Antagonism 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... 

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. 

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. 

Kenakin, T. P., and Boselli, C. (1989). Pharmacologic discrimination between receptor heterogeneity and allosteric interaction Resultant analysis of gallamine and pirenzeipine antagonism of muscarinic responses in rat trachea. J. Pharmacol. Exp. Ther. 250 944—952. 

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... 

There are two practical reasons to err toward the correction of the ICso of an antagonist to estimate the Kb- The first is that an overestimation of antagonist potency will only result in a readjustment of values upon rigorous measurement of antagonism in subsequent analysis. However, more importantly, if the correction is not applied then there is a risk of not detecting weak but still useful antagonism due to an underestimation of potency (due to nonapplication of the correction factor). These reasons support the application of the correction in all cases as a default. 

There are instances where it is important to know if a given regression line is linear. For example, simple competitive antagonism should yield a linear Schild regression (see Chapter 6). A statistical method used to assess whether or not a regression is linear utilizes analysis of covariance. A prerequisite to this approach is that there... 

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. 

Resultant analysis, this procedure, developed by James Black and colleagues (Br. J. Pharmacol. 84,561-571, 1985), allows measurement of the receptor affinity of a competitive antagonist, which has secondary properties that obscure the receptor antagonism see Chapter 6.6 for further discussion. 

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... 

One-way analysis of variance, 229-230, 230f—231f Operational model derivation of, 54-55 description of, 45—47, 46f function for variable slope, 55 for inverse agonists, 221 of agonism, 47f orthosteric antagonism, 222 partial agonists with, 124, 220-221 Opium, 147 Orphan receptors, 180 Orthosteric antagonism... 

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