Classes of Allosteric Modulators

Similar to that of agonists and inverse agonists, allosteric modulators stabilize a select subset of receptor conformations. Allosteric modulators can alter the binding and/or functional properties of orthosteric ligands and, in some cases, when an active receptor conformation is stabilized, can have efficacy in their own right. As such, in addition to the various classes of orthosteric ligands, there are a number of different categories of allosteric ligands -64-66] . At equilibrium, positive and negative allosteric modulators enhance or inhibit orthosteric ligand binding and/or function, respectively, neutral allosteric modulators have no effect, and allosteric agonists mediate receptor activation in the absence of an orthosteric ligand. However, the properties of an allosteric ligand can rarely be confined to a single category. For example, at the M4 muscarinic acetylcholine receptor (mAChR), the allosteric ligand LY2033298 can increase basal receptor activity, enhance agonist binding, and inhibit antagonist binding. As such, LY2033298 behaves as an allosteric agonist, as a positive allosteric modulator, and as a negative allosteric modulator [67]. The contrasting properties of LY2033298 highlight the probe dependence of allosteric modulators, that is, the ability of the orthosteric ligand used in the experiment to define the direction and degree of modulation mediated by an allosteric ligand.

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