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Antihistamin.ppt

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AbebawSimachew

Histamine is a chemical messenger that acts as a local hormone. It is synthesized in mast cells and basophils and signals through four receptor types, H1-H4. Antihistamines are drugs that block the effects of histamine by competing for binding at histamine receptors. There are three classes of H1 receptor antagonists: first generation cause sedation; second generation are more selective; third generation are enantiomers of second generation drugs with fewer side effects. Common first generation drugs include diphenhydramine; second generation include loratadine and cetirizine; third generation include levocetirizine. H2 receptor antagonists like cimetidine are used to treat gastric ul

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Histamine, histamine antagonists and related Gastrointestinal therapeutic agents By :Abebe T.
Outline • Overview: what is histamine? • Biosynthesis, Metabolism • Receptor types and physiological effects • H1, H2, H3, H4,… • Chemistry of histamine • What are antihistamines? • Classes of histamine antagonists • H1 receptor antagonists (blockers) » 1st generation antihistamines » 2nd generation antihistamines » 3rd generation antihistamines • H2 receptor antagonists (blockers) • Proton Pump Antagonists • Miscellaneous Gastrointestinal agents
What is Histamine? Overview • a chemical messenger released by cells. • widely distributed in the body • acts as a local hormone • One of the major inflammatory mediator • The highest concentrations in human tissues: Lung, stomach and skin [33μg/g tissue]
Biosynthesis Synthesized chiefly in • Mast cells : stomach, liver, L/S intestine, heart and lung • Basophilic granulocytes : blood Other sites of synthesis include:  Neurons of the CNS and  Epidermis of the skin When synthesized?
Termination of Histamine Action • Cellular uptake • Metabolism (Major)
Receptors • GPCR, membrane receptors H1 Receptor • Human H1 receptor gene encodes for 487 a. as protein. •shows 40% homology with M1 and M2 receptors Asp, Asn, and Lys responsible for ligand binding Asp suggested for recognition site for protonated aliphatic amine.
d d ~ 4-6Ao Bulky region Anionic site The binding requirements for histamine to the HI
H1 receptors • found in periphery smooth muscle (bronchi, L/S intestine, B.V), skin and CNS • Activates PLC • mediates the increase in vascular permeability induced by Histamine • Mediates of Inflammation and allergic response • V.D BP Shock » Increased blood flow, redness, itchy eyes, hives • B.C. • Sm. Ms. Contraction – Nausea • Implicated in neurotransmission, arousal and sexual behavior. – sleep disorders
H2 Receptor The human gene for H2 receptor encodes for 359 a. as protein. † Receptor is smaller • Asp (recognition site for protonated 1o amine), Thr, and Asp responsible for binding of imidazole portion increases cAMP production • found in the stomach and heart • mediates the release of gastric acid » Stomach ulcers Protonation on the τ-nitrogen is most important for histamine binding at H2 receptors. H +
H3 and H4 Receptors H3 Receptor… Thought to be a GPCR • May play role in CNS (auto receptors) • Possible regulation of synthesis and release of Hist • Signaling pathway unknown H4 Receptor… • GPCR • Found in intestines, spleen, T-cells and neutrophils • Suggests role in Immunity.
Chemistry and SAR of histamine • Hydrophilic Hetrocyclic molecule •Contains imidazole ring linked with alkyl amino group • pka’s 9.40 (aliphatic amine) 5.74 (imidazole N, 2o amine) There are two tautomeric forms of histamine. • 4-(β-aminoethyl) imidazole and • 5-(β-aminoethyl) imidazole Both forms are active physiologically. N HN NH N     2 5 4 NH2 NH2 3 1 1 2 3 4 5    
• In aqu. soln, the tautomeric composition of imidazole ring apparently favors the Nτ-H tautomer by about 4:1. • The free base also favors the Nτ-H tautomer. • Tautomeric composition of imidazole is important for agonist-receptor interaction. • Changes of tautomeric composition of analogues occur with changes in the 4-substituent • eg. Me Vs Cl • Proportion of Nτ-H is ↓ed in Cl substituted congener to 12 %. • proportion Nτ-H is ↓ed to 70% in Me Substituted congener.
• The binding requirements – for histamine to the HI and H2 receptors are slightly different. At the HI receptor, the essential requirements are as follows: • The side-chain has to have positively charged nitrogen atom with at least one attached proton. Quaternary ammonium salts lacked such a proton are extremely weak in activity. • There has to be a flexible chain between the above cation and a hetero aromatic ring. • The hetero aromatic ring has to contain a nitrogen atom with a lone pair of electrons, ortho to the side-chain.
Antihistamin.ppt
At the H2 receptor, • The essential structure-activity requirements are the same as for the HI receptor except that the hetero aromatic ring had to contain an amidine unit (HN-CH- N:).
Antihistamin.ppt
ACTIVITY DETERMINED INVITRO on: Guinea pig ileum (H1),Guinea pig atrium (H2) Guniea Pig cerebral cortex (H3) N HN NH2 Cl N HN NH2 H3C N HN NH2 H3C N N HN NH2 N S NH2 S HN NH2 N NH2 N NH2 Relative H1 activity Vs histamine Relative H2 activity Vs histamine Relative H3 activity Vs histamine Histamine 100 100 100 1.7 12 ND 0.23 39 < 0.008 0.49 1.0 1550 12.7 13.7 ND 26 0.3 < 0.008 0.01 0.1 ND 5.6 2.5 < 0.06 INACTIVE INACTIVE ND
• structural studies show that some of its conformations are less stable than others. In particular, conformation I in Fig. above is disallowed due to a large steric interaction between the 4-methyl group and the side-chain. • The selectivity observed suggests that 4-methylhistamine (and by inference histamine) has to adopt two different conformations in order to fit the HI or the H2 receptor. • Since 4-methylhistamine is more active at the H2 receptor, it implies that the conformation required for the H2 receptor is a stable one for 4-methylhistamine (conformation II), whereas the conformation required for the HI receptor is an unstable one (conformation I).
SAR (CONTD) •Addition of other alkyl substituents onto histamine molecule generally ↓ed potency at H1 and H2 receptors •Imidazole N-substitution (N1 and N3) with methyl groups result in inactive agents. •
What are an antihistamines? • “compete against the receptors’ natural substrate, histamine, in binding to the receptors “ • drugs that reduce or eliminate the effects mediated by the chemical histamine • The term antihistamine only refers to H1 receptor antagonists (actually inverse agonists) • Antihistamines compete with histamine for binding sites at the receptors. AND cannot remove the histamine if it is already bound
• Classes of antihistamines • H1 receptor antagonists (blockers) » 1st generation antihistamines » 2nd generation antihistamines » 3rd generation antihistamines • H2 receptor antagonists (blockers)
Common Structural Features of antihistamines • 2 aromatic rings, connected to a central carbon, nitrogen, or oxygen • Spacer between central atom and the amine, usually 2-3 carbons in length. (Can be linear, ring, branched, saturated or unsaturated) • The amine is substituted with small alkyl groups • Chirality at X and having the rings in different planes influences potency of the drug C H2 N X Ar Ar' R' R n General H1 Receptor Antagonist d ~ 4-6Ao
Classes of First generation H1 receptor antagonists • Ethylenediamines • Ethanolamines • Alkylamines (Propylamines) • Tricyclics C H2 N X Ar Ar' R' R n General H1 Receptor Antagonist Spacer X n Class of Antihistamines O 2 Ethanolamines N 2 Ethylenediamines C 2 Propylamines
Ethylenediamines • These were the first group of clinically effective H1-antihistamines Mepyramine (Pyrilamine)
Ethanolamines • This class has significant anticholinergic side effects and sedation, however reduced the gastroinestinal side effects Diphenhydramine (Benedryl) • Oldest and most effective antihistamine on the market • Available over the counter • Because it induces sedation, it’s used in nonprescription sleep aids • Also inhibits the reuptake of serotonin, which led to the search for viable antidepressants with similar structures (prozac) • Removes secretion from respiratory tract • has antinauseating effect • also used in motion sickness
The 8-chloro-theophylline salt of diphenydramine Clemastine (Tavist) Dimenhydrinate (Dramamine) •Exhibits fewer side effects than most antihistamines •Widely used as an antiprurtic (stops itching) •Anti-emetic (anti nausea) •Also causes strong sedation •Readily crosses the BBB
Alkylamines (Propylamines) Long acting 4x active than ethanolamines • Isomerism is an important factor in this class of drugs, which is due to the positioning and fit of the molecules in the H1- receptor binding site • These drugs have fewer GI adverse effects, but a greater incidence of CNS sedation.
Akylamines Chlorpheniramine Brompheniramine (Dimetap) •Originally used to prevent allergic conditions •Shown to have antidepressant properties and inhibit the reuptake of serotonin •The first SSRI was made as a derivative of chlorpheniramine •Available over the counter •Used to treat the common cold by relieving runny nose, itchy, watery eyes and sneezing * * Two optical isomers and d form is active
Akylamines Triprolidine hydrochloride • Used to alleviate the symptoms associated with allergies • Can be combined with other cold medicine to relieve “flu-like” symptoms There are Two geometrical isomers trans form is active
X (Y)n R A B C X = O; Alkyl amino ether = N; ethylenediamine = C; propyleneamine Y could be CH2, hetro atom, or CH2-hetro atom When Tricyclics • These drugs are structurally related to tricyclic antidepressants, which explains why they have cholinergic side effects • The general structural feature R = -CH3-CH CH3 N CH3 CH3
Promethazine (Phenergan) •This drug has extremely strong anticholinergic and sedative effects • It was originally used as an antipsychotic, however now it is most commonly used as a sedative or antinausea drug (also severe morning sickness) and requires a prescription
Cyproheptadine Ketotifen (Zaditor) •This drug both an antihistamine and an antiserotonergic agent •It is a 5-HT2 receptor antagonist and also blocks calcium channels •Used to treat hay fever and also to stimulate appetite in people with anorexia •It is also rarely used to treat SSRI induced sexual dysfunction and also Cushing’s Syndrome (high level of cortisol in the blood) and migraine headaches • This drug is available in two forms: an ophthalmic form used to treat allergic conjunctivitis or itchy red eyes and an oral form used to prevent asthma attacks • It has several adverse side effects including drowsiness, weight gain, dry mouth, irritability and increased nosebleeds
Clinical Uses of Antihistamines • Allergic rhinitis (common cold) • Allergic conjunctivitis (pink eye) • Allergic dermatological conditions • Urticaria (hives) • Angioedema (swelling of the skin) • Pruritus (atopic dermatitis, insect bites) • Anaphylactic reactions (severe allergies) • Nausea and vomiting (first generation H1- antihistamines)
side effects • first generation H1-antihistamines – due to their lack of selectivity for the H1 receptor and anti-cholinergic activity. Side effects are due to CNS depression: • Sedation, Dizziness • Tinnitus (ringing in the ear) • Blurred vision • Un coordination, Tremor • Dry mouth/dry cough • Newer second generation H1-antihistamines are more selective for the peripheral histamine receptors and have far less side effects (drowsiness, fatigue, headache, nausea and dry mouth)
Second generation H1-receptor antagonists • These are the newer drugs and they are much more selective for the peripheral H1-receptors involved in allergies as opposed to the H1- receptors in the CNS • Therefore, these drugs provide the same relief with many fewer adverse side effects. • The structure of these drugs varies and there are no common structural features associated with them • They are bulkier and but less lipophilic than the first generation drugs, therefore they do not cross the BBB as readily. • Recent studies have also showed that these drugs also have anti- inflammatory activity and therefore, would be helpful in the management of inflammation in allergic airways disease.
Second generation H1-receptor antagonists Acrivastine (Semprex-D) Astemizole (Hismantol) •This drug has a long duration of action •It suppresses the formation of edema and pruritis •It doesn’t cross the BBB •It has been taken off the market in most countries because of adverse interactions with erythromycin and grapefruit juice •This drug relieves itchy rashes and hives •It is non-sedating because it does not cross the BBB readily
Cetirizine (Zyrtec) • Structurally related to the ethylenediamines and the ethanolamines and thus produce significant anti-cholinergic effects • Used most often to treat motion sickness, vertigo, nausea, vomiting and itching (skin rash)
Second Generation H1-receptor antagonists Loratadine (Claritin) Terfenadine •It is the only drug of its class available over the counter •It has long lasting effects and does not cause drowsiness because it does not cross the BBB readily •It was formerly used to treat allergic conditions •In the 1990’s it was removed from the market due to the increased risk of cardiac arrhythmias
Second generation H1-receptor antagonists Azelastine (Astelin or Optivar) Levocabastine (Livostin) •It is a mast cell stablilizer •Available as a nasal spray (Astelin) or eye drops for pink eye (Optivar) •Both of these drugs are used as eye drops to treat allergic conjunctivitis Olopatadine (Patanol)
Third Generation H1-Receptor Antagonists • These drugs are derived from second generation antihistamines • They are either the active enantiomer or metabolite of the second generation drugs • designed to have increased efficacy and fewer side effects Levocetrizine (Zyzal) • This drug is the active enantiomer of cetirizine and is believed to be more effective and have fewer adverse side effects. • Also it is not metabolized and is likely to be safer than other drugs due to a lack of possible drug interactions • It does not cross the BBB and does not cause significant drowsiness • It has been shown to reduce asthma attacks by 70% in children
Third generation H1-receptor antagonists Deslortadine (Clarinex) Fexofenadine (Allegra) •It is the active metabolite of Lortadine •Even though it is thought to be more effective, there is no concrete evidence to prove this •It was developed as an alternative to Terfenadine •Fexofenadine was proven to be more effective and safe
H2 Histamine antagonists. In the beginning—ulcer therapy in 1964 Ulcers are localized erosions of the mucous membranes of the stomach or duodenum. It is not known how these ulcers arise, but the presence of gastric acid aggravates the problem and delays recovery. In the early 1960s, the conventional treatment was to try and neutralize gastric acid in the stomach by administering bases such as sodium bicarbonate or calcium carbonate. However, the dose levels required for neutralization were large and caused unpleasant side-effects. not effective A better approachwould be to inhibit the release of gastric acidat source. DISORDERS associated with elevated secretion of gastric acid NSAID-Associatkd Ulcer. Zollinger-Ellison Syndrome Helicobacter Pylori (H. Pylor~) Reflux Esophagitis
Antrum Stomach Pyloric Sphincter Oesophagus Duodenum Histamine Acetylcholine Gastrin Cck2 M3 H2 Parietal Cells Stomach Proton pump Receptors Ion channel cAMP + + + + + + + - H HCl Cl Anticholinergic drugs ╠► unwanted side effects Gastrin receptor blocker ╠► unsuccessful
Gastric receptors are pharmacologically distinct. The classic H1 antagonists don’t interact with H2 receptors. No effect on gastric acid release Developing a Lead Compound • A classic example of rational drug design • work began in 1964 • There was no lead compound to work from • Take a closer look at Histamine to vary the structure of histamine in such a way that it will be recognized by the receptor but… H2 Histamine antagonists.
The First Hit • Targeted Functional changes of the amino group Partial Agonist Very weakly antagonist Nα-Guanylhistamine H N HN N NH2 H2N
• Compare the structures of guanylhistamine and histamine. • Both structures contain an imidazole ring and a positively charged group linked by a two carbon bridge. • The guanidine group is basic and protonated at pH7.4 so that the analogue has a positive charge similar to histamine. However, the charge on the guanidine group • can be spread around a planar arrangement of the three nitrogens and • can potentially be further away from the imidazole ring H N HN N NH2 H2N H N HN N NH2 H2N H N HN N NH2 H2N H N HN N NH2 H2N Two alternative binding sites might be available for the cationic group
This leads to the possibility that the analogue could be interacting with another binding group on the receptor which is 'out of reach' of histamine. If most of the analogue molecules bind to the agonist site and the remainder bind to the antagonist site, then this could explain the partial agonist activity. Two alternative binding sites might be available for the cationic group Antagonist binding region Agonist binding region Imidazole ring binding region Antagonist binding region NH3 HN N HN N NH3 No interaction as an antagonist Strong interaction as an agonist Binding as an antagonist Receptor not activated Binding as an agonist Receptor activated Agonist binding region Imidazole ring binding region Antagonist binding region HN N NH NH2 H2N HN N NH H2N NH2
Burimamide • Burimamide is the prototype H2-receptor antagonist. • highly specific competitive antagonist of histamine at H2 receptors, • 100 times more potent than Nα-guanylhistamine. • It is the 4 carbons bridged analogue with guanidine moiety of Nα- guanylhistamine is replaced with thiourea group as well as addition of an N-methyl group [provides a beneficial increase in hydrophobicity ] • HN N N H NHMe S Chain extension e-withdrawing H N NH2 S Thiourea H N NH2 NH2 Guanidine Neutral Basic Burimamide The positive charge now restricted
• Generally, the H2 antagonistic activity of burimamide is too low for oral use – basicity of the imidazole ring • The imidazole ring of histamine is not ionised when it interacts with the imidazole binding region – the agonist Vs antagonist binding mode CH2CH2NH3 HN N H HN N CH2CH2CH2CH2NHCSNHMe HN N Imidazole pKa = 6.80 Histamine pKa = 5.74 Ionisation = 3% Burimamide pKa = 7.25 Ionisation = 40% e-withdrawing e-donating
Metiamide • analogue of burimamide with • side-chain electron withdrawing atom sulfur) inserted into the side-chain • an electron donating methyl group added at position 4 of the imidazole ring • increase the population of N-H tautomer which affords enhanced H2 receptor affinity. • Maintain the preferred conformation of metiamide – methyl group acts as a conformational blocker HN N S N H NHMe S Me Electron donating
Conformational patterns of 4-methyl histamine
kidney damage and granulocytopenia Not common in body biochemistry Note guanidine is one of the strongest bases in organic chemistry. argenine b/c……. Metiamide is ten times more active than burimamide HN N S H N Me NHMe N CN Electron withdrawing cyanide group
N H NHMe S Thiourea Toxic side effects N H NHMe NH Guanidine Drop in activity but no agonist activity! H N NHMe N CN Cyanoguanidine group Cimetidine inhibits H2 receptors and thus inhibits gastric acid release. The drug does not show the toxic side-effects observed for metiamide and has been shown to be slightly more active. • The cyanoguanidine moiety acts as a bio-isostere for the thiourea group. • Both groups are planar and of similar geometry. • Both groups are polar but essentially neutral. • Both groups have high dipole moments. • Both groups have low partition coefficients. • They are weakly basic and also weakly acidic such that • They are un-ionized at pH 7.4 and hence possess enhanced antagonistic activity
• Cimetidine first marketed in the UK in 1976
Metabolism of cimetidine . Cimetidine is metabolically stable and is excreted largely unchanged. The only metabolites which have been identified are due to oxidation of the sulfur link or oxidation of the ring methyl group. cimetidine inhibits the P-450 cytochrome oxidase system in the liver. This is an important enzyme system in the metabolism of drugs and care must be taken if other drugs are being taken at the same time as cimetidine, since cimetidine may inhibit the metabolism of these drugs, leading to higher blood levels and toxic side-effects.
Structure of some H2 receptor blockers Analogues of Cimetidine terminal nitroketeneaminal + different heterocyclic ring 30 times more active than cimetidine equipotent with ranitidine
Other Therapies: Proton-Pump Inhibitors… Proton- Pump Inhibitors… Antrum Stomach Pyloric Sphincter Oesophagus Duodenum Histamine Acetylcholine Gastrin Cck2 M3 H2 Parietal Cells Stomach Proton pump Receptors Ion channel cAMP + + + + + + + - H HCl Cl
PPIs work by forming a covalent disulfide bond with the ATPase enzyme, leading to an irreversible inhibition of the pump. The PPI pharmacophore is 2-pyridylmethylsulfinylbenzimidazole
• Benzimidazole are Pro-Drugs • Form active electrophile in Perietal Cells • Cys from pump act as Nuclephile.
Antihistamin.ppt
Antihistamin.ppt
Proton pump inhibitors (PPIs) • There are 5 PPIs currently on market which includes omeprazole, esmoprazole, lansoprazole, pantoprazole and rabeprazole • All the PPIs have pyridyl methylsulfinyl benzamidazole skeleton and act as pro-drugs, as they are activated when they reach the acidic canaliculi of parietal cells.
• THE END OF THE CLASS 10 Q ALL!

More Related Content

Antihistamin.ppt

  • 1. Histamine, histamine antagonists and related Gastrointestinal therapeutic agents By :Abebe T.
  • 2. Outline • Overview: what is histamine? • Biosynthesis, Metabolism • Receptor types and physiological effects • H1, H2, H3, H4,… • Chemistry of histamine • What are antihistamines? • Classes of histamine antagonists • H1 receptor antagonists (blockers) » 1st generation antihistamines » 2nd generation antihistamines » 3rd generation antihistamines • H2 receptor antagonists (blockers) • Proton Pump Antagonists • Miscellaneous Gastrointestinal agents
  • 3. What is Histamine? Overview • a chemical messenger released by cells. • widely distributed in the body • acts as a local hormone • One of the major inflammatory mediator • The highest concentrations in human tissues: Lung, stomach and skin [33μg/g tissue]
  • 4. Biosynthesis Synthesized chiefly in • Mast cells : stomach, liver, L/S intestine, heart and lung • Basophilic granulocytes : blood Other sites of synthesis include:  Neurons of the CNS and  Epidermis of the skin When synthesized?
  • 5. Termination of Histamine Action • Cellular uptake • Metabolism (Major)
  • 6. Receptors • GPCR, membrane receptors H1 Receptor • Human H1 receptor gene encodes for 487 a. as protein. •shows 40% homology with M1 and M2 receptors Asp, Asn, and Lys responsible for ligand binding Asp suggested for recognition site for protonated aliphatic amine.
  • 7. d d ~ 4-6Ao Bulky region Anionic site The binding requirements for histamine to the HI
  • 8. H1 receptors • found in periphery smooth muscle (bronchi, L/S intestine, B.V), skin and CNS • Activates PLC • mediates the increase in vascular permeability induced by Histamine • Mediates of Inflammation and allergic response • V.D BP Shock » Increased blood flow, redness, itchy eyes, hives • B.C. • Sm. Ms. Contraction – Nausea • Implicated in neurotransmission, arousal and sexual behavior. – sleep disorders
  • 9. H2 Receptor The human gene for H2 receptor encodes for 359 a. as protein. † Receptor is smaller • Asp (recognition site for protonated 1o amine), Thr, and Asp responsible for binding of imidazole portion increases cAMP production • found in the stomach and heart • mediates the release of gastric acid » Stomach ulcers Protonation on the τ-nitrogen is most important for histamine binding at H2 receptors. H +
  • 10. H3 and H4 Receptors H3 Receptor… Thought to be a GPCR • May play role in CNS (auto receptors) • Possible regulation of synthesis and release of Hist • Signaling pathway unknown H4 Receptor… • GPCR • Found in intestines, spleen, T-cells and neutrophils • Suggests role in Immunity.
  • 11. Chemistry and SAR of histamine • Hydrophilic Hetrocyclic molecule •Contains imidazole ring linked with alkyl amino group • pka’s 9.40 (aliphatic amine) 5.74 (imidazole N, 2o amine) There are two tautomeric forms of histamine. • 4-(β-aminoethyl) imidazole and • 5-(β-aminoethyl) imidazole Both forms are active physiologically. N HN NH N     2 5 4 NH2 NH2 3 1 1 2 3 4 5    
  • 12. • In aqu. soln, the tautomeric composition of imidazole ring apparently favors the Nτ-H tautomer by about 4:1. • The free base also favors the Nτ-H tautomer. • Tautomeric composition of imidazole is important for agonist-receptor interaction. • Changes of tautomeric composition of analogues occur with changes in the 4-substituent • eg. Me Vs Cl • Proportion of Nτ-H is ↓ed in Cl substituted congener to 12 %. • proportion Nτ-H is ↓ed to 70% in Me Substituted congener.
  • 13. • The binding requirements – for histamine to the HI and H2 receptors are slightly different. At the HI receptor, the essential requirements are as follows: • The side-chain has to have positively charged nitrogen atom with at least one attached proton. Quaternary ammonium salts lacked such a proton are extremely weak in activity. • There has to be a flexible chain between the above cation and a hetero aromatic ring. • The hetero aromatic ring has to contain a nitrogen atom with a lone pair of electrons, ortho to the side-chain.
  • 15. At the H2 receptor, • The essential structure-activity requirements are the same as for the HI receptor except that the hetero aromatic ring had to contain an amidine unit (HN-CH- N:).
  • 17. ACTIVITY DETERMINED INVITRO on: Guinea pig ileum (H1),Guinea pig atrium (H2) Guniea Pig cerebral cortex (H3) N HN NH2 Cl N HN NH2 H3C N HN NH2 H3C N N HN NH2 N S NH2 S HN NH2 N NH2 N NH2 Relative H1 activity Vs histamine Relative H2 activity Vs histamine Relative H3 activity Vs histamine Histamine 100 100 100 1.7 12 ND 0.23 39 < 0.008 0.49 1.0 1550 12.7 13.7 ND 26 0.3 < 0.008 0.01 0.1 ND 5.6 2.5 < 0.06 INACTIVE INACTIVE ND
  • 18. • structural studies show that some of its conformations are less stable than others. In particular, conformation I in Fig. above is disallowed due to a large steric interaction between the 4-methyl group and the side-chain. • The selectivity observed suggests that 4-methylhistamine (and by inference histamine) has to adopt two different conformations in order to fit the HI or the H2 receptor. • Since 4-methylhistamine is more active at the H2 receptor, it implies that the conformation required for the H2 receptor is a stable one for 4-methylhistamine (conformation II), whereas the conformation required for the HI receptor is an unstable one (conformation I).
  • 19. SAR (CONTD) •Addition of other alkyl substituents onto histamine molecule generally ↓ed potency at H1 and H2 receptors •Imidazole N-substitution (N1 and N3) with methyl groups result in inactive agents. •
  • 20. What are an antihistamines? • “compete against the receptors’ natural substrate, histamine, in binding to the receptors “ • drugs that reduce or eliminate the effects mediated by the chemical histamine • The term antihistamine only refers to H1 receptor antagonists (actually inverse agonists) • Antihistamines compete with histamine for binding sites at the receptors. AND cannot remove the histamine if it is already bound
  • 21. • Classes of antihistamines • H1 receptor antagonists (blockers) » 1st generation antihistamines » 2nd generation antihistamines » 3rd generation antihistamines • H2 receptor antagonists (blockers)
  • 22. Common Structural Features of antihistamines • 2 aromatic rings, connected to a central carbon, nitrogen, or oxygen • Spacer between central atom and the amine, usually 2-3 carbons in length. (Can be linear, ring, branched, saturated or unsaturated) • The amine is substituted with small alkyl groups • Chirality at X and having the rings in different planes influences potency of the drug C H2 N X Ar Ar' R' R n General H1 Receptor Antagonist d ~ 4-6Ao
  • 23. Classes of First generation H1 receptor antagonists • Ethylenediamines • Ethanolamines • Alkylamines (Propylamines) • Tricyclics C H2 N X Ar Ar' R' R n General H1 Receptor Antagonist Spacer X n Class of Antihistamines O 2 Ethanolamines N 2 Ethylenediamines C 2 Propylamines
  • 24. Ethylenediamines • These were the first group of clinically effective H1-antihistamines Mepyramine (Pyrilamine)
  • 25. Ethanolamines • This class has significant anticholinergic side effects and sedation, however reduced the gastroinestinal side effects Diphenhydramine (Benedryl) • Oldest and most effective antihistamine on the market • Available over the counter • Because it induces sedation, it’s used in nonprescription sleep aids • Also inhibits the reuptake of serotonin, which led to the search for viable antidepressants with similar structures (prozac) • Removes secretion from respiratory tract • has antinauseating effect • also used in motion sickness
  • 26. The 8-chloro-theophylline salt of diphenydramine Clemastine (Tavist) Dimenhydrinate (Dramamine) •Exhibits fewer side effects than most antihistamines •Widely used as an antiprurtic (stops itching) •Anti-emetic (anti nausea) •Also causes strong sedation •Readily crosses the BBB
  • 27. Alkylamines (Propylamines) Long acting 4x active than ethanolamines • Isomerism is an important factor in this class of drugs, which is due to the positioning and fit of the molecules in the H1- receptor binding site • These drugs have fewer GI adverse effects, but a greater incidence of CNS sedation.
  • 28. Akylamines Chlorpheniramine Brompheniramine (Dimetap) •Originally used to prevent allergic conditions •Shown to have antidepressant properties and inhibit the reuptake of serotonin •The first SSRI was made as a derivative of chlorpheniramine •Available over the counter •Used to treat the common cold by relieving runny nose, itchy, watery eyes and sneezing * * Two optical isomers and d form is active
  • 29. Akylamines Triprolidine hydrochloride • Used to alleviate the symptoms associated with allergies • Can be combined with other cold medicine to relieve “flu-like” symptoms There are Two geometrical isomers trans form is active
  • 30. X (Y)n R A B C X = O; Alkyl amino ether = N; ethylenediamine = C; propyleneamine Y could be CH2, hetro atom, or CH2-hetro atom When Tricyclics • These drugs are structurally related to tricyclic antidepressants, which explains why they have cholinergic side effects • The general structural feature R = -CH3-CH CH3 N CH3 CH3
  • 31. Promethazine (Phenergan) •This drug has extremely strong anticholinergic and sedative effects • It was originally used as an antipsychotic, however now it is most commonly used as a sedative or antinausea drug (also severe morning sickness) and requires a prescription
  • 32. Cyproheptadine Ketotifen (Zaditor) •This drug both an antihistamine and an antiserotonergic agent •It is a 5-HT2 receptor antagonist and also blocks calcium channels •Used to treat hay fever and also to stimulate appetite in people with anorexia •It is also rarely used to treat SSRI induced sexual dysfunction and also Cushing’s Syndrome (high level of cortisol in the blood) and migraine headaches • This drug is available in two forms: an ophthalmic form used to treat allergic conjunctivitis or itchy red eyes and an oral form used to prevent asthma attacks • It has several adverse side effects including drowsiness, weight gain, dry mouth, irritability and increased nosebleeds
  • 33. Clinical Uses of Antihistamines • Allergic rhinitis (common cold) • Allergic conjunctivitis (pink eye) • Allergic dermatological conditions • Urticaria (hives) • Angioedema (swelling of the skin) • Pruritus (atopic dermatitis, insect bites) • Anaphylactic reactions (severe allergies) • Nausea and vomiting (first generation H1- antihistamines)
  • 34. side effects • first generation H1-antihistamines – due to their lack of selectivity for the H1 receptor and anti-cholinergic activity. Side effects are due to CNS depression: • Sedation, Dizziness • Tinnitus (ringing in the ear) • Blurred vision • Un coordination, Tremor • Dry mouth/dry cough • Newer second generation H1-antihistamines are more selective for the peripheral histamine receptors and have far less side effects (drowsiness, fatigue, headache, nausea and dry mouth)
  • 35. Second generation H1-receptor antagonists • These are the newer drugs and they are much more selective for the peripheral H1-receptors involved in allergies as opposed to the H1- receptors in the CNS • Therefore, these drugs provide the same relief with many fewer adverse side effects. • The structure of these drugs varies and there are no common structural features associated with them • They are bulkier and but less lipophilic than the first generation drugs, therefore they do not cross the BBB as readily. • Recent studies have also showed that these drugs also have anti- inflammatory activity and therefore, would be helpful in the management of inflammation in allergic airways disease.
  • 36. Second generation H1-receptor antagonists Acrivastine (Semprex-D) Astemizole (Hismantol) •This drug has a long duration of action •It suppresses the formation of edema and pruritis •It doesn’t cross the BBB •It has been taken off the market in most countries because of adverse interactions with erythromycin and grapefruit juice •This drug relieves itchy rashes and hives •It is non-sedating because it does not cross the BBB readily
  • 37. Cetirizine (Zyrtec) • Structurally related to the ethylenediamines and the ethanolamines and thus produce significant anti-cholinergic effects • Used most often to treat motion sickness, vertigo, nausea, vomiting and itching (skin rash)
  • 38. Second Generation H1-receptor antagonists Loratadine (Claritin) Terfenadine •It is the only drug of its class available over the counter •It has long lasting effects and does not cause drowsiness because it does not cross the BBB readily •It was formerly used to treat allergic conditions •In the 1990’s it was removed from the market due to the increased risk of cardiac arrhythmias
  • 39. Second generation H1-receptor antagonists Azelastine (Astelin or Optivar) Levocabastine (Livostin) •It is a mast cell stablilizer •Available as a nasal spray (Astelin) or eye drops for pink eye (Optivar) •Both of these drugs are used as eye drops to treat allergic conjunctivitis Olopatadine (Patanol)
  • 40. Third Generation H1-Receptor Antagonists • These drugs are derived from second generation antihistamines • They are either the active enantiomer or metabolite of the second generation drugs • designed to have increased efficacy and fewer side effects Levocetrizine (Zyzal) • This drug is the active enantiomer of cetirizine and is believed to be more effective and have fewer adverse side effects. • Also it is not metabolized and is likely to be safer than other drugs due to a lack of possible drug interactions • It does not cross the BBB and does not cause significant drowsiness • It has been shown to reduce asthma attacks by 70% in children
  • 41. Third generation H1-receptor antagonists Deslortadine (Clarinex) Fexofenadine (Allegra) •It is the active metabolite of Lortadine •Even though it is thought to be more effective, there is no concrete evidence to prove this •It was developed as an alternative to Terfenadine •Fexofenadine was proven to be more effective and safe
  • 42. H2 Histamine antagonists. In the beginning—ulcer therapy in 1964 Ulcers are localized erosions of the mucous membranes of the stomach or duodenum. It is not known how these ulcers arise, but the presence of gastric acid aggravates the problem and delays recovery. In the early 1960s, the conventional treatment was to try and neutralize gastric acid in the stomach by administering bases such as sodium bicarbonate or calcium carbonate. However, the dose levels required for neutralization were large and caused unpleasant side-effects. not effective A better approachwould be to inhibit the release of gastric acidat source. DISORDERS associated with elevated secretion of gastric acid NSAID-Associatkd Ulcer. Zollinger-Ellison Syndrome Helicobacter Pylori (H. Pylor~) Reflux Esophagitis
  • 44. Gastric receptors are pharmacologically distinct. The classic H1 antagonists don’t interact with H2 receptors. No effect on gastric acid release Developing a Lead Compound • A classic example of rational drug design • work began in 1964 • There was no lead compound to work from • Take a closer look at Histamine to vary the structure of histamine in such a way that it will be recognized by the receptor but… H2 Histamine antagonists.
  • 45. The First Hit • Targeted Functional changes of the amino group Partial Agonist Very weakly antagonist Nα-Guanylhistamine H N HN N NH2 H2N
  • 46. • Compare the structures of guanylhistamine and histamine. • Both structures contain an imidazole ring and a positively charged group linked by a two carbon bridge. • The guanidine group is basic and protonated at pH7.4 so that the analogue has a positive charge similar to histamine. However, the charge on the guanidine group • can be spread around a planar arrangement of the three nitrogens and • can potentially be further away from the imidazole ring H N HN N NH2 H2N H N HN N NH2 H2N H N HN N NH2 H2N H N HN N NH2 H2N Two alternative binding sites might be available for the cationic group
  • 47. This leads to the possibility that the analogue could be interacting with another binding group on the receptor which is 'out of reach' of histamine. If most of the analogue molecules bind to the agonist site and the remainder bind to the antagonist site, then this could explain the partial agonist activity. Two alternative binding sites might be available for the cationic group Antagonist binding region Agonist binding region Imidazole ring binding region Antagonist binding region NH3 HN N HN N NH3 No interaction as an antagonist Strong interaction as an agonist Binding as an antagonist Receptor not activated Binding as an agonist Receptor activated Agonist binding region Imidazole ring binding region Antagonist binding region HN N NH NH2 H2N HN N NH H2N NH2
  • 48. Burimamide • Burimamide is the prototype H2-receptor antagonist. • highly specific competitive antagonist of histamine at H2 receptors, • 100 times more potent than Nα-guanylhistamine. • It is the 4 carbons bridged analogue with guanidine moiety of Nα- guanylhistamine is replaced with thiourea group as well as addition of an N-methyl group [provides a beneficial increase in hydrophobicity ] • HN N N H NHMe S Chain extension e-withdrawing H N NH2 S Thiourea H N NH2 NH2 Guanidine Neutral Basic Burimamide The positive charge now restricted
  • 49. • Generally, the H2 antagonistic activity of burimamide is too low for oral use – basicity of the imidazole ring • The imidazole ring of histamine is not ionised when it interacts with the imidazole binding region – the agonist Vs antagonist binding mode CH2CH2NH3 HN N H HN N CH2CH2CH2CH2NHCSNHMe HN N Imidazole pKa = 6.80 Histamine pKa = 5.74 Ionisation = 3% Burimamide pKa = 7.25 Ionisation = 40% e-withdrawing e-donating
  • 50. Metiamide • analogue of burimamide with • side-chain electron withdrawing atom sulfur) inserted into the side-chain • an electron donating methyl group added at position 4 of the imidazole ring • increase the population of N-H tautomer which affords enhanced H2 receptor affinity. • Maintain the preferred conformation of metiamide – methyl group acts as a conformational blocker HN N S N H NHMe S Me Electron donating
  • 51. Conformational patterns of 4-methyl histamine
  • 52. kidney damage and granulocytopenia Not common in body biochemistry Note guanidine is one of the strongest bases in organic chemistry. argenine b/c……. Metiamide is ten times more active than burimamide HN N S H N Me NHMe N CN Electron withdrawing cyanide group
  • 53. N H NHMe S Thiourea Toxic side effects N H NHMe NH Guanidine Drop in activity but no agonist activity! H N NHMe N CN Cyanoguanidine group Cimetidine inhibits H2 receptors and thus inhibits gastric acid release. The drug does not show the toxic side-effects observed for metiamide and has been shown to be slightly more active. • The cyanoguanidine moiety acts as a bio-isostere for the thiourea group. • Both groups are planar and of similar geometry. • Both groups are polar but essentially neutral. • Both groups have high dipole moments. • Both groups have low partition coefficients. • They are weakly basic and also weakly acidic such that • They are un-ionized at pH 7.4 and hence possess enhanced antagonistic activity
  • 54. • Cimetidine first marketed in the UK in 1976
  • 55. Metabolism of cimetidine . Cimetidine is metabolically stable and is excreted largely unchanged. The only metabolites which have been identified are due to oxidation of the sulfur link or oxidation of the ring methyl group. cimetidine inhibits the P-450 cytochrome oxidase system in the liver. This is an important enzyme system in the metabolism of drugs and care must be taken if other drugs are being taken at the same time as cimetidine, since cimetidine may inhibit the metabolism of these drugs, leading to higher blood levels and toxic side-effects.
  • 56. Structure of some H2 receptor blockers Analogues of Cimetidine terminal nitroketeneaminal + different heterocyclic ring 30 times more active than cimetidine equipotent with ranitidine
  • 57. Other Therapies: Proton-Pump Inhibitors… Proton- Pump Inhibitors… Antrum Stomach Pyloric Sphincter Oesophagus Duodenum Histamine Acetylcholine Gastrin Cck2 M3 H2 Parietal Cells Stomach Proton pump Receptors Ion channel cAMP + + + + + + + - H HCl Cl
  • 58. PPIs work by forming a covalent disulfide bond with the ATPase enzyme, leading to an irreversible inhibition of the pump. The PPI pharmacophore is 2-pyridylmethylsulfinylbenzimidazole
  • 59. • Benzimidazole are Pro-Drugs • Form active electrophile in Perietal Cells • Cys from pump act as Nuclephile.
  • 62. Proton pump inhibitors (PPIs) • There are 5 PPIs currently on market which includes omeprazole, esmoprazole, lansoprazole, pantoprazole and rabeprazole • All the PPIs have pyridyl methylsulfinyl benzamidazole skeleton and act as pro-drugs, as they are activated when they reach the acidic canaliculi of parietal cells.
  • 63. • THE END OF THE CLASS 10 Q ALL!

Editor's Notes

  1. JemH...MedChem I-Histamine & Antagonists
  2. JemH...MedChem I-Histamine & Antagonists
  3. JemH...MedChem I-Histamine & Antagonists
  4. JemH...MedChem I-Histamine & Antagonists
  5. JemH...MedChem I-Histamine & Antagonists