Noncompetitive antagonism

This is formally identical to the equation derived by Gaddum and colleagues [3] (see Section 6.8.2) for noncompetitive antagonism. In this case, it is assumed that the only available receptor population in the presence of a fractional receptor occupancy pB by a noncompetitive antagonist is the fraction l-pB. Thus, agonist receptor occupancy is given by... 

The equation describing agonist receptor occupancy under conditions of noncompetitive antagonism is given... 

It can be seen that when there is no effect on the affinity of the receptor for the agonist (a=l) Equation 7.6 is identical to the describing orthosteric noncompetitive antagonism derived by Gaddum and colleagues [31] (see Equation 6.10). However, while the equation is identical and the pattern of concentration-response curves is the same as that for an orthos teric antagonist it should be... 

Equation 7.6 defines the allosteric noncompetitive antagonism of receptor function and predicts insurmountable effects on agonist maximal response (i.e., as [A] oo) the expression for maximal response is... 

Noncompetitive Antagonism in Systems with Receptor Reserve... 

In cases where the plot of [A ]/Kd vs ICS0 is not linear, other mechanisms of antagonism may be operative. If there is a nearly vertical relationship, this be due to noncompetitive antagonism in a system with no receptor reserve (see Figure 12.2d). Alternatively, if the plot is linear at low values of [A ]/Kd and then approaches an asymptotic value the antagonism may be allosteric (the value of a defines the value of the asymptote) or noncompetitive in a system with receptor reserve (competitive shift until the maximal response is depressed, Figure 12.2d). 

Gadduin equation (noncompetitive antagonism), this technique measures the affinity of a noncompetitive antagonist based on a double reciprocal plot of equiactive agonist concentrations in the absence and presence of the noncompetitive antagonist. The antagonist must depress the maximal response to the agonist for the method to be effective see Chapter 6.4. 

Uncompetitive antagonism, form of inhibition (originally defined for enzyme kinetics) in which both the maximal asymptotic value of the response and the equilibrium dissociation constant of the activator (i.e., agonist) are reduced by the antagonist. This differs from noncompetitive antagonism where the affinity of the receptor for the activating drug is not altered. Uncompetitive effects can occur due to allosteric modulation of receptor activity by an allosteric modulator (see Chapter 6.4). 

FIGURE 1.25 Noncompetitive antagonism. A stylized receptor carries two sites, one of which can combine with agonist (A) and the other with antagonist (B). Four conditions are possible, only one of which (agonist site occupied, antagonist site empty see upper right) is active. 

A. Here, the second ligand, B, has been assumed to have a high preferential affinity for the inactive forms of the receptor. The outcome closely mimics classical, noncompetitive antagonism. 

C. Here, B is assumed to combine mainly with the active forms of the receptor to form complexes (BR, ABR ) that are inactive. An example is the action of an open channel blocker. Note the convergence of the curves at low agonist concentrations (contrast with the pattern expected for noncompetitive antagonism, as in panel A and as shown in Figure 1.26). 

Jensen, A. A., Sheppard, P. 0., Jensen, L. B., O Hara, P. J., and Brauner-Osbome, H. (2001) Construction of a high affinity zinc binding site in the metabotropic glutamate receptor mGluRl. Noncompetitive antagonism from the amino-terminal domain of a family C G protein-coupled receptor. J. Biol. Chem. 276,10110-10118. 

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