorless crystals ◘ It is insoluble in water , soluble in alcohol and in dilute acetic acid. ◘ It is unstable especially in alkaline solution. ◘ Soluble in water and dilute acetic acid, ◘ It is insoluble in chloroform and benzene. ◘ Upon phosphorylation  psilocybin. ◘ It is the only natural indole alkaloid that contains a phosphate radical. ◘ Upon hydrolysis  psilocin + phosphoric acid. Properties

12. Color tests: 1) Marqui’s reagent: + Psilocin  greenish brown color + Psilocybin  orange color 2) Ammonium molybdate solution: + Psilocin  a greenish blue color + Psilocybin  gray color  blue  green yellow Uses Psilocin and Psilocybin are hallucinogenic and sympathomimetic properties similar to those of LSD.It is less potent than LSD . ( Psychedelic drugs) = causing thought and visual/auditory changes.

13. Physostigma alkaloids ( Calabar bean alkaloids ) Physostigmine ( Eserine ) * Present in the seed of Physostigma venenosum Fam. Leguminosae . * Eserine is a tertiary base, possessing an ester linkage Uses 1- Glaucoma ( myotic drug) . 2- Reversal of drug-induced CNS antimuscarinic effects , it has a cholinergic effect and stimulates gland secretion ( c.f. Atropine ).

14. Properties ◘ Eserine on alkaline hydrolysis  eseroline + methylamine + CO 2 ◘ Eserine upon oxidation , in presence of trace of alkali e.g. NaOH , or traces of metals is transformed to rubreserine (red compound ). ◘ Therefore, it could be affected by the alkalinity of glass containers during storage .

15. Tests for identification 1) Eserine blue test : Eserine + strong NH 3 solution  yellowish red color which on evaporation  a bluish residue that is soluble in alcohol ( eserine blue ) 2) Eserine + NaOH  red color . 3) Eserine ( due to its reducing characters ) + potassium ferricyanide + FeCl 3  Prussian blue color .

16. Terpenoid Indole Alkaloids Nux vomica alkaloids Dried ripe seed of Strychnos nux vomica (Fam. Loganiaceae ). * Strychnine and Brucine are poisonous alkaloids .

17. ◘ The major alkaloids are Strychnine and Brucine . ◘ They are Dihydro indole and quinoline derivatives.

18. Properties Brucine Strychnine  White crystalline powder. More soluble in CH 3 OH and C 2 H 5 OH. Unstable in presence of H 2 SO 4 and HNO 3 . Soluble in acetone and 25% C 2 H 5 OH. Precipitate very slowly by K. ferrocyanide . Mono-acidic base . It is dimethoxy strychnine  Colorless rhombic crystals Less soluble in CH 3 OH and C 2 H 5 OH. Very stable in presence of H 2 SO 4 and HNO 3 . Insoluble in acetone and 25% C 2 H 5 OH. Precipitate quickly by K. ferrocyanide . It is a mono-acidic base (only the N atom, farthest from the benzene ring forms salts, while the other N is an amide and has no basic characters ).

19. Separation of a mixture of Strychnine and Brucine Strychnine can be separated from brucine by one of the following methods:  Shaking with acetone , only brucine will dissolve.  Shaking with 25% ethanol , only brucine will dissolve.  Treating with k. ferrocyanide : Strychnine precipitates quickly Brucine precipitates slowly . Treating with conc. H 2 SO 4 + HNO 3 , ( only brucine is destroyed) ( strychnine is more stable, this method is only used for purification of strychnine from brucine ).

20. Uses: 1- Strychnine was formerly used as bitter stomachic ( improves the appetite) and stimulant . 2- Strychnine is the main principle of many rodenticides ( used as a poison for rats) . 3- In large doses , it causes violent convulsions , involving the respiratory muscles and death occurs due to asphyxia. 4- Brucine is less toxic than Strychnine but not present in clinical use.

21. Chemical Tests

22. Ergot Alkaloids * Ergot is a fungal disease commonly found on many wild and cultivated grasses, and is caused by species of Claviceps . * The disease is eventually characterized by the formation of hard, seed-like ‘ ergots ’ instead of normal seeds . * Medicinal ergot is the dried sclerotium of the fungus Claviceps purpurea ( Clavicipitaceae ) developed on the ovary of rye, Secale cereale ( Graminae / Poaceae ).

23. ◘ Ergot alkaloids are N- monosubstituted amide derivative of both: Lysergic acid and its isomer Isolysergic acid . ◘ These acids forms with ammonia the corresponding amide: Lysergic acid  Ergine Isolysergic acid  Isoergine

24. * Ergot alkaloids contains 12 major alkaloids divided into 6 pairs according to their peptide moieties. * Members related to Lysergic acid e.g. Ergotamine and Ergometrine . * Members related to Isolysergic acid e.g. Ergotaminine and Ergometrinine .

25. The simple Lysergic acid amides * They are water soluble * They are all amides of Lysergic acid with simple amines ( 2- aminopropanol ) * e.g. Ergometrine (L-lysergic acid with 2-aminopropanol) and Ergometrinine (D-lysergic acid with 2-aminopropanol)

26. The Polypeptide Alkaloids * Contain a cyclized tripeptide fragment bonded to lysergic acid via an amide linkage . * Based on the nature of the three amino acids , these structures can be subdivided into three groups : 1) Ergotamine group. 2) Ergoxine group. 3) Ergotoxine group. * The amino acids involved are ( alanine, valine , leucine , isoleucine, phenylalanine, proline , and α- aminobutyric acid. * All contain proline in the tripeptide , and one of the amino acids is effectively incorporated into the final structure in the form of an α- hydroxy -α-amino acid. * Thus, ergotamine incorporates alanine , phenylalanine , and proline residues in its peptide portion. * Hydrolysis  (+)-lysergic acid + proline + phenylalanine together with pyruvic acid and ammonia .

27. Properties Ergotamine Ergometrine (Ergnovine)  Insoluble in water. Hygroscopic.  Freely soluble in CHCl 3 . Upon Water hydrolysis  proline + pyruvic acid + β-phenylalanine + Lysergic acid . Decompose by air, heat.  Soluble in water with blue fluorescence.  Soluble in alcohol.  Insoluble in CHCl 3 . Upon Water hydrolysis  2-amino propanol + Lysergic acid .

28. Uses of Ergometrine Used as an Oxytocic (Ecbolic), [ causes vigorous contraction of the uterus ], in order to aid delivery or to prevent postpartum hemorrhage .  Injected during the final stages of labour and immediately following childbirth , especially if hemorrhage occurs .  Bleeding is reduced because of its vasoconstrictor effects , and it is valuable after Caesarian operations .  Ergometrine is also orally active . It produces faster stimulation of uterine muscle

29. Uses of Ergotamine Treatment of acute attacks of migraine , Ergotamine is effective orally, or by inhalation in aerosol form, and may be combined with caffeine.

30. Vinca alkaloids ( Catharanthus alkaloids ) Catharanthus or Vinca is the dried whole plant of Catharanthus roseus ( Fam. Apocyanaceae ).

31. They differ in the presence of: N-methyl group in vinblastine. N- formyl group in vincristine.

32. * Vinca alkaloids are Dimeric alkaloids having Indole and Dihydroindole nuclei. * Vincristine and Vinblastine are the major alkaloids in Vinca , they differs only in the substitution on the N - atom of the Dihydroindole nucleus . Uses: Vincristine used in treatment of Leukemia in children . Vinblastine is used for treatment of Hodgkin’s disease.