Antagonism allosteric modulation

FIGURE 7.7 Effect of the allosteric modulator ebumamonine on the potency of muscarinic agonists on m2 receptors. It can be seen that while no change in potency is observed for APE (arecaidine propargyl ester) pilocarpine is antagonized and arecoline is potentiated, illustrating the probe dependence of allosterism. From [1],... 

Allosteric modulators that block receptor function produce insurmountable antagonism. In addition, modulators that block function also can alter (increase or decrease) affinity. 

Surmountable antagonism, an antagonist-induced shift to the right of an agonist dose-response curve with no diminution of the maximal response to the agonist (observed with simple competitive antagonists and some types of allosteric modulators). 

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). 

It can be seen that a feature of allosteric antagonists is that their effect is saturable (i.e., a theoretically infinite concentration of [B] will cause Kobs to reach a maximal asymptote value of KA/a). This is in contrast to simple competitive antagonists where the degree of antagonism theoretically is infinite for an infinite concentration of antagonist. Therefore, the maximal change in affinity that can be produced by the allosteric modulator is Kobs/KA = KA/aKA = a-1. Thus, a modulator with a = 0.1 will reduce the affinity of the receptor for the agonist by a maximal value of 10. 

Effects on maximal antagonism in a pIC5o mode can detect partial agonists, allosteric modulation, and inverse agonism. 

Allosteric effects can be confirmed in separate experiments (vide infra). In general, allosterism, while it can appear as an orthosteric antagonism under a variety of conditions, may be uncovered through observing the extremes of the antagonist behavior. There are three characteristic features of allosteric modulators. They are... 

The equation for the relationship between the pA2 and the Kb of an allosteric modulator that produces insurmountable antagonism then becomes... 

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