Histamine and its receptor
PHAR3014 Medicinal Chemistry & Drug Design
Cimetidine
According to Patrick (2009), cimetidine stops the gastric acid production by inhibiting pentagastrin. At the same time, it inhibits the cytochrome P450 enzymes in the liver making this drug to have high interaction with other drugs. Inhibition of cimetidine may result in increased blood levels. Hence, caution is required when taking this drug with diazepam, lidocaine, warfarin or theophylline.
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The guanidine and thiourea groups in cimetidine are polar and hydrophilic which enhances the ligand binding. Dipole moment plays a crucial part as drug approaches the receptor, its dipole interacts with the dipole on the receptor surface for it to form an alignment. This orientates the drug in a specific way before the formation of hydrogen bonding with the amino acid residue of the receptor.
Ranitidine
After further optimization of cimetidine analogues, it was found that the imidazole ring could be replaced by furan ring bearing a nitrogen-containing substituent. Ranitidine is said to have lesser side effects and ten times more potent that cimetidine. 2,5-disubstitution of furan ring increases the binding affinity towards receptor.
Figure 21 Cimetidine molecules with dipole moments forming two hydrogen bonds with receptor.
Figure 22 Ranitidine with 30° dipole moments forming hydrogen bonds with receptor.