Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-<i>a</i>]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2

Abstract

We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu₂ positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters k_on, k_off and residence time (RT) were determined. The PAMs showed various kinetic profiles; k_on values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant k_on was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu₂ PAMs with high values for k_on but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo.