Drug receptor-interaction irreversible

All the above-mentioned pharmacokinetic-dynamic models are characterized by reversibility of the drug-receptor interaction. In several cases, however, drug action relies on an irreversible bimolecular interaction thus, enzyme inhibitors and chemotherapeutic agents exert their action through irreversible bimolecular interactions with enzymes and cells (bacteria, parasites, viruses), respectively. 

B R Baker, Design of Active-Site-Directed Irreversible Enzyme Inhibitors, Wiley, New York (1967), L A Cohen, Ann Rev Biochem 37, 695, (1968), J F Moran and D J Tnggle, in Fundamental Concepts in Drug-Receptor Interactions (J F Danielli, J F Moran, and D J Tnggle, eds ), Academic Press, New York (1970)... 

The strongest of bonds involved in drug-receptor interactions is the covalent bond, in which two atoms, one from the ligand and one from the receptor, share a pair of electrons. Because of the significant strength of the covalent bond (50-150 kcal/mol), covalent bonding often produces a situation in which the ligand is irreversibly bound by the receptor and, thus, leads to the receptor s eventual destruction via endocytosis and chemical destruction. Full recovery of cellular function therefore requires the synthesis of new receptors. 

Covalent bonds are not as important in drug-receptor binding as noncovalent interactions. Alkylating agents in chemotherapy tend to react and form an immonium ion, which then alkylates proteins, preventing their normal participation in cell divisions. Baker s concept of active site directed irreversible inhibitors was well established by covalent formation of Baker s antifolate and dihydrofolate reductase (46). 

Long-acting P-2-adrenergic drugs show a prolonged pulmonary residence time because of a specific interaction of these drug molecules with their cellular targets. It has been shown that salmeterol binds reversibly to an active site on the P2-receptor and irreversibly to an exosite, which may be a domain adjacent to the active site within the P2 -receptor in the lipid bilayer of the cell membrane... 

Drug-receptor bonds Drugs bind to receptors with a variety of chemical bonds. These include very strong covalent bonds (which usually result in irreversible action), somewhat weaker electrostatic bonds (eg, between a cation and an anion), and much weaker interactions (eg, hydrogen, van der Waals, and hydrophobic bonds). 

If a drug undergoes a covalent reaction with its receptor, the receptor molecules affected will be irreversibly blocked and thus altogether removed from the total receptor pool available for the interaction with the agonist. Thus, the agonist-receptor equilibrium now plays out in that reduced total pool. The number of occupied receptors will therefore be proportionally reduced (Figure 3.4). 

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