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![Clemastine
IUPAC nomenclature
(2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine
Classification
•H1-receptor antihistamine
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H1 and H2.pptx
- 1. H1 AND H2RECEPTOR BLOCKERS PREPARED BY: N.SRILAKSHMI
- 2. HISTAMINE • Histamine isan organic nitrogenous compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord and uterus. • Histamine is involved in the inflammatory response and has a central role as a mediator of itching. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues.
- 3. Synthesis and metabolism •Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine. • Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N- methyltransferase or diamine oxidase. In the central nervous system, histamine released into the synapses is primarily broken down by histamine-N-methyltransferase, while in other tissues both enzymes may play a role.
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- 5. HISTAMINE AND ITSRECEPTORS • H1 – Smooth muscle, endothelium, CNS.- Bronchoconstriction, vasodilation, separation of endothelial cells, pain and itching, allergic rhinitis, motion sickness. • H2 – gastric parietal cell, basophils. Regulate gastric acid secretion, inhibition of IgE-dependent degranulation. • H3 - CNS cells, and some in peripheral NS. Presynaptic, feedback inhibition of histamine synthesis and release. They also control release of DA, GABA, ACh, 5- HT & NE. • H4 - Highly expressed in bone morrow and white blood cells. • Mediate mast cell chemotaxis..
- 7. ANTIHISTAMINES • Histamine hasno therapeutic applications, but drugs that block its effects at H1 and at H2 receptors are very important in clinical medicine. • very less antagonists of H3 or H4 receptors are currently available for clinical use. • H1 antihistamines antagonize all actions of histamine except for those mediated by H2 receptors.
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- 9. H1 RECEPTOR BLOCKERS ▶1st generation h1 blockers ▶ Aminoalkylethers(ethanolamines): Ex. Diphenhydramine,dimenhydrinate,doxylamine succinate ▶ Ethylenediamines: Ex Tripelennamine,pyrilamine maleate,antazoline phosphate ▶ Propylamine derivatives: Ex. Chlorpheniramine,pheniramine maleate. ▶ Phenothiazine derivatives: Ex. Promethazine,trimeprazine tartrate. ▶ Piperazine derivatives: Cyclizine,chlorocyclizine,meclizine ▶ Debenzocycloheptenes: Cyproheptadine, azatadine ▶ Miscellaneous drug: Diphenyl pyraline
- 10. Second-Generation antihistamines. ▶ Thesecond-generation antihistamines bind only to peripheral H1 receptors, and reduce allergic response with little or no sedation. ▶ These newer agents are structurally divers, but are derivatives of first generation drugs. ▶ The new second generation drugs currently on the market include: ▶ Acrivastine ▶ Cetrizine and levocetrizine ▶ Desloratadine and loratidine ▶ Fexofenadine ▶ terfenadine
- 11. SAR OF 1STGENERATION H1 BLOCKERS • A protonatable amine • A connecting atom X which can be O, C or N • A carbon chain, usually ethyl • Variations in the diaryl groups, connecting moiety, substituents on the connecting moiety, and substituents on the terminal nitrogen account for the differences observed in potency as well as pharmacologic, metabolic, and adverse reaction profiles.
- 12. SAR OF 1STGENERATION H1 BLOCKERS • The nitrogen should be 3° in nature for maximum antihistaminic activity. The ‘N’ may also form a part of heterocyclic moieties like piperidine, or piperazine or diazocine. Generally two aromatic rings - phenyl, benzyl, or an isostere such as pyridyl; Pyridyl generally results in more potent compounds than phenyl. • The group present between nitrogen atom and group X may be saturated or unsaturated or substituted. • The Ar group may be aryl or heteroaryl, which may be substituted.
- 13. SAR OF 1STGENERATION H1 BLOCKERS • X • Atom X can be an oxygen, nitrogen, or carbon, which links the side chain to an “aromatic tail.” The nature of atom X is the basis for the structural classification of H1 antagonists. The classical H1 antagonists are divided into six classes based on what X equals: • X =C–O: (Aminoalkyl Ethers) • 1. Ethanolamines • X = C: • 2. Propanolamines (clemastine, diphenylpyraline) • 3. Propylamines (Saturated and Unsaturated) • X = N: • 4. Ethylenediamines • 5. Piperazines (Cyclizines) and Tricyclics.
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- 19. AMINOALKYL ETHERS • Derivativesof N,N-dimethyl ethanolamines. • Characterized by the CHO connecting Moiety between the key diaryl and tertiary amino groups and a two or three carbon moiety. • The simple diphenyl derivative diphenhydramine was the firt clinically useful member of the ethanolamines series and serves as a prototype.
- 20. AMINOALKY ETHERS • Replacementof one of the phenyl rings of the diphenhydramine with a 2-pyridyl group, as in doxylamine enhances the antihistaminic activity. • The diaryl tertiary aminoalkyl ether structure serves as a pharmacophore for the muscarinic receptors. • Drowsiness ,as well as other CNS effects, is a common side effect of tertiary amino alkyl ethers because of the ability of these compounds to penetrate BBB and bind to the central H1 receptors. • Conversion to a quaternary ammonium salt does not alter the antihistaminic activity but does increases in anticholinergic action.
- 21. AMINOALKYL ETHERS Diphenhydramine HCL Doxylamine carbinoxaminebromodiphenhydramine
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- 23. ETHELENDIAMINES • R1 andR2 should be small (CH3) for maximum H1-antagonist activity. • Ar1 and Ar2 can be benzene ring or any other isosteric rings such as heterocycles. • One of the aromatic should be benzyl for better activity which has P- substitution. Isosteric rings to benzen
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- 25. Piperazines • Are derivativesof the piperazine nucleus • They are the cyclic analogues of ethelendiamines.
- 26. USES • They havemainly CNS depressant effects. • Main uses: • In allergy. • As antiemetic agents. • In motion sickness. CYLIZINE 1-(diphenylmethyl)-4-methyl piperazine.
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- 28. PHENOTHIAZINES • Possess atricyclic system • Phenothiazine derivatives possess two or three carbon chain bridge between basic phenothiazine nucleus and terminal nitrogen.
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- 30. 2ndGeneration H1 Blockers •Piperazine derivative • CETIRIZINE and levocetrizine • Piperidine derivative • FEXOFENADINE • TERFENADINE • dibenzepines • LORATADINE • DESLORATADINE • AZELASTIN
- 31. 2nd generation drugs •The second generation antihistamines are more similar pharmacologically than structurally. • Structurally they are all diaryl substituted piperazines (cetirizine) or piperidines • (all others). • As discussed earlier in this module, these compounds were developed as selective H1- receptor antagonists with relatively high potency. • Most of these compounds also produce prolonged antihistaminic effects as a result of slow dissociation from H1-receptors, and the formation of active metabolites with similar receptor binding profiles. TERFENADINE FEXOFENDINE
- 32. • The secondgeneration agents have little affinity for muscarinic, adrenergic or serotonergic receptors and therefore display a lower degree of side effects associated with antagonism at these receptors, but their affinities for these receptors is somewhat variable. • Generally, the large aralkyl groups or polar groups linked to the piperidine/piperazine rings of these compounds reduces their affinity for muscarinic or adrenergic receptors. CETRIZINE
- 33. loratadine • Loratadine isa non–sedating H1 antagonist with no anticholinergic side effects • Introduction of a Cl and carboxyethyl increases potency • Since carbamate nitrogen is neutral rapidly absorbed and quick acting • Metabolized by CYP3A4 and 2D6 directly to Desloratadine via an oxidative process without hydrolysis • Prodrug??
- 34. H2 receptor blockers •Cimetidine ( Tagamet) • Ranitidine ( Zantac) • Famotidine (Pepcid , Pepcid AC) - Nizatidine ( Axid) • These products have been approved for the relief of “heartburn associated with acid indigestion, and sour stomach.” They should not be taken for longer than 2 weeks and are not recommended for children < 12 years of age.
- 35. What conditions arethey used to treat? • To reduce acid reflux which may cause heartburn or inflammation of the gullet (esophagitis). These conditions are sometimes called gastroesophageal reflux disease (GERD). • To treat ulcers in the stomach and in part of the gut (the duodenum). • To help heal ulcers associated with anti-inflammatory medication called non-steroidal anti-inflammatory drugs (NSAIDs). • In other conditions where it is helpful to reduce acid in the stomach. • Also : • Damage to the stomach and/or intestines due to stress or • trauma, Hives • Pancreatic problems • Stomach or intestinal ulcers (sores) resulting from damage caused by medication used to treat rheumatoid arthritis.
- 37. MOA of h2blockers • The H2 antagonists are competitive antagonists of histamine at parietal cell H2 receptor . • They suppress the normal secretion of acid by parietal cells and the meal – stimulated secretion of acid . • They accomplish this by two mechanism : Histamine released by ECL (enterochromaffin – like) cells in the stomach is blocked from binding on parietal cell H2 receptor , which stimulate acid secretion : therefore other substances that promote acid secretion ( such as gastrin and acetylcholine ) have a reduce effect on parietal cell when the H2 receptors are blocked
- 38. Side effects ofh2 blockers • Some of the side effects that may occur with H2 receptor blockers include: • constipation • diarrhea • difficulty sleeping • dry mouth • dry skin • headaches • ringing in the ears • a runny nose • trouble urinating
- 39. SAR • The Firstapproach in synthesizing H2-antagonists was the use of Histamine as the lead compound to produce antagonist activity. • Can be done by: • Adding extra hydrophobic group to the structure. • Varying the polar amino group. • Make extension to the ethyl linker between the amino and the imidazole ring.
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- 41. SAR • The nextapproach was to vary the polar groups in histamine with other polar functional groups. • The first derivative was N-guanylhistamine: • Has a weak H2-antagonist (partial agonist). • The guanidine moiety has a positive charge at physiological pH which will be distributed over the three nitrogen atoms.
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- 43. • The imidazolering proofed to be important for both agonist and antagonist binding. So the pka of this ring should be closer to the histamine one (5.74). • The pka of imidazole from burimamide is 7.25 which means that around 40% of the imidazole ring is ionized. • The side chain of burimamide should be electron withdrawing to make the pka of the ring close to 5.74.
- 44. Guanylhistamine providedthe lead. Extension of the side chain increased anti H2 potency but some agonist activity remained. Replacing the basic guanidino group with the neutral thiourea yielded effective H2 antagonists. Burimamide lacked agonist action but was not orally absorbed In Metiamide (1) reduce the pKa of the ring N, reduced ionization, increased membrane permeability and absorption and 10X more potent than Burimamide, (2) cause thetautomer to predominate which interact with H2 But caused kidney damage and granulocytopenia, possibly due to the thiourea so was replaced by the isosteric guanidine. This compound being highly basic was 20 times less potentReplacement of this group with strong electron withdrawer but more lipophilic cyano derivative yielded Cimetidine.
- 46. References • 1) https://en.wikipedia.org/wiki/H2_antagonist •2) Wilson and gisvold’s textbook of organic medicinal and pharmaceutical chemistry.
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