Fig. 6. Mechanism of action of allosteric modulators.⁶³ Reprinted with permission from Springer Nature: Springer Nature, Nature Reviews Drug Discovery, Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders, P. J. Conn, A. Christopoulos and C. W. Lindsley, Copyright (2009). (a) Allosteric ligands bind to an alternative binding site on a receptor to modulate the activities of an orthosteric ligand efficacy (blue) and/or affinity (red). A number of allosteric ligands can also directly disrupt signalling in their own right (green). (b) Results from simulation show the effects on the function (right) or binding (left) of an orthosteric agonist mediated by three allosteric potentiators depicted in red, blue and green; red enhanced orthosteric agonist affinity only, blue enhanced only the efficacy, green was observed to modestly enhance both efficacy and affinity, as well as showing allosteric agonism.⁶³.