HISTAMINES & ANTIHISTAMINES, 1ST & 2ND GENERATION, H1 & H2 ANTAGONIST

HISTAMINES & ANTIHISTAMINES, CHEMISTRY & STRUCTURAL ACTIVITY RELATIONSHIP.

1. ANTIHISTAMINES AY-2019-20 Purushotham K N Assistant professor Dept. of Ph. Chemistry SACCP. 1

2. HISTAMINE AND ANTIHISTAMINES 2

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4. Histamine ( β- Aminoethyl imidazole or [2-( imidazol-4-yl)ethylamine]) is a hydrophilic molecule consisting of an imidazole ring with amino group connected by two methylene groups . Analogs of histamine activated the four classes of histamine receptors (H1, H2, H3 and H4). 2-Methylhistamine and 4(5 )-Methyl histamine have a preferential effect on H1 and H2 receptors respectively. HISTAMINE 4

5. Histamine or B - imidazolylethylamine is synthesized from L- histidine by histidine decarboxylase, an enzyme that is expressed in many mammalian tissues including gastricmucosa parietal cells, mast cells, and basophils and the central nervous system (CNS ). As a result, histamine plays an important role in human physiology including regulation of the cardiovascular system, smooth muscle, exocrine glands , the immune system, and central nerve function. It is also involved in embryonic development, the proliferation and differentiation of cells, hematopoiesis, inflammation, and wound healing. Histamine exerts its diverse biologic effects through four types of receptors. 5

6. The involvement of histamine in the mediation of immune and hypersensitivity reactions and the regulation of gastric acid secretion has led to the development of important drug classes useful in the treatment of symptoms associated with allergic and gastric hypersecretory disorders. 6

7. Types 7

8. DISTRIBUTION Widely distributed in animal kingdom and is presented in venoms , bacteria and plants . Particularly tissues having high concentration of histamine and that contain large number of mast cells such as skin, bronchial tree mucosa and intestinal mucosa . 8

9. SYNTHESIS, STORAGE AND METABOLISM OF HISTAMINE Histamine is a dibasic vasoactive substance formed from the decarboxylation of the amino acid histidine by the enzyme L- histidine decarboxylase . SSM 9

10. The main site of histamine storage in most tissues is the mast cells and basophil in the blood. In these cells, histamine is synthesized and stored in secretory granules that are then carried through the axons and stored in nerve terminals located in the median eminence or posterior pituitary gland. Histamine is positively charged with the pH of approximately 5.5, and ionically complexed with negatively charged acidic groups on other constituents of the secretory granule . Non-mast cell sites of histamine formation or storage include the epidermis, gastric mucosa , neurons within the CNS and cells in regenerating or rapidly growing tissues . Histamine is released continuously rather than stored because of rapid turnover at non-mast cell sites. Non-mast cell sites of histamine production contribute significantly to the daily excretion of histamine metabolites in the urine. 10

11. Metabolism of histamine 11

12. CLASSIFICATION 12

13. First Generation Antihistamines (Sedative Type) Alkylamines - Diphenhydramine HCL, Bromo Diphenhydramine HCL, DimenHydrinate , Doxylaminesuccinate . Ethylenediamines - Tripelennamine Citrate, Tripelennamine HCl , Pyrilamine Maleate. Piperazines ( Cyclizines ) - Cyclizines HCl , Cyclizines Lactate, ChloroCyclizines HCl , Meclizine HCl . Propylamines - Pheniramine Malete , Chlorpheniramine Malete , DexChlorpheniramine Malete , BromoPheniramine Malete , DexbromoPheniramine Malete , Phenothiazines - Promethazine HCl , Trimeprazine Tartaret . Dibenzocycloheptenes & Dibenzocycloheptanes - Cyproheptidine HCl , Azatadine Maleate, H-1 1 st Gen. 13

14. Second Generation Antihistamines (Non- Sedative Type) Fexofenadine HCl , Terfenadine Loratadine Cetirizine Acrivastine H-1 2 nd Gen . 14

15. Like histamine, most of the classic antihistamines may be described by a substituted ethylamine moiety i.e., GAS . Aryl group: In the above structure, 1. Ar is aryl(including phenyl & heteroaryl group like 2-pyridyl). 2. Ar ’ is aryl or aryl methylgroup . Some times the two aromatic rings are bridged, which constitutes tricyclic ring derivatives. General Antihistamine Structure [GAS] SAR 15

16. Nature of X : The nature of X provides the basis of chemical classification of classical anti-histamines e.g., 1. When X = O i.e., GAS = Aminoalkylether’s 2. When X = N i.e., GAS = Ethylene- diamine’s 3. When X = C i.e., GAS = Monoaminopropyl’s General Antihistamine Structure [GAS] SAR 16

17. Nature of Alkylchain : Most of the structures of classical antihistamines contain an ethylene chain. Extension or Branching of this chain results in a less active compound (promethazine is an exception). Homologation plays an important role in the development of Neuroleptics & tricyclic antidepressants from anti-histamines. General Antihistamine Structure [GAS] SAR 17

18. Nature of Terminal ‘ N’ atom : Terminal ‘ N ’ atom should be a 3º amine for the maximum activity. The terminal ‘ N ’ may be a part of heterocyclic ring as in Chlorocyclizine, and still retains high antihistaminic activity. General Antihistamine Structure [GAS] SAR 18

19. AMINOALKYL ETHERS (ETHANOLAMINES) General structure The aminoalkyl ether antihistamines are characterized by the presence of a CHO connecting moiety (X) and a two- or three-carbon atom chain as the linking moiety between the key diaryl and tertiary amino groups 19

20. General structure 20 8-chlorotheophylline

21. Ethylenediamines The Ethylenediamine antihistamines are characterized by the presence of a nitrogen-connecting atom (X) and a two-carbon atom chain as the linking moiety between the key diaryl and tertiary amino moieties General structure 21

22. General structure 22

23. PIPERAZINES ( CYCLIZINES ) The piperazines or cyclizines can also be considered ethylenediamine derivatives or cyclic ethylenediamines ; in this series, however, the connecting moiety (X) is a CHN group , and the carbon chain , terminal amine functionality, and the nitrogen atom of the connecting group are all part of a piperazine moiety. GENERAL STRUCTURE 23

24. GENERAL STRUCTURE 24 4-methylpiperazine

25. PROPYLAMINES The propylamine antihistamines are characterized structurally by an sp3 or sp2 carbon-connecting atom with a carbon chain of two additional carbons linking the key tertiary amino and diaryl pharmacophore moieties GENERAL STRUCTURE 25

26. GENERAL STRUCTURE 26 2,3,4,9-tetrahydro-2-methyl-9-phenyl-1H-indeno[2, 1-c] pyridine bitartrate

27. (E)-2-[3-(1-pyrrolidinyl)-1-p-tolylpropenyl]pyridine monohydrochloride monohydrate 27

28. PHENOTHIAZINES The phenothiazine derivatives that display therapeutically useful antihistaminic actions contain a two- or three-carbon , branched alkyl chain between the ring system and terminal nitrogen atom GENERAL STRUCTURE 28 Phenothiazine ring

29. GENERAL STRUCTURE 29

30. DIBENZOCYCLOHEPTENES & DIBENZOCYCLOHEPTANES- GENERAL STRUCTURE The dibenzocycloheptene and dibenzocycloheptane antihistamines may be regarded as phenothiazine analogs in which the sulfur atom has been replaced by an isosteric vinyl group ( cyproheptadine ) or a saturated ethyl bridge ( azatadine ), and the ring nitrogen has been replaced by an sp2 carbon atom. 30

31. GENERAL STRUCTURE 31 1-methylpiperidine

32. The first generation antihistamines penetrate blood brain barrier and also possess anticholinergic properties. This has lead to the development of second generation antagonists known as non sedating antihistamines . i.e . the second generation antihistamines do not penetrate the B lood B rain B arrier and as such do not cause drowsiness. SECOND GENERATION 32

33. SECOND GENERATION 33

34. Drugs whose pharmacological action primarily involves antagonism of the action of histamine at its H2-receptors find therapeutic application in the treatment of acid-peptic disorders including heartburn , gastroesophageal reflux disease (GERD ), erosive esophagitis , gastric and duodenal ulcers, and gastric acid pathologic hypersecretory diseases such as Zollinger -Ellison syndrome. They are also useful in combination with H1-antihistamines for the treatment of chronic urticaria and for the itching of anaphylaxis and pruritis . H2-RECEPTORS ANTAGONIST 34

35. HORMONAL REGULATION OF ACID SECRETION BY PARIETAL CELLS. 35

36. H 2 Receptor A ntagonists 36

37. 37 REFERENCES Wilson and Gisvold’s Textbook of Organic medicinal & pharmaceutical chemistry edition -12, pg.no :733-755 https://en.wikipedia.org/wiki/Antihistamine https:// en.wikipedia.org/wiki/Histamine

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