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ANTI-HISTAMINES AND ITS DRUGS WITH SAR AND

1) Histamine is an organic nitrogenous compound involved in local immune responses and regulating physiological functions. It is synthesized from histidine by decarboxylation. 2) Histamine acts through four types of G protein-coupled receptors: H1, H2, H3, and H4. H1 receptor blockers are used to treat allergic disorders by blocking the effects of histamine. 3) There are two generations of H1 receptor blockers. First generation blockers include aminoalkylethers, ethylenediamines, propylamine derivatives, and phenothiazines. Second generation blockers have less sedative effects.

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H1 AND H2 RECEPTOR BLOCKERS PREPARED BY: N.SRILAKSHMI
https://www.pharmaguideline.com/2007/02/heterocyclic-compounds-nomenclature- and.html About heterocyclic compounds
HISTAMINE • In a general sense, histamine plays an important role as a 'chemical messenger" component of a variety of pathways that have evolved in multicellular organisms, • The involvement of histamine in the mediation of allergic 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. • structurally is composed of an imidazole heterocycle and ethylamine side chain.
HISTAMINE • Histamine: It is a (Histo + amine = histamine) means tissue amine. It is a Organic Nitrogenous compound • Histamine is an 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.
Structure of Histamine • It is having imidazole nucleus (5 membered heterocyclic ring which contains 2 nitrogen’s at 1,3 positions in its structure • To the imidazole nucleus at 4th position it is having ethyl amine(CH2-CH2-NH2) side chain • In the side chain it is having 2 carbons. That carbon one we call it as alfa and the other is beta • Totally in the structure of histamine it is having 3 nitrogen's(1st position and 3rd position and the other is at substituted ethylamine) α β 1
IUPAC NAME : α β 4-(1-amino ethyly)-imidazole or β- imidazole ethyl amino BIO SYNTHESIS OF HISTAMINE: • Histamine is synthesised in Golgi apparatus of storage cell, mast cell, beta cell • L-Histidine is the starting material for the biosynthesis of histamine • This histidine undergoes decarboxylation by means of L-Histidine decarboxylase Histidine Decorboxylation(co2 is removed) Histamine 2
Bio synthesis of histamine • Histamine is synthesised in Golgi apparatus of Storage cells , mast cells, and basophils • L-Histidine is the starting material for the biosynthesis of histamine Let us see what is meant by L-Histidine • L-Histidine is also having imidazole nucleus and at the 4th position it is having • CH2-CH-COOH-NH2 • CH2-CH-COOH-NH2 this undergoes decarboxylation by means of L-Histidine decarboxylase or aromatic L-aminoacid decarboxylase
Decarboxylation L-Histidine decarboxylase or aromatic L-aminoacid decarboxylase Enzyme This enzyme is inhibited by α- fluoro methyl histidine by this histamine will not be synthesised L-Histidine Histamine
1. Histamine is formed from Histidine by A.Oxidation B. Reduction C. Deamination D. Decarboxylation
Metabolism of histamine First it undergoes n-menthylation by means of n-methyl transferase enzyme • This n-methyl transferase enzyme transfers methyl group to nitrogen group in imidazole nucleus N-methyl-imidazole-4-ethylamine
It reacts with MAO(mono amine oxidase) • In the above structure only one amine is there that is NH2. • That NH2 undergo oxidation (Oxidation means removal of hydrogen or addition of oxygen) • In the above CH2 CH2 NH2 is there one hydrogen from second carbon is removed and taken up by nitrogen to get NH3. • That NH3 is removed and oxygen is added by the enzyme MAO to form CH2-CHO N-methyl-imidazole-4-ethylamine -NH3
The other metabolites are Di amine oxidase or Histaminase • This enzyme has the same action that of MAO • That NH2 undergo oxidation (Oxidation means removal of hydrogen or addition of oxygen) • In the above CH2 CH2 NH2 is there one hydrogen from second carbon is removed and taken up by nitrogen to get NH3. • That NH3 is removed and oxygen is added by the enzyme MAO to form CH2-CHO -NH3
By using the enzyme aldehyde dehydrogenase Imidazole-4-acetic acid • This reacts with aldehyde dehydrogenase(Removal of hydrogen(oxidation)) • As we know that aldehyde in dehydrogenase we will get an acid • So here also aldehyde CH2-CHO on dehydrogen to form acetic acid CH2COOH • N-methyl-Imidazole-4-acetic acid this is the primary metabolite of Histamine
• This reacts with aldehyde dehydrogenase(Removal of hydrogen(oxidation)) • As we know that aldehyde in dehydrogenase we will get an acid • So here also aldehyde CH2-CHO on dehydrogen to form acetic acid CH2COOH • N-methyl-Imidazole-4-acetic acid this is the primary metabolite of Histamine N-methyl-Imidazole-4-acetic acid
Imidazole-4-acetic acid-1-roboside • Then Imidazole-4-acetic acid reacts with Phospho ribosyl transferase • This Phospho ribosyl transferase enzyme transfers the ribose group and attach to first nitrogen of imidazole with first carbon of ribose group • Imidazole-4-acetic acid-1-roboside is the another metabolite of histamine
• Histamine is found in almost all mammalian tissues in concentrations ranging from I to more than 100. This substance is in particularly high concentration in skin, bronchial mucosa. and intestinal mucosa. It is found in higher concentrations in mammalian cerebrospinal fluid than in plasma and other body fluids
HISTAMINE AND ITS RECEPTORS • 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..
ANTIHISTAMINES • Histamine has no 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.
CLASSIFICATION OF ANTIHISTAMINES
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
Second-Generation antihistamines. ▶ The second-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
SAR OF 1ST GENERATION H1 BLOCKERS The general structure of H1 Antihistamines 1. Ar – Aryl groups 2. Nature of X 3. Carbon chain /Alkyl chain 4. Terminal nitrogen We divided the structure in to 4 groups
Aryl groups Ar: means aryl group Eg: Phenyl, substituted phenyl,Hetero aryl Heterocyclic ring Ar’ : means aryl group or aryl methyl group • Here in the structure two aryl groups is essential for significant receptor affinity. • These two aryl rings are linked that means two aromatic rings are fused to form a tricyclic ring system. Eg: Promethazine
Nature of ‘X’ • ‘ X ’ is the connecting atom • It serves as a spacer group for required pharmacophore it may be C,O,N • X = O ( amino alkyl ether analogue) • X = C ( mono amino propyl analogue) • X = N( ethylene diamine derivatives )
Carbon chain /Alkyl chain • It is also called as alkyl chain • Most of the structures are having ethylene chain so we call it as ethylene bridge • Ethylene bridge may be saturated or unsaturated • If extension or branching is there in the structure means it decreases the activity of the compound • But this point is exception in the drug called promethazine. • Promethazine is more potent that unbranched one In this it is straight attached side chain
Terminal nitrogen The terminal Nitrogen must be tertiary amine for producing maximum antihistaminic activity. And also it may be a part of heterocyclic ring structure . It may be • piperazine (Chlorcyclizine, Meclizine, Buclizine ) • Pyrrolidine • Piperidines (Cyproheptadine hydrochloride) • Phenothiazines (Promethazine hydrochloride, Trimeprazine tartrate ) • Dibenzocycloheptenes(Cyproheptadine )
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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