Abstract

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 disease, Alzheimer 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 the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu₅ NAM, N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu₅ NAM MPEP but displays weak negative cooperativity. Because of 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]inositol phosphate (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 central nervous system (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.