Analysis of competitive antagonism when this property occurs as part of a pharmacological resultant

Abstract

I In this paper, pharmacological resultant is defined as the net effect of a single compound resulting from the simultaneous expression of two or more specific actions. 2 The principles of concentration-ratio analysis are extended to develop a method for detecting and quantifying competitive antagonism when this property is a component of a pharmacological resultant. The method is general to the extent that it allows analysis of competitive antagonism in combination with all types of post-receptor intervention. Essentially it depends on the altered expression of competition by a reference antagonist. It incorporates tests for validating its application and it is independent of agonist concentration-effect curve shape: in these respects the method is analogous to Schild plot-analysis of simple competition. 3 The methodology for the practical application of the analysis is exemplified by studying the net effect of a combination of a phosphodiesterase inhibitor (isobutylmethylxanthine) and histamine H2-receptor antagonist (metiamide) on histamine-stimulated tachycardia in guinea-pig, isolated, right atrium. Cimetidine was used as the reference antagonist. 4 The equation used in this analysis is similar in form to one recently described by to elucidate the situation when competitive antagonism occurs in combination with functional interactions. The relation between their method and the present analysis is discussed.

Pharmacological analysis of agonist‐antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay

“…Similarly, the combined competitive antagonism of muscarinic receptors by HC-3 (C) and N-methylatropine (B) was simulated using the relationship (Black et al, 1986), log(r …”

Combined dose‐ratio analysis of cholecystokinin receptor antagonists, devazepide, lorglumide and loxiglumide in the guinea‐pig gall bladder

“…Consequently, it seemed pertinent to question whether these ligands compete for the same site at the CCKA-receptor. We have applied a combined dose-ratio analysis (Paton & Rang, 1965;Black et al, 1986;Shankley et al, 1988) which, as far as we are aware, provides the only currently available test for…”

International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

“…However, classic pharmacological principles remain very powerful in that they are designed to evaluate the effects of drugs by cancelling out systemdependent variables using null methods. Approaches such as Schild or resultant analyses are still highly relevant in evaluating allosteric mechanisms (Arunlakshana and Schild, 1959;Spedding, 1985b;Black et al, 1986;Colquhoun, 2007). For example, VGICs have multiple allosteric sites that interact to different extents, allowing tissue selectivity and facilitating discovery of multiple therapeutic agents.…”