H2 receptors - Lecture notes .. PDF

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Summary

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Description

H2 receptor antagonists and proton pump inhibitors Peptic Ulcer •

Duodenal and gastric ulcers

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Most common disease of GIT in western countries

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10-20% of adult, male population will experience peptic ulcer at some time

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Factors associated with PUD Helicobacter pylorii infection NSAID’s

Rudolf Valentino •

Died, 1926

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Perforated ulcer

Traditional treatments •

Antacids

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Surgery

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Sucralfate (a sucrose-aluminium complex)

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Diet

All aimed at reducing acid concentration None of these was especially effective

Drug targets for reducing acid secretion? •

Anticholinergic drugs Tropane alkaloids, e.g. atropine Tincture of Belladonna (deadly nightshade) Effectiveness limited by side effects

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Gastrin antagonists

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Histamine antagonists

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Proton pump inhibitors

Control of acid secretion •

Proton pump

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H+,K+-ATPase

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Stimulated by histamine, Ach, gastrin

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Inhibited by PGE2

Histamine •

Derived from amino acid, histidine

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Known since 1920’s to stimulate acid secretion when injected into dogs

Histamine •

Role in inflammatory response well established

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1940’s – histamine antagonists developed

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Mepyramine, diphenhydramine

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Effective in treatment of allergic conditions, e.g. urticaria and hay fever

H-receptor subtypes •

1948 – recognised that ‘classical’ histamine antagonists had no effect on acid secretion

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Postulated that there was more than one receptor subtype

Sir James W Black •

Nobel Prize in Physiology or Medicine for 1988

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in 1964 developed the first clinically useful beta-receptor blocking drug, propranolol

SAR’s on histamine- acid secretion •

Side chain needed positively charged nitrogen with at least one hydrogen

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Flexible side chain

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Heteroaromatic ring with nitrogen atom having lone pair of electrons, ortho to side chain

Histamine pharmacophore - acid secretion

Structural studies •

To find an antagonist

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Make structural changes at various sites

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Many molecules (>200) were synthesised

REMEMBER -STRUCTURE- 5 MARKER 4-methyl histamine

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Showed selectivity for H2 receptor

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Still an agonist

Nα-Guanylhistamine

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Locus of positive charge is greater than for histamine

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Has partial agonist activity

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Had been synthesised in 1928 and reported to be devoid of any interesting activity

Nα-Guanylhistamine •

Suggested that two distinct binding regions were reached by Nα-Guanylhistamine The agonist site also reached by histamine An antagonist site not reached by histamine Extending the side chain in Nα-Guanylhistamine increased antagonist activity

POSSIBLE 5 MARKER QUESTION •

Histamine needs a positively charged Nitrogen for agonist activity

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Would the side chain group on an antagonist need to be charged?

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What is the nature of the bonding interaction?

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Ionic or H-bonding?

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Explain MOA of drugs

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Explain concepts behind SARs •

Key SAR requirements for H2 antagonists and PPIs...