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بسم هللا الرحمن الرحيم Antihistaminic drugs Histamine NH2 NH2 Ntautomer Ntautomer HN N N NH Tautomers of Histamine Histamine is an autacoid i.e physiologically active, endogenous substance that is produced within the body by decarboxylation of the amino acid Histidine and then stored in mast cells and basophils. It is released in response to a wide variety of stimuli mediating a hypersensitivity reaction. Histamine action is terminated by cellular reuptake and enzymatic inactivation. Biosynthesis of histamine NH2 NH2 COOH HN N N Histidine NH Histamine Nomenclature 5 4 1 HN N3 2 NH2 NH2 4 5 3 N NH 1 2 4(5)(2-aminoethyl)1H imidazole Histamine Receptors or physiological effects of histamine 1. H1–receptors : Has a role in hypersensitivity reactions [Pruritis , Increased vascular permeability (oedema, swelling), Increased prostaglandin generation] and also Mediate smooth muscle contraction. 2. H2–receptors : mediate the gastric acid secretion as they are located on the cell membrane of acid secretory cells of the gastric mucosa 3. H3 – receptor : described in 1999 , modulate histamine synthesis and release in the CNS. N.B. H4 subtype is recently discovered in 2000 and was suggested to have a role in regulation of immune system. Histamine exhibits a wide variety of both physiologic and pathologic functions and this include: 1- An important but limited role as a chemical mediator of hypersensitivity reactions. 2- A major role in the regulation of gastric acid secretion. 3- A role as a neurotransmitter in the CNS. Histamine has no therapeutic application. The compound is mainly used 1- as a positive control in the allergy skin testing. 2- a diagnostic agent to test the secretory action of the stomach. Histamine H1- Receptor Antagonists Histamine H1- Receptor Antagonists • H1- antagonists are the drugs that competitively inhibit the action of histamine on the tissues containing H1-Receptors. No reaction histamine Drug Drug H1 receptor H1 receptor Competitive inhibition • The H1-antagonists are commonly subdivided into two broad groups: The first generation or classical antihistamines (sedating) The second generation or (non sedating) antihistamines. Structure Activity Relationship (S A R) of the first generation antihistamines Ar R X - (CH2)n N R- Ar Connecting atom C.chain Terminal nitrogen or tertiary amino moiety 1- connecting atom X C O X= C O CH2CH2 N Aminoalkyl ether or ethanolamine dr. C CH2CH2 N Propylamine dr. X= C C N X= CHCH2 CH2CH2 N N Ethylenediamine dr. N Ar R X (CH 2)n N - Ar R- 2- The carbon chain of typical H1–antagonists consists of two or three carbon atoms. 3- The terminal nitrogen atom is a simple dimethyl amino moiety. However, it may be a part of a heterocyclic structure as in (piperazine, pyrrolidine , piperidine, imidazole…….). H3C N N Triprolidine 4- Ar and Ar` are aryl groups, including phenyl, substituted phenyl (specially with halogen in para position) and heteroaryl such as 2-pyridly. The two aryl moieties must be non coplanar to each other for optimal interaction with H1 receptor. The two aromatic systems may be linked as in the tricyclic antihistamines. X Characters of first generation antihistamines 1- They have high lipid solubility so, they can penetrate BBB blocking central H1 receptors and some CNS receptors. Sedation, dizziness. 2- They contain the basic pharmacophore required for binding to muscarinic as well as adrenergic and serotonergic receptors overlaping actions different pharmacological actions. ***** A- Amino alkyl Ethers (Ethanolamines). R-- Ar H2 H2 C O C C Ar R N R- 1- Diphenhydramine HCl (Benadryl) 2 1 CH O CH2CH2 N CH3 CH3 HCl 2-(Diphenylmethoxy)-N,N dimethylethylamine HCl • It is used in the treatment of urticaria, seasonal rhinitis, and some dermatoses.*** • It is used as a sleep aid product. *** Synthesis HO Br N CH3 CH O CH2CH2 N CH3 CH3 Na2CO3 HCl Metabolism Question? CH3 2 1 CH O CH2CH2 N CH3 CH3 HCl B- Propylamine derivatives 1- Saturated dr. (pheneramines) 2- Unsaturated dr. (Olefinic) open chain dr. Cyclic analogues R Ar CH - Ar CH2CH2 N R- 1- saturated dr. A- chlorpheniramine Maleate Cl 1 CH 2 2 CH2CH2 N N1 CH3 . CHCOOH CHCOOH CH3 2-[ p-chloro-α-[ 2-dimethylaminoethyl ] benzyl] pyridine maleate. • Insertion of a halogen into the para position of the phenyl ring increases potency and duration. D optical isomer with S absolute configuration is more active ( dexchlorpheneramine maleate) 2- unsaturated dr. A- open chain dr. Triprolidine Hydrochloride H3C (E)-2- [ 1-(4-methylphenyl)3-(1Pyrrolidinyl) 1-propenyl] pyridine. H 3 2 1 2 N Cl- N1 E (trans geometric isomer in which the methylpyrolidinyl group is trans to the 2- pyridyl group) is more active than the Z (cis) isomer. • N.B. adding polar group……..as 2-propenoic acid ……second generation (acrivastine). B- Cyclic analogue Dimethindene maleate (fenistil) 1 1 2 1 2 CH2CH2 3 2 CH H3C 2 CH3 CHCOOH N . CH3 CHCOOH N 1 2- [ 1-[2-(2-dimethylamino) ethyl] indene-3-yl]ethyl]] pyridine maleate. The potent antihistaminic activity resides mainly in the levorotatory isomer. c- Ethylenediamines The earliest series of H1-antagonists Characterized by high CNS side effects and lower anticholinergic and antiemetic effects R Ar N - Ar CH2CH2 N R- E-Tricyclic ring system 1-Phenothiazine 2- phenothiazine analogues (Cycloheptane and cycloheptene dr.) S N R1 CH2CH(CH2)n R N R2 1- Promethazine HCl [ phenergan] 1 9 2 S 3 10 4 8 7 6 N CH3 2 5 1CH2CH N 3 CH3 CH3 (±)10-[2-(Dimethylamino)propyl ] phenothiazine. It is the parent member of this series . It forms HCl salt with the more basic nitrogen ? In addition to its antihistaminic action, it has antiemetic, anticholinergic and sedating effects Preparation of Promethazine HCl S S N Fusion N H H ne e u l To / NH 2-HCl Na Cl Promethazine H2 H C C CH3 N CH3 CH3 Phenothiazine analogues 1-Pimethixene 5 10 6 S 7 9 8 4 3 2 4 1 1 N CH3 1-methyl-4-[ 9H-thioxanthen-9-ylidene]piperidine 1- It is an example for thioxanthene derivatives as potent H1 antagonist. 2- It is an example for the bioisosteric replacement of the nitrogen of phenothiazine nucleus by an SP2 carbon atom. 2- Cyproheptadine HCl (periactin) 1 a d 2 b c 5 4 3 4 1 4-(5H-Dibenzo [a,d] cyclohepten-5-ylidene)-1- N methylpiperidine H3C • It is an example for the bioisosteric replacement of the nitrogen of phenothiazine nucleus by an SP2 carbon atom and the sulphur atom is replaced by an isosteric vinyl group. • This compound can be used as an appetite stimulant and it exhibits both H1-antagonist and antiserotonergic activity. S S N CH3 CH2CH N CH3 CH3 Promethazine pimethixene N CH3 N Azatidine N CH3 Cyproheptadine N H3C O S Ketotifen (Zaditine) N CH3 1- It is structurally analogous to cyproheptadine. 2- It is a dual acting antihistaminic which acts as potent H1-antagonist and and mast cell stabilizer (it inhibits the release of the mediators which are involved in the allergic reaction) 3- It is used in prophylaxis of asthma