Insurmountable antagonism

FIGURE 6.17 Fitting of data to models, (a) Concentration response curves obtained to an agonist in the absence (circles) and presence of an antagonist at concentrations 3 jiM (triangles) and 30 j.lM (diamonds), (b) Data fit to model for insurmountable orthosteric antagonism (Equation 6.31) with Emax = 1, Ka = 1 pM, t = 30 and KB = 1 pM. 

The kinetics of offset of the antagonist from the receptor can dictate whether surmountable or insurmountable antagonism is observed. 

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. 

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... 

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

The next consideration is to determine whether the antagonism is surmountable or insurmountable (see Figure 10.13). In the case of surmountable antagonism, a Schild analysis is carried out (dose ratios can be used from... 

If the antagonism is insurmountable, then there are a number of molecular mechanisms possible. The next question to ask is if the maximal response to the agonist can be completely depressed to basal levels. If this is not the case, then there could be partial allosteric alteration of the signaling properties of the receptor. Alternatively, this could be due to a hemi-equilibrium condition that produces a partial shortfall to true competitive equilibrium, leading to incomplete depression of the maximal response but also antagonist concentration-related dextral displacement of the concentration response curve to the agonist (see Figure 10.19a). The model (see Section 10.6.5) used to fit these data is discussed in Section 6.5 and shown in... 

Surmountable antagonism can be quantified by pA2 values. Insurmountable antagonism through IC50 values that in some cases can be corrected for the strength of stimulation in the system. 

Orthosteric insurmountable antagonism operational model with variable slope... 

Aim This method is designed to measure the affinity of an antagonist that produces insurmountable antagonism (depression of maximal response to the agonist) but also shifts the curve to the right by a measurable amount. 

In this variant of insurmountable antagonism, the antagonist acts by combining with a separate inhibitory site on the receptor macromolecule. Agonist and antagonist molecules can be bound at... 

Drugs that bind irreversibly to receptors include phenoxybenzamine (to the a-adrenoceptor). Since such a drug cannot be displaced from the receptor, increasing the concentration of agonist does not fully restore the response and antagonism of this type is said to be insurmountable. 

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