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MOA OF HISTAMINE AND ANTIHISTAMINES
- 4. What is an antihistamine? • A drug that reduces or eliminates the effects mediated by the chemical histamine. • Histamine is released by your body during an allergic reaction and acts on a specific histamine receptor. • True antihistamines are only the agents that produce a therapeutic effect that is mediated by negative modulation of histamine receptors (other agents may have anti-histaminergic action but are not true antihistamines) • The term antihistamine only refers to H1 receptor antagonists (actually inverse agonists) • Antihistamines compete with histamine for binding sites at the receptors. Antihistamine cannot remove the histamine if it is already bound.
- 5. What are allergies? • Allergies are caused by a hypersensitivity reaction of the antibody class IgE (which are located on mast cells in the tissues and basophils in the blood) • When an allergen is encountered, it binds to IgE, which excessively activates the mast cells or basophils, leading them to release massive amounts of histamines. • These histamines lead to inflammatory responses ranging from runny nose to anaphylactic shock • If both parents have allergies, you have a 70% of having them, if only one parent does, you have a 48% chance (American Academy of Asthma, Allergies and Immunology, Spring 2003).
- 6. Allergies Mast Cells •Histamine is distributed in Mast Cells in all peripheral tissues of the body and basophils, which circulate in the blood Structure of Histamine •When it is released, histamine causes inflammation by increasing vasodilation, capillary permeability, causing smooth muscle contraction, mucus secretion, and parasympathetic nerve stimulation
- 7. Synthesis of Histamine ■ Formed from the amino acid Histadine in a decarboxylation reaction with the enzyme histadine decarboxylase ■ Occurs primarily in mast cells and basophils
- 9. Clinical Uses of Antihistamines ■ Allergic rhinitis (common cold) ■ Allergic conjunctivitis (pink eye) ■ Allergic dermatological conditions ■ Urticaria (hives) ■ Angioedema (swelling of the skin) ■ Puritus (atopic dermatitis, insect bites) ■ Anaphylactic reactions (severe allergies) ■ Nausea and vomiting (first generation H1- antihistamines) ■ Sedation (first generation H1-antihistamines)
- 10. ■ ■ Adverse effects Associated with the first generation H 1-antihistamines and due to their lack of selectivity for the H 1receptor and anti-cholinergic activity. Side effects are due to CNS depression: ■ Sedation ■ Dizziness ■ Tinnitus (ringing in the ear) ■ Blurred vision ■ Euphoria ■ Uncoordination ■ Anxiety ■ Insomnia ■ Tremor ■ Nausea/vomitting ■ 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)
- 11. Mole Percentage of Species at pH 7.4 3.3 96.2 0.4 ~0 3 a2 3 3 a1 a3 Structural Considerations NH HN + NH pK = 5.94 Dication NH HN N Monocation N NH NH pK = 9.75 NH2 NH2 Nτ HN N Unionized N NH Nπ pK = 14 NH2 N – N • • Anion About 80% of histamine monocation exists in aqueous solution that binds receptors The t tautomer (H on the t nitrogen) permits binding with the receptors However, tautomerism does not appear to be important in H1 binding but does appear to be important in the H2 interaction • Electron donating groups on C5 increase the t tautomer while electron withdrawers increase the p tautomer fraction
- 12. st H1-Antagonists- Classification 1 Generation Antihistamines (Classical antihistamines) •Competitive inhibitors of histamine action at tissue level. •Binding is reversible and displaced by higher levels of histamine. •Additional anticholinergic activity, some possess anti- serotoninergic activity and many of them also inhibit neuronal uptake of norepinephrine. •Also have local anesthetic effect, but carry risk of irritation and sensitization.
- 13. st 1 Generation Antihistamines (Classical antihistamines) 1.Ethylene diamines 2.Ethanolamines (Aminoalkylethers) 3.Alkylamines (Propylamines) 4.Piperazines (Cyclizines) 5.Tricyclics (Piperidines) 6.Phenothiazine
- 14. Common Structural Features of classical first generation 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 increases potency of the drug
- 16. 1. Ethylene diamines Tripelenamine Pyrilamine IUPAC: N,N-dimethyl-N-(phenylmethyl)- N-pyridin-2-ylethane-1,2-diamine IUPAC: N-(4-methoxybenzyl)- N',N'dimethyl- N-pyridin-2-ylethane-1,2- diamine IUPAC:N-(4,5-Dihydro-1H-imidazol-2- ylmethyl) -N-(phenylmethyl)aniline Antazoline
- 18. 2. Ethanolamines (Aminoalkylethers) Diphenhydramine Doxylamine IUPAC: 2-(diphenylmethoxy)- N,N-dimethylethanamine Orphenadrine IUPAC: (RS)-N,N-dimethyl-2-(1-phenyl-1- pyridin-2-yl-ethoxy)-ethanamine Clemastine IUPAC: N,N-dimethyl-2-[(2-methylphenyl) - phenyl-methoxy]-ethanamine IUPAC: (2R)-2-{2-[(1R)-1-(4-chlorophenyl) - 1-phenylethoxy]ethyl}-1-methylpyrrolidine
- 20. 3. Alkylamines (Propylamines) Pheniramine Chlorpheniramine IUPAC: N,N-dimethyl-3-phenyl-3- pyridin-2-yl-propan-1-amine Triprolidine IUPAC: 3-(4-chlorophenyl)-N,N-dimethyl- 3-pyridin-2-yl-propan-1-amine Phenindamine IUPAC: 2-[(E)-1-(4-methylphenyl)-3- pyrrolidin-1-yl-prop-1-enyl]pyridine IUPAC: 2-methyl-9-phenyl-2,3,4,9- tetrahydro-1H-indeno[2,1-c]pyridine
- 22. 4. Piperazines (Cyclizines) Chlorcyclizine Cyclizine IUPAC: 1-benzhydryl-4-methyl-piperazine IUPAC:1-[(4-Chlorophenyl)(phenyl) methyl]-4-methylpiperazine IUPAC: (RS)-1-[(4-chlorophenyl)(phenyl)methyl]- 4-(3-methylbenzyl)piperazine Meclizine
- 23. Hydroxyzine IUPAC: (±)-2-(2-{4-[(4-chlorophenyl)-phenylmethyl] piperazin-1-yl}ethoxy)ethanol Buclizine IUPAC: (RS)-1-[(4-chlorophenyl)- phenyl-methyl] -4- [(4-tert-butylphenyl) methyl] piperazine
- 25. 5. Tricyclics (Piperidines) Cyproheptadine Azatadine IUPAC: 4-(5H-dibenzo [a, d]cyclohepten-5- ylidene) -1-methylpiperidine hydrochloride IUPAC: 11-(1-methylpiperidin-4-ylidene)- 6,11-dihydro- 5H-benzo[5,6]cyclohepta [1,2-b]pyridine
- 28. 2nd Generation Antihistamines Antagonists at H1 receptors Competitive antagonists though some are noncompetitive at higher doses High therapeutic index Poorly lipophilic - do not readily traverse blood brain barrier Highly selective with little or no anticholinergic activity Additional anti-allergic mechanisms of some, like inhibition of late phase allergic reaction by acting on leukotrienes or anti platelet factor activating effect
- 29. Ethylenediamines Acrivastine IUPAC: (E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidin- 1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoic acid Piperazines IUPAC: (±)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1- piperazinyl]ethoxy]acetic acid Cetrizine
- 31. IUPAC: Ethyl4-(8-chloro-5,6-dihydro-11H- benzo [5,6]Cyclohepta[1,2-b]pyridin-11-ylidene) -1- piperidinecarboxylate Loratadine
- 32. rd3 Generation Antihistamines Levocetrizine Desloatadine IUPAC: 2-(2-{4-[(R)-(4-chlorophenyl)(phenyl) methyl]piperazin-1-yl}ethoxy)acetic acid IUPAC: 8-chloro-6,11-dihydro-11- (4-piperdinylidene)- 5H-benzo[5,6] Cyclohepta [1,2-b]pyridine Fexofenadine IUPAC: (±)-4-[1 hydroxy-4-[4-(hydroxyl diphenylmethyl)-1- piperidinyl]-butyl]-a, a-dimethyl benzene acetic acid hydrochloride
- 33. Ar1 Ar2 SAR X C C N R1 R2 A protonable amine A connecting atom X which can be O, C or N A carbon chain, usually ethyl Variations in the diaryl groups , connecting moiety, substituents on the connecting moiety, and substituents on the terminal nitrogen account for the differences observed in potency as well as pharmacologic, metabolic, and adverse reaction profiles.
- 34. Ar1 and Ar2 substituents These provide bulk producing antagonistic activity Generally two aromatic rings - phenyl, benzyl, or an isostere such as pyridyl ; Pyridyl generally results in more potent compounds than phenyl If fused must be non–coplanar as in the three ringed structures related to TCA’s and phenothiazines Para substitution with small lipophilic groups increases potency and decreases metabolism due to decreased ring hydroxylation. Ortho or meta substitution reduces antihistaminic activity
- 35. X This diaryl pattern is present in both first- and second-generation antihistamines. Atom X can be an oxygen, nitrogen, or carbon, which links the side chain to an “aromatic tail.” The nature of atom X is the basis for the structural classification of H1 antagonists. The classical H antagonists are divided into six classes based on what X equals: 1 X =C–O: (Aminoalkyl Ethers) 1. Ethanolamines 2. Propanolamines (clemastine, diphenylpyraline) X = C: 3. Propylamines (Saturated and Unsaturated)
- 36. X = N: 4. Ethylenediamines 5. Piperazines (Cyclizines) and Tricyclics 6. Miscellaneous: This forms the sixth class of traditional antihistamines and would include many of the newer antihistamines since they do not fall into one of the older, traditional, classes Connecting Chain Its function is to separate the nitrogen from the rings by 5–6 Å May be saturated, unsaturated, branched or part of a ring Branching decreases antihistaminic potency except for the phenothiazines where β carbon branching increases antihistaminic potency.
- 37. Basic aliphatic amine Must be able to accept a proton (basic) at physiological pH R1 and R2 : Potency order is 3° > 2° > 1° Quaternization does not increase antihistaminic but does increase anti-cholinergic activity May be incorporated into a heterocycle which is although larger, the heterocycle constrains Dimethyl is the optimum configuration Larger substituents decrease antihistaminic potency due to steric hindrance unless they are part of a heterocycle structure when the ring constrains the two ethyls so they are still active
- 38. Receptor Interaction The H1 antagonists do not occupy the same area or space as the natural receptor substrate Only the protonated nitrogen binds the same anionic site as Histamine The aromatic tail binds adjacent to the Histamine binding site thus produces the nonspecific conformational perturbation of the receptor. This changes the shape of the receptor decreasing the affinity for Histamine It seems that sites outside may be chiral because steroselectivity is observed with some H1 antagonists As previously discussed the optical isomers of α-Methyl histamine are equipotent as agonists
- 39. 2 2 N 2 2 2 N 2 2 2 2 N 3 2 2 2 2 3 N 2 2 2 3 N 3 Histamine H2-Antagonists Guanylhistamine provided the lead. Extension of the side chain increased anti H2 potency but some agonist activity remained. Replacing the basic guanidino group with the neutral thiourea yielded effective H2 antagonists. a b HN HN H CH CH N C NH2 NH Guanylhistamine H CH CH CH N C NH S SK&F 91581 2 Burimamide lacked agonist action but was not orally absorbed c HN H CH CH CH CH N C NH S SK&F 91863 2 In Metiamide (1) reduce the pKa of the ring N , reduced ionization , increased membrane permeability and absorption and 10X more potent than Burimamide, (2) cause the t tautomer to predominate which interact with H2 d e HN H C HN H CH CH CH CH N C NHCH S Burimamide H CH –S–CH CH N C NHCH S Metiamide But caused kidney damage and granulocytopenia , possibly due to the thiourea so was replaced by the isosteric guanidine. This compound being highly basic was 20 times less potent f H H C HN C3 CH N CH 2 2 –S–CH –S–CH 2 2 CH CH 2 2 H N C NHCH NH H N C NHCH 3 3 Replacement of this group with strong electron withdrawer but more lipophilic cyano derivative yielded Cimetidine. g HN N N Cimetidine ™ I CN
- 40. SAR H3C NH N H N S Cimetidine N H N C CH N 3 Need an aromatic ring with n electrons next to the side chain . The imidazole ring is not required (the other H2 antagonist don’t have it) but if it is present the t tautomer should predominate . The t tautomer is promoted by electron donors at position 5 and electron withdrawers at position 4. The terminal nitrogen group should be polar but not basic for maximal potency Separation of the ring from the nitrogen group by 4 atoms gives maximal potency. Cimetidine is an extremely successful drug in the treatment of ulcers. Note the electron donor methyl at C5 and electron withdrawing side chain at C Also the non basic cyano guanidine terminal nitrogen group. 4 However, cimetidine has several disadvantages . It is an inhibitor of CYP , which leads to many drug–drug interactions. It exhibits anti-androgenic action and can cause gynecomastia. Further it has 60 to 70% oral bioavailability.
- 41. Ranitidine is a furan derivative, an isostere of the imidazole with n electrons on the oxygen , with 50% bioavailability. It is 4 - 10 X potent than Cimetidine with a longer DoA. Further, it is a weaker CYP inhibitor. The tertiary amine side chain allows the formation of salts. O N CH S CH3 3 H N HC Ranitidine H N CH3 NO2 Famotidine, a thiazole derivative, is 9–15 X potent than Ranitidine or 40–60 X than Cimetidine. No cases of S N S N SO2NH H N H 2 gynecomastia have been reported. It is a weak inhibitor of CYP. Like Ranitidine salts can easily be prepared for this N NH2 compound. but its absorption is incomplete with only 40 NH2 Famotidine to 50% bioavailability. Nizatidine is also a thiazole derivative similar to Ranitidine ( 5–18 X Cimetidine ), but more bioavailable, 90%, with no antiandrogenic or enzyme inhibition. S N N CH S CH3 3 H N HC Nizatidine H N CH NO2 3
- 42. Histamine H2 Receptor Interaction Cationic Histamine binds to the receptor via the formation of three hydrogen bonds The cationic nitrogen and t–nitrogen of the imidazole ring are hydrogen donors and the p–nitrogen acts as a proton acceptor Participation of the ammonium group in the hydrogen bonding inevitably leads to a decrease of the positive charge on the ammonium group This decrease in positive charge induces a tautomeric change in the imidazole ring resulting in a stronger binding of the p–nitrogen and proton release by the t– nitrogen The net result is a proton shift at the receptor surface which is believed to trigger the H2 stimulating effect This mechanism calls for the presence of a hydrogen atom in position 3 of histamine, and recall that 3–methylhistamine is unable to stimulate the receptor.
- 43. H3-Receptor Antagonists Potential for treating asthma, migraine, hypertension, septic shock, and in learning and memory degenerative disorders like AD Thioperamide and its congeners (4(5)-substituted imidazole derivatives) are examples of the potent and selective H3 receptor antagonist Some of the more prominent new H3 receptor antagonists are GT-2016, and GR- 175737, which show receptor affinities in the low nanomolar range. None of this class of compounds is in clinical use; however, few are undergoing further pharmacologic evaluation as potential therapeutic agents. Cl S O N NH N O N N HN N Thioperamide HN N GT-2016 HN N GR-175737