Schild analysis

FIGURE 6.7 Schematic diagram of some of the logic used in Schild analysis. 

A schematic diagram of some of the logic used in Schild analysis is shown in Figure 6.7. It should be pointed out... 

Patterns of Dose-Response Curves That Preclude Schild Analysis... 

There are patterns of dose-response curves that preclude Schild analysis. The model of simple competitive antagonism predicts parallel shifts of agonist dose-response curves with no diminution of maxima. If this is not observed it could be because the antagonism is not of the competitive type or some other factor is obscuring the competitive nature of the antagonism. The shapes of dose-response curves can prevent measurement of response-independent... 

One of the strengths of Schild analysis is the capability of unveiling nonequilibrium conditions in experimental preparations such as inadequate time of equilibration or removal of drugs from the receptor compartment. Figure 6.11 shows a range of possible experimentally observed but problematic linear Schild regressions that could be encountered for competitive antagonists. 

FIGURE 6.12 Schild analysis for constitutively active receptor systems, (a) Competitive antagonism by the inverse agonist in a constitutively active receptor system with DR values calculated at the EC80. 

One shortcoming of Schild analysis is an overemphasized use of the control dose-response curve (i.e., the accuracy of every DR value depends on the accuracy of the control EC o value). An alternative method utilizes nonlinear regression of the Gaddum equation (with visualization of the data with a Clark plot [10], named for A. J. Clark). This method, unlike Schild analysis, does not emphasize control pECS0, thereby giving a more balanced estimate of antagonist affinity. This method, first described by Lew and Angus [11], is robust and theoretically more sound than Schild analysis. On the other hand, it is not as visual. Schild analysis is rapid and intuitive, and can be used to detect nonequilibrium steady states in the system that can corrupt... 

Schild analysis, like all pharmacological tools, necessarily is predicated on the idea that the drugs involved have one and only one pharmacological activity. This often may not be the case and selectivity is only a function of concentration. If the concentrations used in the assay are below those that have secondary effects, then the tool will furnish the parameter of interest with no obfuscation. However, if a secondary effects are operative in the concentration range required to measure antagonism then the resulting parameter may be tainted by this secondary activity. 

The most common method used to measure the affinity of surmountable competitive antagonists is Schild analysis. This method is visual and also is useful to detect nonequilibrium steady states in receptor preparations. 

The same principles (Schild analysis) can be applied to competitive antagonists that demonstrate either positive (partial agonists) or negative (inverse agonists). 

When an antagonist produces parallel shifts to the right of the dose-response curve with no diminution of the maximal response, the first approach used to quantify potency is Schild analysis (see Section 6.3.1). In cases where the value of a is low (i.e., a = 0.01), a tenfold concentration range of the antagonist would cause shifts commensurate with those produced by a simple competitive antagonist. 

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... 

Data for Figure 11.15. Schild analysis for atenolol trachea. in guinea pig... 

Schild Analysis for the Measurement of Competitive Antagonist Affinity... 

Gadduin equation (competitive antagonism), the pivotal simple equation (see Chapters 6.2 and 6.8.1) describing the competition between two ligands for a single receptor site. It forms the basis for Schild analysis. 

Schild analysis, this powerful method of quantifying the potency of a competitive antagonist was developed by Heinz Schild (Br. J. Pharmacol. 14,48-58, 1959 see Chapter 6.3). It is based on the principle that the antagonist-induced dextral displacement of a dose-response curve is due to its potency (K% value) and its concentration in the receptor compartment. Because the antagonism can be observed and the concentration of antagonist is known, the KB can be calculated. 

Competitive antagonists affinity of, 261-264 description of, 75 IC50 correction factors for, 223 Schild analysis, 261-264 Concentration-dependent antagonism, 99 Concentration-response curve, 13 Confidence intervals, 228-229 Conformations, 13-14 Constitutive activity of receptors description of, 49—51 receptor density and, 56 Schild analysis, 108-111 Context-dependent biological effect, 188 Correction factors, 211-213, 223 Correlational research, 231 CP320626, 128... 

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