Abstract

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu₅) have emerged as an exciting new approach for the treatment of schizophrenia and other central nervous system (CNS) disorders. Of interest, some mGlu₅ PAMs act as pure PAMs, only potentiating mGlu₅ responses to glutamate whereas others [allosteric agonists coupled with PAM activity (ago-PAMs)] potentiate responses to glutamate and have intrinsic allosteric agonist activity in mGlu₅-expressing cell lines. All mGlu₅ PAMs previously shown to have efficacy in animal models act as ago-PAMs in cell lines, raising the possibility that allosteric agonist activity is critical for in vivo efficacy. We have now optimized novel mGlu₅ pure PAMs that are devoid of detectable agonist activity and structurally related mGlu₅ ago-PAMs that activate mGlu₅ alone in cell lines. Studies of mGlu₅ PAMs in cell lines revealed that ago-PAM activity is dependent on levels of mGlu₅ receptor expression in human embryonic kidney 293 cells, whereas PAM potency is relatively unaffected by levels of receptor expression. Furthermore, ago-PAMs have no agonist activity in the native systems tested, including cortical astrocytes and subthalamic nucleus neurons and in measures of long-term depression at the hippocampal Schaffer collateral-CA1 synapse. Finally, studies with pure PAMs and ago-PAMs chemically optimized to provide comparable CNS exposure revealed that both classes of mGlu₅ PAMs have similar efficacy in a rodent model predictive of antipsychotic activity. These data suggest that the level of receptor expression influences the ability of mGlu₅ PAMs to act as allosteric agonists in vitro and that ago-PAM activity observed in cell-based assays may not be important for in vivo efficacy.