Irreversible ligands

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,... 

When the irreversible ligand is applied by itself, the change in the proportion of sites occupied, pLR, with time will be given by ... 

CV Thomas, AC Cater, JJ Wheeler. HPCE as an analytical probe for assessing irreversible ligand/macromolecule binding interactions. J Liq Chromatogr 16 1903-1921, 1993. 

An NIH group has examined irreversible ligands based on oripavine, etonitazene (p. 387), and fentanyl (p. 287), termed FAO, BIT, and FIT, respectively (see 10). Of these, FIT and FAO proved highly selective alkylators of 5-receptors, while BIT was equally specific toward /x-sites.<34) The N-CPM analog of FAO also had 5-selectivity and displayed the properties of a narcotic antagonist as judged by its effect on the adenylate cyclase activity of hybrid... 

Several derivatives of K-selective compounds containing an isothiocyanate have been prepared as potential irreversible ligands... 

Bidlack JM, Seyed-Mozaffari A, ArcherS (1991) 14P-Thioglycolamido-7, 8-dihydromorphi-none, a p-selective irreversible ligand. Med Chem Res 1 43-46... 

An example of a tetrahedral tetraamido V(IV) complex, bis(A,iV -bistrimethylsilylethylenediamine)vana dium(IV) was reported (Fig. 9) [63,] which had reversible oxidation and quasireversible reduction features in its CV at 0.41 and —1.51V versus Ag/AgCl/THF respectively. A second, irreversible ligand-based oxidation was observed at 1.34 V. A related bimetallic complex forms when VCl3(THF)3 is treated with dimethylhydrazine (Fig. 10) where three N2Me2 units bridge the two V atoms which are joined by... 

Burke TR Jr, Bajwa BS, Jacobson AE, et ai. Probes for narcotic receptor mediated phenomena. 7. Synthesis and pharmacological properties of irreversible ligands specific for p or 5 opiate receptors. J Med Chem 1984 27 1570-1574. 

The use of cyclic voltammetry (CV) has been mentioned earlier during the characterization of the two mononuclear Fe(III) complexes (5), and (6). ° An acetonitrile solution was used with 0.1 M TRAP as the supporting electrolyte. It was shown that (5) exhibits a one-electron redox process at Ei/ 2 = 0.316 V attributed to the Fe " Fe + e redox system, and the process is chemically as well as electrochemically irreversible as indicated by ipc/jpa 1 and an extremely high AEp value of 632 mV. In addition there is another oxidation peak at 1.072 V attributed to the irreversible ligand oxidation. Similarly complex (6) also exhibits an irreversible redox couple for Fe /Fe oxidation at E1/2 = 0.106 V with AEp = 212 mV along with the ligand oxidation peak at 1.159 V. 

Based on this description, the rate constant for reaction (3) would reflect the onset of two coupled initial equihbria (Kec, K )), followed by the irreversible ligand-interchange reaction, i.e., = x X fe H20- From an... 

It should be pointed out here that the half inhibition concentration of an irreversible ligand such as aBgt or cobrotoxin, is not an inhibition constant, but a variable depending on the concentration of binding sites in the incubation mixture. As the line between irreversible binding and slowly reversible binding can in practice not always be drawn very accurately, similar considerations may hold for the ionenes... 

Inhoff Oliver, R. J. M. Briet, I.W. Lowe, G. Krauth-Siegel, R. L. Coupling of a competitive and an irreversible ligand generates mixed type inhibitors of Trypanosoma cruzi trypanothione reductase. J. Med. Chem. 2002, 45, 4524-4530. 

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