Introduction of Anti-Histamine

Dr. Sanaa Bardaweel

Histamine

Dr. Sanaa Bardaweel

Local hormone.

A chemical messenger component of various A chemical messenger component of various biological pathways. It is involved in biological pathways. It is involved in mediation of allergic and hypersensitivity mediation of allergic and hypersensitivity reactions as well as regulation of gastric acid reactions as well as regulation of gastric acid secretion.secretion.

Source?

Histamine Properties

NotesNotes •Two possible tautomersTwo possible tautomers•pKpKaa for the for the -NH-NH22 group = 9.80. group = 9.80. •% ionisation at pH 7.4 = 99.6% ionisation at pH 7.4 = 99.6•pKpKaa for the imidazole ring = 5.74 for the imidazole ring = 5.74 •Imidazole ring is not ionised at blood pH.Imidazole ring is not ionised at blood pH.•SAR studies suggest that the (SAR studies suggest that the ()- NH3+ monocation is)- NH3+ monocation is important for agonist activity at H-receptors important for agonist activity at H-receptors

•What type of interactions do you expect to see?What type of interactions do you expect to see?

Dr. Sanaa Bardaweel

Receptors• H1- receptors mediate:

• smooth muscle contraction• increased vascular permeability• pruritus• prostaglandin generation• decreased AV conduction time+ tachycardia

• H2-receptors mediate:• Gastric acid secretory action of histamine

• H3-receptors • Neural auto receptors which modulate histamine synthesis and release in the

CNS.

• H4-receptor:• WBCs, They have been shown to mediate mast cell chemota.xis

• Termination of histamine action :

Three principal ways exist for terminating the physiological effects of histamine

• cellular uptake

• desensitization of cells

• metabolism (the most common pathway)

SAM

SAH HMT

NN

NH2

NN

H

OH

O

CH3

N-Methylhistamine Imidazole acetic acid

N N

OH

ONNO

OH OH

HO

OH

O

CH3

N-Methylimidazoleacetic acid

Imidazole Acetic acid riboside

NNH

NH2

DAO

[ HMT: histamine N-methyl transferase . SAM: S-adenosyl-L-methionine SAH: S-adenosyl-L-homocysteine . DAO: Diamine oxidase]

Histamine H1-receptor Antagonists: Antihistaminic agents

Mechanism of action: H1- antagonists are defined as those drugs that competitively inhibit the action of histamine on tissues containing these receptors.

H1-antagonists are subdivided into two groups: the first generation or classical histamines & second generation or non-sedating antihistamines.

First Generation H1-Antagonists:• Aminoalkyl ethers (ethanolamines) • The drugs in this group possess significant anticholinergic activity.• Drowsiness is a common side effect as a result of the ability of

these compounds to penetrate the BBB and occupy central H1-receptors.

• GI side effects are relatively low compared to the ethylenediamines.

Dr. Sanaa Bardaweel

Ar'

R''

Ar

O-CH2-CH2-N

R

R'

(General Sructure of the Aminoalkyl ethers)

Diphenhydramine (Benadryl®)

• pka of 3ry amine?

• Ionization at pH=7

• 5% unionized

• CNS effect

• Mixtures : Pectolyn antitussive contains dextromethorphan + diphenhydramine + sodium citrate.

• Uses: Sleep aid, allergy, anxiolytic.

• No addiction but dependence.

Dr. Sanaa Bardaweel

• Propylamines : • Characterized structurally by an sp3 or sp2 carbon connecting atom with a

carbon chain of two additional carbons linking the key tertiary amino and diaryl pharmacophore moieties.

• Those Propylamines with a saturated carbon connecting moiety are commonly referred to as the Pheneramines.

• The halogenated ones are more potent and have a longer duration of action.• All Pheneramines are chiral molecules, and the anti-histaminic activity resides

almost exclusively in the S-stereoisomers.

CH CH2 CH2 NR

R'

Chlorpheniramine(Polaramine, Allerfin)

• 3ry amine, side effects?

• Both Cl and Pyridine increase potency.

• Mixtures: Tussifin contains chlorpheniramine + codeine + glyceryl guaiacolate + potassium citrate + sodium benzoate + liquorice

Dr. Sanaa Bardaweel

• Piperazine ( cyclizines):

• In this series the connecting moiety is a CHN group, and the carbon chain, terminal amine functionality as well as the nitrogen atom of the connecting group are all part of the Piperazine moiety.

• They are moderately potent anti-histaminic with lower incidence of drowsiness, and characterized by a slow onset and long duration of action. These agents exhibit central and peripheral antimuscarinic activity and this may be responsible for the anti-emetic and anti-vertigo effects. Some members exhibit a strong teratogenic potential.

CH N N

X

R

Hydroxyzine (Atarax)

• Potency compared to diphenylhydramine, chlorpheniramine?

• Piprezine ring?

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Meclozine (Navidoxine with B6)

• Sedation• Anticholenregic effect• Motion sickness and

morning sickness

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Dimetindene (Fenistil)

• Potency due to pyridine( H-π)

• Indene group, hypnotic

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Triprolidine (Trifed)

• 3ry amine(Pyrrolidine)

• Mixtures : Trifed.. Conatins guaiphenesin + pseudoephdrine + triprolidine.

Dr. Sanaa Bardaweel

Phenothiazines:

• Differs from the phenothiazine antipsychotics which requires an unbranched propyl chain.

• The enantiomers have similar anti-histaminic and other pharmacologic properties.

• Lengthening of the side chain and substitution of lipophilic groups in 2-position of the aromatic ring decrease anti-histaminic activity and increase psychotherapeutic properties.

S

N

CH2 CH CH2 NR

R'R''

Oxomemazine (Rectolyn, Rictamol)

• Rectolyn?• Phenothiazine ring?• Used for psycosis

Dr. Sanaa Bardaweel

Promethazine (Histazin)

• I.M• Subcutaneous or intra-

arterial injection are contraindicated!

Dr. Sanaa Bardaweel

Ketotifen (Zaditen)

• Isosteres.

Dr. Sanaa Bardaweel

Second generation H1-Antagonist drug classes:

• Second generation agents have little affinity for muscarinic, adrenergic or serotonergic receptors, therefore they produce less side effects.

• All these agents are devoid of sedating effects at therapeutic concentrations due to poor CNS penetration and lowered affinities for central histaminic, cholinergic and adrenergic receptors.

• Terfenadine:

• Selective long acting (>12 hr) H1-antagonist (first generation).

• Histamine receptor affinity is related primarily to the diphenylmethylpiperidine moiety.

• Oxidative demethylation yields COOH.

• CA pka=4, completely ionized and does not pass BBB.

• Long duration of action due to slow dissociation from receptor.

•

C

OH

N CH2CH2CH2CH

OH CH3

CH3

CH3

• Fexofenadine HCl (TelFast):

• It is a metabolite of terfenadine, not only active and effective in allergic disorders, but also less cardio toxic than terfenadine.

• Selective H1-receptor blocker with no clinically significant cholinergic or adrenergic receptor blockade.

• No sedative or other CNS effects. (doesn't cross BBB)

HO N

HO CH3

CH3

COOH

Acrivastine (Semprex capsules)

• 2nd generation H1-blocker.

• t0.5 increased, due to increased protein binding, lysine!

• Binding, potency regions?

Dr. Sanaa Bardaweel

Cetirizine (zyrtec)

• High potency, longer duration of action?

• Chiral?• Levocetrizine( xyzal)• 6 times more potent

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Loratadine (Claritine)

• Amide not amine?• Prodrug• Long duration of

action, late onset of action

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Desloratadine (Aerius)

Dr. Sanaa Bardaweel

2nd amine, CNS?

Histamine H2-Receptor Antagonist:

• Their primarily pharmacological action involves antagonism of the action of histamine at its H2-receptors.

• Used in the treatment of acid peptic disorders including:Heartburn to peptic ulcer disease, Zollinger – Ellison syndrome, GERD, Acute stress ulcers and erosions.

•No known HNo known H22 antagonist at the time - no lead compound antagonist at the time - no lead compound

•SK&F decide to use histamine itself as the lead compoundSK&F decide to use histamine itself as the lead compound

•Aim is to alter an agonist into an antagonistAim is to alter an agonist into an antagonist

•Need to know SAR requirements for HNeed to know SAR requirements for H22 agonists agonists

•Analogues tested by their ability to promote gastric acid releaseAnalogues tested by their ability to promote gastric acid release

Histamine as a lead compound

Dr. Sanaa Bardaweel

Two nitrogen atoms are required for HTwo nitrogen atoms are required for H11 agonist activity agonist activity

All three nitrogen atoms are required for HAll three nitrogen atoms are required for H22 agonist activity agonist activity

SAR for H1 and H2 agonists

H1 Receptor H2 Receptor

NH3

HNN

NH3

HNN

Dr. Sanaa Bardaweel

Receptor (Inactive)

Histamine

NH3

HN

N

Extra Functionality

NH2

HN

N

Induced Fit - Receptor 'Switched on'

NH3

HN

N

Receptor (Inactive)

NH2

HN

N

Strategies for converting agonists to antagonists

Different induced fitDifferent induced fitDr. Sanaa Bardaweel

ExamplesExamples - extra hydrophobic groups - extra hydrophobic groups

ResultsResults•No antagonist activity observed with extra hydrophobic groupsNo antagonist activity observed with extra hydrophobic groups•Try adding extra hydrophilic groups instead Try adding extra hydrophilic groups instead •Aim is to search for extra polar binding regionsAim is to search for extra polar binding regions

NHR1R2

NN

NHR1R2

HNNR3

Strategies for converting agonists to antagonists

Dr. Sanaa Bardaweel

N-Guanylhistamine

7.1 Biological properties7.1 Biological properties •Partial agonist - promotes HCl release but less strongly than Partial agonist - promotes HCl release but less strongly than histaminehistamine

•Prevents histamine from fully promoting the release of HClPrevents histamine from fully promoting the release of HCl

•SK&F suggest that SK&F suggest that NNguanylhistamine is binding to the proposed guanylhistamine is binding to the proposed HH22 receptor, resulting in weak activation receptor, resulting in weak activation

• Whilst present, Whilst present, NNguanylhistamine blocks histamine from guanylhistamine blocks histamine from bindingbinding

HN

HNN

NH2

H2N

Guanidine moietyGuanidine moiety

Dr. Sanaa Bardaweel

•The guanidine group is basic and ionisedThe guanidine group is basic and ionised•Different tautomers are possibleDifferent tautomers are possible•The positive charge can be delocalisedThe positive charge can be delocalised

The positive charge is more diffuse and can be further away The positive charge is more diffuse and can be further away from the imidazole ringfrom the imidazole ring

HN

HNN

NH2

H2N

HN

HNN

NH2

H2N

HN

HNN

NH2

H2N

HN

HNN

NH2

H2N

N-GuanylhistamineStructure and chemical properties

Dr. Sanaa Bardaweel

Antagonistbinding region

Agonistbinding region

Imidazole ringbinding region

Antagonistbinding region

NH3

HN

N

HN

N

NH3

•Histamine has a short chainHistamine has a short chain•Charged Charged -nitrogen can only reach the polar agonist region-nitrogen can only reach the polar agonist region•The antagonist binding region is out of rangeThe antagonist binding region is out of range•Histamine can only bind as an agonist Histamine can only bind as an agonist •Histamine acts as a pure agonistHistamine acts as a pure agonist

Binding theory for agonists and antagonists

No interaction as an antagonistNo interaction as an antagonist Strong interaction as an agonistStrong interaction as an agonist

Binding of histamine

Dr. Sanaa Bardaweel

Binding as an antagonistBinding as an antagonistReceptor not activatedReceptor not activated

Binding as an agonistBinding as an agonistReceptor activatedReceptor activated

•Positive charge on the structure is more diffuse and further outPositive charge on the structure is more diffuse and further out•Allows Allows NN-guanylhistamine to bind in two different modes-guanylhistamine to bind in two different modes•Structure binds as an agonist in one mode and as an antagonist in Structure binds as an agonist in one mode and as an antagonist in the other mode, making it a partial agonistthe other mode, making it a partial agonist

Agonistbinding region

Imidazole ringbinding region

Antagonistbinding region

HN

N

NH

NH2

H2N

HN

N NH

H2N

NH2

Binding theory for agonists and antagonists Binding of N-guanylhistamine

Dr. Sanaa Bardaweel

SK&F propose that the guanidine moiety interacts with a carboxylate ion in the SK&F propose that the guanidine moiety interacts with a carboxylate ion in the antagonist binding region by meansantagonist binding region by means of two H-bonds and an ionic interactionof two H-bonds and an ionic interaction

Chelation binding theoryThe proposal

ReceptorX=NH,S

Strong interactionHN

HNN

N

N

H

H

H H

O

O

Dr. Sanaa Bardaweel

AimAim To push the polar guanidine group further out and to increase the To push the polar guanidine group further out and to increase the interaction with the antagonist binding regioninteraction with the antagonist binding region

Chain extension strategy

Partial agonistPartial agonistAntagonist activity increasesAntagonist activity increases

ResultsResults

•Antagonist activity of the extended guanidine analogue increases as expectedAntagonist activity of the extended guanidine analogue increases as expected

3C Bridge3C Bridge

HNN

NH

NH2

NH2

Guanidine

Dr. Sanaa Bardaweel

Good binding as an antagonistGood binding as an antagonist Binding as an agonistBinding as an agonist

Antagonistbinding region

Agonistbinding region

Imidazole ringbinding region

HN

N

HN

NH2

NH2HN

N

HN

NH2

NH2

Chain extension strategy Proposed binding for 3C extension analogues

Dr. Sanaa Bardaweel

Strategy:Strategy:•Retain the guanidine groupRetain the guanidine group•Guanidine is a natural group present in the amino acid arginineGuanidine is a natural group present in the amino acid arginine•Increase activity by making the guanidine group neutralIncrease activity by making the guanidine group neutral•Add a strong electron-withdrawing group to decrease basicity (e.g. Add a strong electron-withdrawing group to decrease basicity (e.g. NONO22 or CN) or CN)

CimetidineCimetidine

HNN

S

HN

Me

NHMe

NCN

Cimetidine

Electron-withdrawingElectron-withdrawingcyanide groupcyanide group

Dr. Sanaa Bardaweel

PropertiesProperties

•Inhibits HInhibits H22-receptors and lowers levels of gastric acid released-receptors and lowers levels of gastric acid released

•Marketed in 1976Marketed in 1976

•Biggest selling prescription drug until ranitidineBiggest selling prescription drug until ranitidine

•Metabolically stableMetabolically stable

•Inhibits cytochrome p450 enzymesInhibits cytochrome p450 enzymes

•Drug-drug interactions with diazepam, lidocaine and warfarinDrug-drug interactions with diazepam, lidocaine and warfarin

Cimetidine (Tagamet)

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Famotidine (Pepcidin, Famodar)

• More potent than Cimetidine (2 guanido gps)

Dr. Sanaa Bardaweel

•Contains a nitroketeneaminal groupContains a nitroketeneaminal group•Different heterocyclic ringDifferent heterocyclic ring•Took over from cimetidine as the most widely sold prescription Took over from cimetidine as the most widely sold prescription drug in the worlddrug in the world

34

SNH

NHMe

CHNO2

O

Me2N

25

Ranitidine (Zantac)

Dr. Sanaa Bardaweel