A Novel Metabotropic Glutamate Receptor 5 Positive Allosteric Modulator Acts at a Unique Site and Confers Stimulus Bias to mGlu5 Signaling

Metabotropic glutamate receptor 5 (mGlu(5)) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu(5) has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term potentiation (LTP), which is thought to be involved in cognition. Multiple mGlu(5)-positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds. Previous work has extensively characterized a common allosteric site on mGlu(5), termed the MPEP (2-Methyl-6-(phenylethynyl)pyridine) binding site. However, one mGlu(5) PAM, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl] phenyl)-2-hydroxybenzamide), interacts with a separate allosteric site on mGlu(5). Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu(5) PAM from the CPPHA series termed NCFP (N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide). NCFP binds to the CPPHA site on mGlu(5) and potentiates mGlu(5)-mediated responses in both recombinant and native systems. However, NCFP provides greater mGlu(5) subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu(5) in CNS preparations. Of interest, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/LTP), setting it apart from other previously characterized MPEP site PAMs. This suggests that although mGlu(5) PAMs may have similar responses in some systems, they can induce differential effects on mGlu(5)-mediated physiologic responses in the CNS. Such stimulus bias by mGlu(5) PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes.