Irreversible antagonists

Irreversible antagonists, irreversible ligands have negligible rates of offset (i.e., once the ligand binds to the receptor it essentially stays there). Under these circumstances, receptor occupancy does not achieve a steady state but,... 

Unfortunately, this does not reveal where the active site or binding site is and so it is better to get an X-ray structure of the macromolecule with an antagonist irreversibly bound to the binding site. The antagonist then acts as a label for the binding site. 

J. Bock, M.G. Baillie, T.A. Prueksaritanont, T. Bioactivation of 2,3-diaminopyridine-containing bradyki-nin Bi receptor antagonists Irreversible binding to liver microsomal proteins and formation of glutathione conjugates. Chem. Res. Toxicol. 2005,18, 934-945. 

Fig. 8. Agonist, dose—response curves, (a) For an agonist where a value of 10 M is indicated at the concentration giving 50% response, (b) For an agonist alone, Aq, and in the presence of increasing amounts of irreversible receptor antagonists, B—F. There is a progressive rightward shift of the dose—response curve prior to reduction of maximum response. This pattern is consistent with the presence of a receptor reserve.

In systems where there is insufficient time for the agonist, antagonist, and receptor to equilibrate according to mass action slow-offset antagonists can produce essentially irreversible occlusion of a portion of the receptor population. This can result in insurmountable antagonism. 

Used to estimate system-independent potency of an orthosteric antagonist with a slow rate of offset. Under these conditions, a portion of the receptor population is irreversibly inactivated leading to a depression of agonist maximal response. 

Proton Pump Inhibitors and Acid Pump Antagonists. Figure 1 Irreversible proton pump inhibitors (PPIs). 

Proton Pump Inhibitors and Acid Pump Antagonists. Figure 2 Chemical mechanism of irreversible PPIs. PPIs are accumulated in acidic lumen and converted to active sulfenic acid and/or sulfenamide by acid catalysis. These active forms bind to extracytoplasmic cysteines of the gastric H.K-ATPase [3]. 

IRAK Family Iron Chelator Irreversible Antagonists Irritable Bowel Syndrome (DBS)... 

Neonicotinoids are potent broad-spectrum insecticides that exhibit contact, stomach and systemic activity. Acetamiprid, imidacloprid, nitenpyram, thiamethoxam and thiacloprid are representatives of the neonicotinoid insecticides (Figure 1). The mechanism of action is similar to that of nicotine, acting on the central nervous system causing irreversible blocking of postsynaptic nicotinic acetylcholine receptors (nAChR). Neonicotinoid insecticides are often categorized as antagonists of the... 

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