RT Journal Article
SR Electronic
T1 Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 120
OP 133
DO 10.1124/mol.111.075184
VO 81
IS 2
A1 Meredith J. Noetzel
A1 Jerri M. Rook
A1 Paige N. Vinson
A1 Hyekyung P. Cho
A1 Emily Days
A1 Y. Zhou
A1 Alice L. Rodriguez
A1 Hilde Lavreysen
A1 Shaun R. Stauffer
A1 Colleen M. Niswender
A1 Zixiu Xiang
A1 J. Scott Daniels
A1 Carrie K. Jones
A1 Craig W. Lindsley
A1 C. David Weaver
A1 P. Jeffrey Conn
YR 2012
UL http://molpharm.aspetjournals.org/content/81/2/120.abstract
AB 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.