Application of an allosteric ternary complex model to the technique of pharmacological resultant analysis.
A simple ternary complex model of drug-receptor interaction has been used to extend the procedure of pharmacological resultant analysis, enabling the quantitation of interactions between allosteric modulators and orthosteric antagonists. Equations derived in the theoretical treatment were used to analyse functional data for the interaction between the allosteric modulator gallamine and the orthosteric antagonist scopolamine, with oxotremorine as the agonist, at rat tracheal muscarinic acetylcholine receptors. Quantitative estimates of the affinity of gallamine for the allosteric site (pKz = 4.7) and the extent of negative, heterotropic co-operativity between gallamine and scopolamine (alpha' = 13.1) were obtained. Furthermore, an alternative direct, model-fitting approach, that does not rely on the determination of concentration ratios, was also developed, and yielded similar results. It is suggested that the approach presented in this paper is useful for quantifying interactions between orthosteric antagonists and allosteric modulators, particularly when the extent of co-operativity is low or the modulators possess multiple pharmacological properties, or both.
Christopoulos
A
A
Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy, Monash University, Parkville, Australia.
Mitchelson
F
F
D000818:Animals; D001667:Binding, Competitive; D005703:Gallamine Triethiodide / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008432:Mathematical Computing; D008954:Models, Biological; D018721:Muscarinic Agonists / Q000378:metabolism* / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000378:metabolism* / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000378:metabolism* / Q000494:pharmacology; D010095:Oxotremorine / Q000378:metabolism* / Q000494:pharmacology; D010600:Pharmacology / Q000379:methods*; D010890:Pirenzepine / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D012601:Scopolamine / Q000378:metabolism* / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D010095:Oxotremorine; D012601:Scopolamine; D005703:Gallamine Triethiodide