Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of Fragile X syndrome, levodopa-induced dyskinesia in Parkinson's disease, Alzheimer’s disease, addiction and anxiety. However, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit therapeutic utility of these compounds. We report discovery and characterization of a novel mGlu5 NAM, VU0477573, that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Due to this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu5 NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [3H]IP accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu5-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu5 occupancy in the CNS with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu5 NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu5 and demonstrate an excellent CNS occupancy/efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models.
- The American Society for Pharmacology and Experimental Therapeutics