TY - JOUR T1 - VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 123 LP - 136 DO - 10.1124/jpet.115.226597 VL - 356 IS - 1 AU - Hilary Highfield Nickols AU - Joannes P. Yuh AU - Karen J. Gregory AU - Ryan D. Morrison AU - Brittney S. Bates AU - Shaun R. Stauffer AU - Kyle A. Emmitte AU - Michael Bubser AU - Weimin Peng AU - Michael T. Nedelcovych AU - Analisa Thompson AU - Xiaohui Lv AU - Zixiu Xiang AU - J. Scott Daniels AU - Colleen M. Niswender AU - Craig W. Lindsley AU - Carrie K. Jones AU - P. Jeffrey Conn Y1 - 2016/01/01 UR - http://jpet.aspetjournals.org/content/356/1/123.abstract N2 - 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. ER -