Figure 3.

mGlu₅ PAMs exhibit dose-dependent reversal of AHL that correlates with increasing total and unbound exposure in brain and plasma. (a) % AHL reversal was calculated based on the total number of beam breaks (Supplemental Figures 2 and 3) from n = 5–13. Brain and plasma concentrations were determined at the conclusion of each experiment via LC–MS/MS (Supplemental Figure 4). Log [compound] was plotted versus the % AHL reversal, and data (all are mean ± s.e.m.) were fitted using a three-parameter logistical equation. EC₅₀ values (horizontal black dotted line) in each of the four matrices (total brain, black vertical dashed line; unbound brain, blue vertical dashed line; total plasma, green vertical dashed line; and unbound plasma, red vertical dashed line) were calculated (Table 2 and Supplemental Tables 1–3). (b–d) Correlations are shown for the calculated EC₅₀ value versus the in vitro potency (pEC₅₀, b), the unliganded affinity (log K_B, c), and cooperativity (log αβ, d). R² and p values for each regression line are listed in Supplemental Table 4.