Antihisminic agents

Antihisminic agents

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  chemistryguru10@gmail.com Surendra Kumar Assistant Professor(M. Pharm) KNIMT, Faculty of Pharmacy, Sultanpur BP501T
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   Histamine wasfirst identified in 1911 by Barger and Dale. Anti-histamines are the drugs which counteract the actions of histamine in the body.  Histamine [2-(imidazol-4-yl) ethylamine], which is biosynthesized by decarboxylation of the basic amino acid histidine, is found in all organs and tissues of the human body. NH N H H H NH2 O OH 2-amino-3-(1H-imidazol-4-yl)propanoic acid Histidine Histamine Histidine decarboxylation -CO2 NH N H H H H NH2 2-(1H-imidazol-4-yl)ethan-1-amine
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   Histamine isstored in the secretory granules of mast cells (pH 5.5) as positively charged and ionically complexed with negatively charged acidic group on other secretory granules which constitutes heparin.  The antigens are proteins or polysaccharides obtained from various source like dust, pollen, grains, and food stuff etc.  The principal target cell of immediate hypersensitivity reactions are mast cells and basophils to generate IgE antibodies that binds to FC (fragment crystallizable) receptor on the granules surface.
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  Figure:- A Fcreceptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system
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   Histamine isan important chemical messenger, communicating information from one cell to another and is involeved in a variety of complex biological actions.  It mainly stored in an inactive bund form, form which its released as a result of an antigen-antibody reaction, initiated by different stimuli such as venoms, toxins, proteolytic enzyme, detergents and numerical chemicals.  Systemically, histamine contracts smooth muscle of the lungs and the GIT and cause vasodilator low BP and increase heart rate.  It also causes symptoms such as itching, sneezing, watery eye and running nose.  Histamine exerts it’s biological function by interacting with atleast three distinctly specific receptors H1, H2, and H3.  The term antihismine has been used to describe a drug that acts on H1 and H2.
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   Histamine iscomposed of an imidazole ring, an ethylamine side chain in which the methylene groups are designed as α and β. NH N NH2 1 2 3 4 5 a b  The side chain β-CH2 group attached to 4th position of imidazole ring.  Histamine is an achiral molecule. It exists in trans-gauche rotameric structures. Its trans- rotamer possesses affinity for both H1 and H2 receptors whereas its guache form possesses affinity only for H3 receptor.
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  HISTAMINE RECEPTORS ANDTHEIR DISTRIBUTION Histamine shows physiological effects by specific cell surface receptors. These receptors are of four types i.e. H1, H2, H3 and H4. All these receptors are G- protein coupled receptors. Histamine receptors, distribution and physiological function are summarized as follows; Receptors Distribution Function H1 Smooth muscle of respiratory and GI tract uterine tissue, epithelial and endothelial cells, T-cells, B-cells, neutrophils, eosinophils and hepatocytes Pruritis, pain, vasodilators, hypertension, headache, severe allergic response. H2 Different tissues or gastric cells Gastric acid secretion, hypotension, headache, inotropic activity H3 CNS (cortex, straitum, sub-stantia nigra) Modulate neuro- transmission H4 Hematopoietic cells Modulate immune function
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  STRUCTURE ACTIVITY RELATIONSHIP H1RECEPTOR ANTAGONISTS Based on the pharmacological profile, the H1 antihistamines are divided into two major groups; 1. First generation or classical antihistamines 2. Second generation or nonsedative antihistamines The SAR of antihistamines is discussed with reference to the first generation antihistamines. The structural requirements for H1 antihistamines are shown below; X Ar1 Ar C C N1 2 3 4
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  ARYL GROUPS  Thediaryl substitution is essential for significant H1 receptor affinity. It is present both in first and second generation antihistamines.  The optimal antihistamines activity depends on the co- planarity of two aryl substitutions. These are follows as; Ar: Phenyl, substituted phenyl and heteroaryl group like 2-pyridyl; Ar1: aryl or aryl methyl group. Two aryl rings may be liked e.g. promethzine, cyproheptadine and azatidine. NATURE OF X  The X- connecting moiety of H1 antihistamines may be simple carbon chain or saturated carbon oxygen moiety, which serves as a spacer group for required pharmacophore.  The active substitution of X are as follows: X= carbon (mono amino propyl analogue), oxygen (amino alkyl ether analogue), and nitrogen (ethylene diamine derivative).
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  ALKYL CHAIN (CH2)n Thecarbon chain two or more atoms in H1 antihistamines, which leads to the distance between the central point of the diaryl ring system and the terminal nitrogen atom in the extended conformation of these compounds in the range of 5-6 Aº. Branching of this carbon chain leads to decrease in antihistamines activity. If the carbon atom adjacent to the terminal nitrogen atom is branched, the possibility of asymmetry exists. C C N R1 R
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  TERMINAL NITROGEN ATOM Thet-N atom should be teriary amine for maximum activity. The t- N may be a part of heterocyclic ring. E.g. anatzoline and chlorcyclizine, which are also retains high anithistaminic activity. CH N N CH3 Chlorcyclizine
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  Ethylene diamine derivativesN Ar1 Ar C C H H H H N CH3 CH3 NAME Ar Ar1 Tripelennamine Pyrilamine Methapyrilene Thonzylamine Zolamine N CH2 N OCH3H2C N S H2 C N N OCH3H2C N S OCH3H2C
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  Amino alkyl etheranalogues O C C H H H H N CH3 CH3 C R Ar2 Ar1 NAME Ar1 Ar2 R Diphenydramine -H Bromodiphenydramine -H Doxylamine -CH3 Carbinoxamine -H Medrylamine -H Br N Cl N H3CO
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  example Cl C CH3 O CH2CH2 N H3C Clemastine H O N CH3 Diphenylpraline
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  Cyclic basic chainanalogues CR1 H N N R2 NAME R1 R2 Cyclizine -H -CH3 Chlorcyclizine -Cl -CH3 Meclizine -Cl Buclizine -Cl C H2 CH3 C H H C
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  Mono amino propylanalogues Saturated analogues CH Ar1 Ar CH2 CH2 N CH3 CH3 NAME Ar Ar1 Pheniramine Chlorpheniramine bromopheniramine N N Cl N Br
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  Unsaturated analogues N Ar Ar1 NAME ArAr1 Pyrrobutamine Triprolidine Cl H2 C H3C N
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  Tricyclic ring system N S R NAMER Promethazine HCl Trimeprazine Methidilazine CH2 C CH3 H CH3 CH3 .HCl CH2 C CH3 H CH2 N N CH3
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  Dibenzocyclohepte nes N CH3 Cyproheptadine (periactin) N N CH3 Azatadine Miscellaneous N CH2 CH2 N H N Antazoline N CH3 Phenindamine
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  Newer agents S O N H3C S O N H3C Cl Ketotifene 7-chloroKetotifene H1 antagonists with nonclassical structures H3CO N H N N N CH2 F Astemizole
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  N N N CH3 CH2 O Cl Azelastine Nonsedative H1antihistamines Nonsedative antihistamines bind only to peripheral H1receptors and produce with little or no sedation because of poor CNS penetration and lower affinity for central histamine activity. These are divided into two main classes;  Piperazine derivatives- cetrizine  Pyridine and piperidine derivatives- Loratadine, Fexofenadine, Terfenadine, etc.
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  N N C2H5OOC Cl Loratadine Cl N N O COOH Cetirizine Inhibitionof histamine release (mast cell stabilizers) Cromolyn sodium O NaOO C O CH2O H C OH O O O COONa
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