Davis MDCH 5210 - Antihistamines, 2006 1 Histamine receptors – H 1 - Allergic responses. Watery eyes, congestion, etc. from allergies. Anaphylaxis – bronchial

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Davis MDCH 5210 - Antihistamines, 2006

Histamine receptors –

H1- Allergic responses. Watery eyes, congestion, etc. from allergies. Anaphylaxis – bronchial larynx constriction.Skin allergic response – reddening, rashes, welts.Edema from injury.

H2 – Gastric secretion. Important for ulcer treatment and acid reflux

H3 – ? CNS receptors. There are also H1 receptors in the CNS.

Antihistamines are also used for motion sickness. In general their antimuscarinic effects are similar to that of scopolamine, although weaker.

Antihistamines

2


HNN

NH2

H

HNN

NH2

H

CH3

HNN

NH2

H3

C

HNN

NH2

H

H

H3

C

(R) α - methyl histamine

H3

Agonist

4-methylhistamine

H2

Agonist

2- methyl histamine

H1

Agonist

Histamine

Histamine Agonists

3


Ethylenediamines

X

Ar1

Ar2

(CH2

)n N

CH3

CH3

N

N

CH3

CH3

N

N

HN

SAR Prototype

Phenbenzamine

Antazoline

Antihistamines – H1 Blockers

4


H

O

N

CH3

CH3

R1

N

CH3

CH3

O

SAR Prototype

R1

is a small group like H, CH3

,OCH3

Diphenhydramine

(Benadryl)

Aminoalkylethers

O

NCH3

Cl

Cl

N

N

CH3

Cl

O

N

CH3

CH3

Diphenylpyraline

Meclizine

Good H1

antagonist, but also

good antimuscarinic

Clemastine

(Tavist)

Piperazine/N-heterocycle Series

Antihistamine SAR

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Antihistamines are stereospecific. Anumber of new, single isomer drugs arebeing developed.

Antihistamines are structurally similarTo SSRIs and to antipsychotics. NoticeThe subtle difference between fluoxetineAnd several antihistamines.

Stereo- and regioisomers

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Alkyl Amines

Long Duration, less sedation than ethylenediamines, ethanolamines. The “next best thing” until the “2nd generation” were developed.

N

N

CH3

CH3

R

N

N

CH3

N

H3C

Cl

Pyrrobutamine (Pyronil)R = H PheniramineR = Cl Chlorpheniramine (Chlortrimeton)R = Br Brompheniramine (Dimetane)

Triprolidine (Actidil)

NCH3

CH3N

Dimethindene (Forhistal)

N CH3

Phenindamine (Nolahist)

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A Cl at the 2-position weakens H1 activity relative to antimuscarinic activity and D2 antagonist activity

N

NCH3

N

S

CH2

CH2

N(CH3

)2

N

S

CH2

CHN(CH3

)2

CH3

Mebhydrolin

Fenthazine

Promethazine

(Pheregan)

N

S

CH

2

CH

2

CH

2

N(CH

3

)

2

Cl

Chlorpromazine

N

N

N

N

OCH3

H

F

Astemizole

(Hismanal)

Rigid Analogs (I)

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Cl

O OCH2CH3

N

N

CH3

N

S

Cl

N

N

H

Primethixene Loratadine (Claritin) Desloratadine (Clarinex)

Rigid Analogs (II)

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Hismanal was FDA approved in 1988 as an antihistamine for allergy and hay fever symptom relief. The FDA first warned consumers and healthcare providers of new safety information regarding Hismanal February 9, 1998 due to the risk of death, cardiovascular adverse events, anaphylaxis, and serious drug interactions.

In addition, Hismanal labeling was changed to stress avoiding the use of Hismanal in combination with certain other medications and for liver disorder patients to completely avoid its' use.

After a series of labeling changes and warnings Hismanal was recalled on June 21, 1999.

N

N

N

N

OCH3

H

F

Astemizole

(Hismanal)

Astemizole

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Terfenadine was discontinued when it became apparent that there was a high frequency of heart arrythmia associated with the drug. Fexofenadine is a metabolite and is the activated form responsible for antihistamine activity. In patients with compromised liver metabolism, or when the presence of other drugs limited the metabolism of terfenadine, persistent levels resulted in the observed arrythmias. Therefore, the fexofenadine replaced terfenadine (1997).

Ventricular Arrythmias are not good!

N

OH

O

Cl

F

Haloperidol (Haldol)

Prototype butyrophenone antipsychotic

10x Chlorpromazine

Antihistamines “related” to butyrophenones

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N

OH

OH

N

OH

COOH

OH

[OX]

Terfenadine

(Seldane)

Fexofenadine

(Allegra)

N N

H

O

Cl OH

O

Cetirizine

(Zyrtec)

Butyrophenone-like structures

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Allegra Propaganda - www.allegra.com

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If you haven't gotten the relief you want from Claritin ｨ (loratadine), Clarinex ｨ (desloratadine), or Allegra ｨ (fexofenadine HCl), ask your doctor if ZYRTEC is right for you.

www.zyrtec.com

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ON

CH3

CH3

N

N

CH3

Cl

N

Cl

NH

N

NOCl

OH

O

DiphenhydramineMeclizine

DesloratadineCetirizine

Linking the first generation with Non-sedative Antihistamines.

Big Picture - Bottom Line

Structural Summary

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Anti-emetics

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SyntheticTropane Alkaloids

Anti-emetic Table

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Press Release: The 2005 Nobel Prize in Physiology or Medicine3 October 2005

The Nobel Assembly at Karolinska Institutet has today decided to award

The Nobel Prize in Physiology or Medicine for 2005

jointly to

Barry J. Marshall and J. Robin Warren

for their discovery of

"the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease”

2005 Nobel Prize

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Gastric Secretions

Cell Biology

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Gastric receptors are pharmacologically distinct. The classic H1 antagonists don’t interact with H2 receptors. Antihistamines are an important treatment for gastric disorders; antacids, ulcer treatment, acid-reflux disease.

HNN

NH2

H

NNH

NH2

H

Basic Heterocycle Flexible Chain Polar, Neutral Group

SAR for Histamine H2

Receptor Antagonists

NT

Tautomer is preferred for H2

H2 Histamine antagonists.

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HH

S

CH3

NNH

NHN

H3C

HH

S

CH3

NNS

NHN

CN

H3C

HH

N

CH3

NNS

NHN

CH2N(CH3)2

HH

CHNO2

CH3

NNS

O

C(NH2)2N

NSO2NH2

NH2S

NS

Burimamide(Non-selective)

Metiamide(H2 Selective)

Cimetidine(Tagamet)

Ranitidine(Xantac)

Famotidine(Pepcid)

H2 Histamine antagonists. - Structures

Documents

Davis MDCH 5210 - Antihistamines, 2006 1 Histamine receptors – H 1 - Allergic responses. Watery eyes, congestion, etc. from allergies. Anaphylaxis – bronchial