PHG 322 Pharmacogonsy II lecture 4 Presented by Assistant Prof. Dr. Ebtesam Alsheddi

1. PHG 322Pharmacogonsy IIlecture 4Presented byAssistant Prof. Dr. EbtesamAlsheddi بسم الله الرحمن الرحيم

2. VI. Alkaloids of the Tropane group There are two important types of tropane alkaloids: 3 They all possess the tropane nucleus.

3. 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. 1 5 The nitrogen is always methylated. The oxygen is substituted with an aromatic acid, therefore , creating an ester. • Being esters, they are unstable towards acid and alkali.

4. a) Solanaceous alkaloids: Hyoscyamus niger Daturastramonium Atropa belladonna

5. 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.

6. The3-hydroxyderivativeoftropaneisknownas TROPINE. Esterificationoftropinewithtropicacidyieldshyoscyamine(tropinetropate) TROPINE TROPANE 3 TROPIC ACID

7. Atropine & Hypscyamine • Hyoscyamine is the major natural alkaloid with negative optical rotation (l- form). • During extraction hyoscyamineracemizes to the optically inactive dl Atropine. • Both alkaloids composed of tropine base and tropic acid.

8. Pharmacological actions and uses of Atropine • Atropine sulfate has an anti-cholinergic effect (parasympatholytic activity). • It is used in medicine as: A mydriatic (causes dilatation of the eye pupil). An antispasmodic (relaxes the intestinal and bronchial smooth muscles). A pre-anesthetic medication to stop body secretions. A CNS stimulant. An antidote to organophosphorus insecticides.

9. Hyoscine (Scopolamine) • Hyoscine is an ester of l-tropic acid with scopoline base. • Hyoscine is a syrupy liquid.

10. violet colour Effects and uses of Scopolamine (Hyoscine): • The action of Scopolamine (Hyoscine) differs from that of Atropine and Hyoscyamine in: → It has no central nervous system stimulation effect, but in high doses it causes hallucination. • HyoscineHBr is commonly used in as sedative • Has antiemetic effect N.B. Vitalis test is a special test for solanaceous alkaloids + conc HNO3 & alc. KOH

11. Synthetic and Semisynthetic Derivatives: • Homatropine: Synthetic drug prepared by passing HCl gas in a mixture of tropine base and mandelic acid in the presence of water. Homatropine is less toxic than Atropine. It is hypnotic in small doses. Homatropine is used as Mydriatic with shorter effect than Atropine.

12. Hyoscine butyl bromide: Quaternary Semisynthetic derivative of Hyscine. It is used as antispasmodic and antiemetic.

13. b- Erythroxylon(Coca) Alkaloids • Occurrence: Coca leaves contain about 2% total alkaloids. • Main Alkaloids are: 1- Cocaine. 2- Cinnamylcocaine. 3. a- truxilline. • The base for Coca Alakloid is called “Ecogonine”

14. Cocaine • It is the major Alkaloid in Coca leaves. • Cocaine is diester Alkaloid. • Heating at 160 0C in conc. HCl leads to hydrolyses of cacaine to MeOH, Benzoic acid and Ecogonine base.

15. Uses: Cocaine was used as local anesthetic. Cocaine has a CNS stimulant activity so is one of the widely abused drugs.

16. V. Indole alkaloids Indole alkaloids are biosynthetically derived from Tryptophan amino acid. Indole This group includes: • Physostigmaalkaloids. • Ergot alkaloids. • Nuxvomica alkaloids. • Vincaalkaloids. • Rauwolfiaalkaloids.

17. Physostigmaalkaloids (Calabar bean alkaloids) Physostigmine (Eserine) * Present in the seed of PhysostigmavenenosumFam. Leguminosae. * Eserine is a tertiary base, possessing an ester linkage Uses A myoticdrug (in the treatment of glaucoma). , it has a cholinergic effect and stimulates gland secretion.

18. 2) Nuxvomica alkaloids *Derived from the ripe seed of Strychnosnux vomica(Fam.Loganiaceae). *The major alkaloids are Strychnine and Brucine. *Brucine is Dimethoxy derivative of Strychnine.

19. Tests for identification: • Nitric acid test: Drops of concentrated nitric + few crystals of the alkaloids: Strychnine gives a faint yellow color that on evaporation turns to yellow color Brucine gives an intense red color, that on evaporation and addition of SnCl2 solution turns to violet. • Tests for strychnine: • Sulfuric acid-dichromate test: Few crystals of strychnine +drops concentrated H2SO4 + few crystals of K2Cr2O7 → deep blue streaks →violet → purplish red → orange → yellow. • Test with Mandalin's reagent: Strychnine gives Deep violet blue color, add water → red → cherry-red.

20. Uses: Strychnine is extremely toxic. • It is used in veterinary medicine as CNS stimulant and tonic. • It is used as antidote in barbiturate poisoning. • It is also used as rodenticide. Brucine is less toxic than strychnine. • It is sometimes used as CNS stimulant, • Commercially it is used as alcohol and oil denaturant

21. 2- Vinca (Catharanthus) Alkaloids Occurrence: Catharanthus or Vinca is the dried whole plant of Catharanthusroseus G. Don (or Vincarosea L), Fam. Apocynaceae. It contains about 150 alkaloids, the most important are vinblastine and vincristine.

22. Classification: 1- Monomeric Alkaloids: These are alkaloids that contain either indole or indoline: • Indole monomers e.g. Catharanthine • Indoline monomers e.g. Vindoline and Vincamine. 2- Dimeric Alkaloids: • Homogenic dimmers: Composed of two indole or indoline monomers. • Mixed dimmers: One indole and one indoline monomers e.g. Vincristine and Vinblastine.

23. 1- Monomeric Alkaloids: • Vincamine Enhances the cerebral blood flow, facilitate cerebral circulation metabolism and increase general activity. Vincamine is used in cerebral vascular deficiency and atherosclerosis in elderly patients.

24. 2- Dimeric Alkaloids:Mixed dimmers • These are dimeric alkaloids having indole and indoline (dihydro-indole) nuclei e.g. Vinblastine and Vincristine • Vinblastine and Vincristine • They are very important for cancer treatment. • Vincristine is more active but isolated in smaller amounts than Vinblastine. Vinblastine can be converted to vincristine chemically or by microbial transformation using Streptomycesalbogriseolu.

25. Vincristineand Vinblastinediffer 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 25

26. Tests for identification: • 1-Vanillin /HCl reagent gives with: Vinblastineapink color. Vincristine an orange-yellowcolor. • 2-Van-Urk's reagent: → Reddish-brown color.

27. 3- Ergot Alkaloids • Occurrence: Ergot is the dried sclerotiumof a fungus,Clavicepspurpurea(Fam. Hypocreacea)that arise on the ovaries of the rye plant(Secalecereale, Fam. Gramineae). • Consumption of flour contaminated with Ergot led to many serious intoxications known as (Ergotism- Ignis Fire) in Europe. • Ergot can be detected in flour by using UV light where contaminated flour will show violet spots.

28. Classification of Ergot Alkaloids: A- Clavine Type Alkaloids: Simple water soluble bases with little medicinal value. All end with “clavine: e.g. Agroclavine. B- Lysergic acid Amides: They are all derivatives of (l)-Lysergic acid and subclassified into: 1- Simple lysergic acid amides: Composed of Lysergic acid and simple amines. 2- Polypeptide Alkaloids: Composed of Lysergic acid and at least 3 amino acids.

29. General Characters: • Ergot alkaloids are N-monosubstituted amide derivatives of both lysergic acid and its isomer isolysergic acid that differ only in configuration at C-8. • On treatment with ammonia lysergic and isolysergic acids give the corresponding amides ergineand isoerginerespectively. • Members related to lysergic acid (e.g. ergotamine andergometrine) are levorotatory, moreactive anddesignated by suffix “ine”. • Members related to isolysergic acid (e.g. ergotaminineandergometrinine), are dextrorotatory, less active anddesignated by suffix “inine”.

30. 1- Simple Lysergic acid amides • Characters: 1- Composed of Lysergic acid and simple amines. 2- Low molecular weight. 3- Water Soluble. Ergonovine (Ergometrine) • Composed of (l)-lysergic acid and 2-aminopropanol. • Its (d) isomer is called Ergometrinine. • Uses: It causes vigorous contraction of the uterus. It is mainly used as an oxytocic in order to aid delivery or to prevent postpartum hemorrhage.

31. Lysergic acid diethylamide (LSD) • It is a semisynthetic product. • LSD has potent CNS stimulant effect. • LSD is one of the abused drugs.

32. 2- Polypeptide Alkaloids • Characters: • They are derivatives of Lysergic acid with a complex polypeptides of at least 3 amino acids. • They have high molecular weight. • They are insoluble in water. • This class include medicinally important members.

33. Ergotamine • Characters: • Its (d) isomer is called Ergotaminine. • The peptide moiety is composed of 3 amino acids: a-Hydroxyalanine Proline Phenylalanine • Uses: Treatment of migraine as it constricts the peripheral blood vessels. Has some oxytocic (ecobolic) activity.

34. Structure Activity Relationship: • Lysergic acid must be in the (l) form. The (d) isomers are inactive. • Saturation of the 9- 10 double bond of Ergotamine gives Dihydroergotamine, a compound with antimigraine effect but no oxytocic effect.

35. Stability: • The active (l) form convert to the (d) isomer by the effect of Alkalis or prolonged storage in alcohol.

36. Chemical Test: Van-Urk's test Solution of Ergot alkaloids + Van-Urk's test (p-dimethylaminobenzaldehyde in 15% H2SO4) containing traces of FeCl3 Deep blue color