Figure 2.

Spatial (a) and temporal (b) fidelity of positive allosteric modulation of the native orthosteric ligand. (a) Endogenous agonist (left panel) is released where it is necessary and activates the receptor in a specific area of the brain. Exogenous orthosteric agonist (middle panel) activates target receptors throughout the brain. Positive allosteric modulator (right panel) is distributed throughout the brain but modifies receptor activity only in the presence of the endogenous ligand, thus maintaining spatial fidelity. (b). Endogenous agonist (yellow triangles) is released and cleared quickly, leading to transient signaling effects. Exogenous orthosteric agonist (dashed blue line) occupies receptor persistently, leading to effects that last until the drug is cleared. Positive allosteric modulator (green dashed triangles) achieves physiological activity only when the endogenous agonist is released, thus maintaining temporal fidelity. Image (b) was modified from Burford et al. (2015) [39].