H1 and H2 Receptor Antagonist.pptx

H1 and H2 Receptor Antagonist.pptx

• 1.
  H1 and H2Receptor Antagonist - Mayur Karanjekar (M. Pharm 1st Year) Department of Pharmaceutical Chemistry Shri. Sadashivrao Patil Shikshan Sanstha’s SMT. KISHORITAI BHOYAR COLLEGE OF PHARMACY, KAMPTEE.
• 2.
  Introduction Histamine = Histos(Tissue) + Amine (Nitrogen Containing Compound) 1-H Imidazole 2- Amino Ethyl 2-(Imidazole-4-yl)ethylamine 1 Histamine is a biogenic amine that stimulates multiple histamine receptor types. In mammals, histamine is found within granules of basophils and mast cells (>90% of body stores) and within tuberomammillary neurons of the CNS. When released, histamine induces complex physiological and pathological effects, including allergic reactions, gastric acid secretion, multiple CNS-regulated effects, smooth muscle contraction and profound vasodilation that can lead to cardiovascular collapse.
• 3.
  • Histamine issynthesized using naturally occurring amino acid L- Histidine or S – Histidine in presence of pyridoxal phosphate dependent enzyme histidine decarboxylase or L- aromatic amino acid decarboxylase. • It is synthesized in Golgi apparatus of its principal mast cells and basophils. • It is found in almost all the mammalian tissues in the concentration ranging from 1 to more than 100 µg/g. • It is found in higher concentrations in mammalians CSF than in plasma and other body fluids. Biosynthesis
• 4.
  Storage and Functionof Histamine 1. Stored in Mast Cells and Basophils Cells 2. In mast cell it stored in secretory granules as a complex. 3. In Basophils stored as a complex with chondroitin sulphate Receptor Receptor Type Distribution in the body; Function Associated H1 Gq-Protein Coupled a) Smooth muscles of Intestine, airway, uterus – Contraction b) Blood Vessels- Endothelium ( Release of Nitrous oxide and PGI2) Causes Vasodilation. Increase Capillary permeability, Vasoconstriction. c) Afferent Nerve Stimulation d) Ganglionic Stimulation e) Release of Catecholamines in adrenaline medulla f) Transmitter in Brain H2 Gs- Protein Coupled a) Acid Secretion in gastric Gland b) Dilation of smooth muscles of blood vessels c) Increase blood pressure in atria, increase strength of ventricles for muscular contraction.
• 5.
  SAR of histamineH1 Antagonist 1. The Nitrogen should be tertiary in nature of maximum antihistaminic activity. 2. The group present between nitrogen atom and group X may be saturated, unsaturated or substituted. 3. The atom X can be a nitrogen, oxygen or carbon which links the side chain to the aromatic tail. 4. The di-aryl substitution is essential for significant H1 receptor affinity. 5. Most of the H1 antihistamines possess substitution in one of the aryl rings and this influence the potency of the compound. 6. Tertiary amine group is necessary for the activity.
• 6.
  Classification First Generation AntihistaminesExamples ( Drugs) Amino alkyl Ethers (Ethanolamine's) Diphenhydramine, Dimenhydrinate, Doxylamine Ethylenediamines Pyrilamine, Tripelennamine, Antazoline Propylamine Chlorpheniramine, Triprolidine Phenothiazine Promethazine, Trimeprazine Piperazine(Cyclizine) Chlorcyclizine, Meclizine Heptanes/Dibenzocycloheptenes Azatadine, Cyproheptadine
• 7.
  Amino-alkyl ethers (Ethanolamine's) SAR 1.The aromatic group may be phenyl or substituted phenyl or heterocyclic ring for good antihistaminic activity. The R and R” may be hydrogen or methyl. 2. Para substitution of Cl, CH3, CH3O or Br on one of the phenyl ring for better therapeutic property and decrease side effects. 3. Replacement of one of the phenyl ring of the diphenhydramine with a 2- pyridyl group enhance antihistaminic activity. 4. Tertiary amine group is necessary for the activity. MOA- They competes with free histamine for binding at H1 receptor leading to a reduction of the negative symptoms brought on by histamine H1- receptor binding.
• 8.
  Diphenhydramine HCL IUPAC name-2-(Diphenyl methoxy)- N,N- dimethylethanamine hydrochloride. Dimenhydrinate IUPAC name- 8- chlorotheophylline 2- (diphenylmethoxy) N,N- dimethylethylamine. Doxylamine Succinate IUPAC name- 2-[4-methoxybenzyl[2- dimethylamino)ethyl]-amino]pyridine
• 9.
  Synthesis of DiphenhydramineHCL Diphenyl bromo methane Dimethyl amino methanol
• 10.
  Ethylenediamines SAR 1. The ethylenediaminesantihistamines are characterised by the presence of a nitrogen connecting atom (X) and a two carbon atom chain as the linking moiety between the diaryl and tertiary amino moieties. 2. Substitution of para methoxy, chloro or bromo group further enhances the activity of the compound. 3. Replacement of benzyl group of tripelennamine with a 2- thienyl methyl group provides potent H1 receptor antagonist. 4. Replacement of phenyl moiety of phenbenzamine with a 2-pyridyl system yielded tripelennamine which is significantly more effective histamine receptor blocker. 5. Tertiary amine group is necessary for the activity. MOA- They bind to histamine H1 receptor. They blocks the action of endogenous histamine, which subsequently leads to temporary relief to the negative symptoms brought on by histamine.
• 11.
  Pyrilamine Maleate IUPAC name- -[4-methoxybenzyl[2-dimethylamino)- ethyl]-amino]pyridine. TripelennamineCitrate IUPAC name- 2-[benzyl[2-dimethylamino- ethyl]amino] pyridine citrate IUPAC name- 2-[(N-benzylanilino)methyl]-2- imidazoline dihydrogen phosphate. Antazoline Phosphate
• 12.
  Propylamine MOA- They bindto H1 receptor, they blocks the action of endogenous histamine which subsequently leads to temporary relief of the negative symptoms brought on by histamine. SAR 1.The Propylamine derivative are characterised structurally by an Sp3 or Sp2 carbon connecting atom with a carbon connecting atom with a carbon chain of two additional carbons linking the key tertiary amino and diaryl pharmacophore moiety. 2. All the pheniramines consist of a phenyl and a 2- pyridyl aryl group and a terminal dimethyl-amino moiety. 3. The Halogenated pheniramines are significantly more potent and have a longer duration of action than pheniramines. 4. In the open chain propylamines, a coplanar aromatic double bond system appears to be an important factor for antihistaminic activity 5. These compounds are asymmetric and the E- isomers are significantly more potent than the Z- isomers.
• 13.
  Chlorpheniramine maleate IUPAC name-2-[p-chloro-ᾰ-[2- dimethylamino)ethyl]benzyl]pyridine bimaleate Triprolidine IUPAC name- 2-[3-(1-pyrrodinyl)1-p- tolylpropneyl] pyridine monohydrochloride hydrate
• 14.
  Synthesis of Triprolidine 4-methylAcetophenone Pyrrolidine 4-methyl-3-pyrrolidino propiophenone Triprolidine
• 15.
  Phenothiazines MOA- They competeswith free histamine for binding at H1 receptor sites in the GI tract, Uterus, Large Blood vessels and bronchial muscles. SAR 1. They contain a two or three carbon branched alkyl chain between the ring system and terminal nitrogen atom 2. This differs significantly from the phenothiazines antipsychotic series in which the unbranched propyl chain is required. 3. The combination of lengthening of the side chain and substitution of lipophilic groups in the 2- position of the aromatic ring results in compounds with decreased antihistaminic activity and increased psychotherapeutic properties 4. Increasing in the branching of carbon chain decreases the activity but increases in Promethazine and Trimeprazine (exception) 5. Homologation helps in the development of new drug moiety ( Tricyclic antidepressant from antihistamines) 6. Tertiary amine group is necessary for the activity.
• 16.
  Promethazine Trimeprazine IUPAC name- 10-]2-(dimethylamino)-propyl]- phenothiazine IUPACname- 10-[1-methyl-3-pyrrolidinyl)methyl] phenothiazine.
• 17.
  Synthesis of Promethazine Phenothiazine1-dimethylamino-2-propylchloride Promethazine
• 18.
  Piperazine MOA- Along withantihistaminic activity, these agent exhibit peripheral and central antimuscarinic activity and thereby diminish vestibular stimulation and act on the medullary chemoreceptor trigger zone SAR 1. 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 piperazine moiety. 2. Both nitrogen atom in the compound are aliphatic and thus display comparable basicities. 3. The primary structural differences within the series involve the nature of para aromatic ring substituent and more importantly the nature of the terminal piperazine nitrogen substituent. 4. Tertiary amine group is necessary for the activity.
• 19.
  Chlor-cyclizine IUPAC name- 1-(p-chloro-ᾰ-phenylbenzyl)-4- methylpiprazine Meclizine IUPAC name- 1-(p-chloro-ᾰ-phenylbenzyl)-4-(m-methylbenzyl)- piprazine dihydrochloride monohydrate
• 20.
  Heptanes/ dibenzocycloheptenes MOA- Theycompete with free histamine for binding at H1 receptor sites. This antagonise the effect of histamine on H1 receptor leading to a reduction of the negative symptoms brought on by histamine. SAR- 1. Placement of Cl at C-3 shows increase in activity while CH3 at C-3 decreases the activity. 2. Presence of double bond at 10 and 11 position increases the activity. 3. These are the phenothiazine analogues in which sulphur atom is replaced by iso-stearic vinyl group(cyproheptadine) or saturated ethyl bridge(azatidine).
• 21.
  Azatidine Cyproheptadine IUPAC name-6,11-dihydro-11-(1-methyl-4- piperidylidene)- 5H-benzo-[5,6] cyclohepta(1,2-b] pyridine IUPAC name- 4-(5H-dibenzo-[a,d]-cycloheptene-5- ylidine)-1-methylpiperidine sesquihydrate.
• 22.
  H2 Receptor Antagonist MOA– They decrease gastric acid secretion by reversibly binding to histamine H2 receptors located on gastric parietal cells, thereby inhibiting the binding and activity of the endogenous ligand histamine. H2 blockers thus function as competitive antagonists. They have a relatively quick onset of action and are useful for episodic symptom relief. 1 SAR 1. Methylation at C-5 position leads to selective agonist action. 2. Imidazole structure is believed to be important for receptor action. 3. Chain of 4 carbon atom is optimal for the antagonistic activity, shorter the chain lesser is the activity. 4. The presence of terminal N group increases the activity. 5. The terminal nitrogen group should be polar non basic substituents for maximum activity. 6. The imidazole ring is not required for competitive antagonism at H2 receptors, other heterocyclic ring may be used (E.g. Furan ring in Ranitidine) 7. In general, antagonist activity varies inversely with the hydrophilic character of the nitrogen group( Ranitidine, Nizatidine)
• 23.
  IUPAC name- N-Cyano-N-methyl-N’-[2-{[2- methylimidazole-4-yl]methyl)-thio)ethyl}guanidine IUPACname- N’-(aminosulfonyl)-3- {[[2[(diamnomethylene)amino]-4- thiazolyl]methyl}thio] propanimidamide IUPAC name- N-[2-[[[5-(dimethylamino)methyl]-2- furanyl]methyl]thiol] ethyl]-N-methyl-2-nitro-l,1-ethenediamine
• 24.
  Proton Pump Inhibitors MOA-Blocks gastric acid secretion by irreversibly binding to and inhibiting the hydrogen potassium ATPase pump that resides on the luminal surface of the parietal cell membrane. Omeprazole Lansoprazole Pantoprazole Rabeprazole
• 25.
  SAR 1. They arethe special type of prodrugs which chemically have pyridine substituted and a benzimidazole ring. 2. Sulfinyl Group is essential for the activity of PPI. 3. Electron donating group like OCH3 increases the protonation at N-3(in protonation the nitrogen takes the proton from the parietal cells). 4. Methoxy Group at 4’ position increase cationic nature which is essential for the activity. 5. Both pyridine and benzimidazole rings are essential for the activity. 6. Methyl group at position 5 of pyridine resist its metabolism( methyl group slows down the metabolism of the drug) 7. 3’ position will be substituted with methyl or methoxy group increases the activity. 8. The electron donating group at position 5 of benzimidazole ring like OCH3 in omeprazole and OCHF2 in pantoprazole increases the nitrogen protonation. 9. Unsubstituted position 5 will show fast metabolism by enzymes. 10. Sulfinyl Group is essential for the activity, removal of the moiety ends the activity of the molecule