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F. E. R. Simons, Advances in H1-Antihistamines. N Engl. J Med, 2004, 351, 2202-2217.

Histamine andH1 Antihistamines

A/Prof Jane HanrahanRm N408

jane.hanrahan@sydney.edu.au

Lecture Objectives

Understand the tautomersim of histamine and the role this plays in it’s interaction with receptors.

Identify the different classes of antihistamines

Identify the structural features of first generation antihistamines which make the likely to cause side-effects such as sedation, anti-cholinergic effects

Describe the binding and of histamine and antihistamines, including the residues and types of bonds involved, the importance of conformation and stereochemistry

Identify the structural features of second generation antihistamines and be able to explain why these do not cause sedation

Histamine

[2-(4-imidazolyl)ethylamine]

Imidazole ringEthyl amine side chain

Histamine Discovered in 1910 Suggested that it mediated symptoms of allergy

eg wheal & flare, rhinitis Now known that it does not account for all

symptoms of allergy Formed by decarboxylation reaction of Histadine

(histadine decarboxylase) Secreted from mast cells and some CNS neurons Similar to a “local hormone” (autocoid), but lacks

endocrine gland

Allergies Hypersensitivity reaction of the antibody class IgE

Allergens bind to IgE, excessively activating mast cells or basophils which release massive amounts of histamine.

histamine causes inflammation by increasing vasodilation & capillary permeability, smooth muscle contraction, mucus secretion, and parasympathetic nerve stimulation

inflammatory responses range from runny nose to anaphylactic shock

H1 Receptors

Found in smooth muscle of intestine, bronchi, blood vessels

Effects blocked by classical H1-antagonists Also found in brain but unevenly distributed

H2 Receptors

Discovered in 1972 by Black et al Gastric parietal cells, guinea pig atria, uterus Control release of gastric acid from gastric

parietal cells

H3 Receptors

Discovered in CNS in 1983 When histamine was shown to inhibit it’s

own synthesis and release Probably via presynaptic autoreceptors Histamine was also shown to modulate the

release of other neurotransmitters eg ACh, dopamine, NAd, serotonin via H3 receptors

Predominantly present in basal ganglia, hippocampus and cortical areas

H4 Receptors

Discovered in 2000

widely expressed in components of the immune system such as the spleen, thymus and leukocytes

May benefit allergic conditions

may lead to the treatment of autoimmune diseases. e.g. rheumatoid arthritis and IBS

TautomersimA basic organic compound,

Np pKa1=5.80

Na, pKa2=9.40

Nt, pKa3=14.0

exists as a mixture of different ionic and uncharged tautomeric species

pH 1

pH 16

Histamine

exists almost exclusively (96.6%) as the monocationic conjugate species (Na as NH3

+ ) at physiological pH (7.4)

Nt-H (tele- tautomer) predominates (~ 80%)

Histamine Receptor

Extracellular Extracellular Extracellular

Intracellular Intracellular Intracellular

Inactive Inactive InactiveActive Active Active

Effect of Agonist(histamine)

Effect of inverseagonist (antihistamine)

N Engl J Med (2004) 351;2203-2217.

G protein-coupled receptors (GPCRs) Seven-transmembrane domain receptors (7TM)

H1 receptor

Histamine Recognition

Histamine Recognition

Histamine Activation

Ethylenediamines

Mepyramine (R=OCH3) 1943Tripelenamine, (R=H) 1946

Significant CNS and sedative effects

MepyramineRelaxatabs - sedationAnthisan – topical

Aminoalkyl ethers

Anticholinergic side-effectsSedationLow GI irritation

e.g. Diphenhydramine maleate(Benadryl)

Benadryl Original, Benadryl Night TimeUnisom SleepGels (50mg)

Aminoalkyl ethers

Dramamine – Dimenhydrinate (50 mg) Mixture of two drugs – diphenydramine (27.2 mg) and 8-chlorotheophylline (22.8 mg)

Aminoalkyl ethers

Doxylamine succinate• Potent anti-cholinergic effects

Mersyndol - paracetamol 450 mg, codeine phosphate 9.75 mg, doxylamine succinate 5 mg.

Clemastine (Tavist, Tavegyl)• anti-puritic (stops itching)

Stereochemistry

R1=Ph or 2-PyridineR2=H or MeR=Cl or H

Aminopropyl Compounds

Less sedation, High incidence of CNS stimulationLow GI irritationUsed mainly in cold & flu remedies

X=H Pheniramine (Visine Allergy Drops)X=Br Brompheniramine (Dimetapp)X=Cl Chlorpheniramine (Demazin)

Dexchlorpheniramine (Polaramine)

H1 Antagonists

Triprolidine (Actifed)

Cyclic Basic Chain

Antazoline• Antistine-Privine eye drops• Albalon eye drops

First Generation H1 Antihistamines

Ar1= Aryl, substituted phenyl, heteroaryl eg 2-pyridylAr2= Aryl, or benzyl (ArCH2)R=tertiary acyclic eg NMe2, or cyclic eg pyrrolidino basic groupAr-N+ distance ~ 5-6 ÅX=N ethylenediaminesCH-O aminoalkyl ethersCH or C=C alkyl amines

Binding of Antihistamines

??????

Which of the two aromatic rings of chlorpheniramine would bind to the hydrophobic site on the H1 receptor?

The pyridine ring The p-chlorophenyl ring

??????

Provide a chemically based explanation for why the p-chlorophenyl ring cannot bind to the H1 receptor hydrophobic site.

Tricyclic Antihistamines

Promethazine (Phenergan)

Tricyclic Antihistamines

Alimemazine/trimeprazine - Vallergan

Available as a syrupOften used to help babies and small children sleep

Antipruritic - eczema or poison ivySedativeAnti-emetic - motion sickness.

Tricyclic Antihistamines

Cyproheptadine - Periactin

Antihistamine, anticholinergic and antiserotonergic activity

AllergyMigraine prophylaxisAppetite stimulant

Tricyclic Antihistamines

Azatadine - Zadine

Antipruritic - eczema or poison ivySedative.

Tricyclic Antihistamines

In potent tricyclic systems, rings A and C are not in the same planei.e. the B ring of phenothiazine is a boat shape

Promethazine

Conformers

trans conformation of diphenhydramine - Active

Fluorene analogue100 times less active

Pharmacophores

Summary

Different tautomeric forms of histamine depending on pH

Role of histamine tautomers in receptor binding and recognition

Recognise basic structural features of different classes of first generation H1 antagonists

Identify side effects of first generation H1 antagonists

Role of stereochemistry in activity

Role of conformers in activity

????

Which of the following properties would be expected of this antihistamine?

Non-sedative

High risk of antimuscarinic side effects

Therapeutic utility as an antipsychotic

Therapeutic utility as an antiemetic

?????? Describe the structural feature of the

antihistamine responsible for each of the anticipated properties.

High risk of antimuscarinic side effects

Therapeutic utility as an antiemetic

Second GenerationAntihstamines

Terfenadine R=CH3

Fexofenadine R=COOH (Telfast )

Terfenadine metabolised in body to Fexofenadine

Terfenadine removed from market due to serious cardiac side-effects

Zwitterionic Roll-Up

C

OH

N CH2 CH2 CH2

H

CH OH

COOC

CH3H3C

+

-ion-ion bond

Fexofenadine

Fexofenadine

Second GenerationH1 Antagonists

Astemizole

also causes cardiac side-effects

slow onset and long duration of action

Second GenerationH1 Antagonists

Loratadine R=COOCH2CH3

Desloratadine R=H

Related to first generation tricyclic antihistamines

No reported cardiac side-effects

Metabolite (desloratadine) reported to be more potent

Metabolism

Second GenerationH1 Antagonists

Cetirizine (Zyrtec)

Long duration of action

No reported cardiotoxicity, but some drowsiness

Single enantiomer - less sedation??

Levoceterizine (Zyzal)

Second GenerationH1 Antagonists

Acrivastine (Hismanal)

Ebastine R=CH3

Carebastine R=COOH

+

Azelastine

Second GenerationH1 Antagonists

Levocabastine

Olopatadine (Patanol)

Second GenerationH1 Antagonists

General structure not as clearly defined as for first generation antihistamines

Most non-sedating H1 antagonists still have large aromatic groups at one side

Lipophillic t-butyl group seems to be associated with cardiotoxicity

Active forms have a carboxylic acid group and are zwitterionic at physiological pH, therefore don’t cross BBB

Metabolism to carboxylic acid removes cardiotoxicity