Allosteric Modulators: The New Generation of Receptor Antagonist

Masquerading antagonists. Both allosteric and orthosteric antagonists can manifest identical behaviors, such as parallel shifts of dose-response curves (with no diminution of maxima) for simple competitive antagonists, depression of maximal response with no shift to the right for noncompetitive antagonists, and sigmoid binding curves (with complete displacement of radioligand). However, the behavior of these types of antagonist diverges in that, unlike orthosteric antagonism, allosteric antagonism can be saturable and probe dependent. Thus, simple competitive antagonists produce identical blockade of all agonists, yielding identical linear Schild regressions, and they also manifest complete displacement of probe radioligand with a linear relationship between the concentration of radioligand and IC₅₀ for antagonism. In contrast, the maximal degree of functional antagonism by allosteric ligands may differ for different agonists, and their Schild regressions can be curvilinear and agonist dependent; radioligand displacement may be incomplete as well. (nsb, nonspecific binding)