H2 receptor antagonists

PHRM 304

H2 receptor antagonists
Histamine congeners Be recognized by the receptor Bind more strongly than histamine Not trigger acid secretion Competitive antagonists

Imidazole

Furan

Thiazole

Thiazole

Structural evolution of Cimetidine:

Histamine H1 = H2 agonist

Structural evolution of Cimetidine:

5-Methylhistamine A highly selective H2 agonist (H2>H1)

Structural evolution of Cimetidine:

N-guanylhistamine Weak antagonist Partial H2 receptor agonist Guanidine: Strongly basic group so remain as charged group

Structural evolution of Cimetidine:

2-4

Methyl thiourea Neutral, non-charged

Burimamide Full antagonist Low potency Poor oral bioavailability Toxic (Thiourea)

Structural evolution of Cimetidine:

Electronegative thioether

Metiamide

Full H2 antagonist Higher potency Improved oral bioavailability Toxic: Bone marrow toxicity (Thiourea)

Structural evolution of Cimetidine:

Cimetidine

Full H2 antagonist Higher potency Improved oral bioavailability Low toxicity

The need to develop more potent antisecretory agents:

Acetylcholine and gastrin act on parietal cells to secrete gastric acid May develop tolerance or resistance Short acting: cannot be used in case of nocturnal acidity Acid rebound property.

Downregulation and upregulation

Downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable. An increase of a cellular component is called upregulation.