Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Abstract

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

“…MTEP also significantly reduced stress-induced hyperthermia (F 3,28 = 4.45, po0.05). In the marble-burying assay (Figure 4d), both partial mGlu 5 NAMs M-5MPEP and Br-5-MPEPy (F 8,76 = 15.90, po0.001) dose-dependently reduced the number of marbles buried, similar to previously reported effects by the full mGlu 5 NAM MTEP (Rodriguez et al, 2010).…”

“…Mice were administered vehicle, M-5MPEP or Br-5MPEPy (5.6-32 mg/kg) and 30 min later individually placed into Plexiglas cages containing 12 evenly distributed marbles (Rodriguez et al, 2010). At the end of the 30-min test, the number of buried marbles-those covered ⩾ 2/3 by bedding-was determined.…”

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…However, the recent development of new negative allosteric modulators of mGluR5 that offer better pharmacokinetic properties for this purpose may provide the necessary tools to further assess the clinical relevance of these drugs in humans (Gasparini et al, 2008;Zhou et al, 2009;Rodriguez et al, 2010;Nicoletti et al, 2011).…”

“…Although MTEP and MPEP are mGluR5 antagonists with high specificity and affinity, their pharmacological profile is not suitable for chronic therapeutic use in humans because of their short half-life and rapid clearance from the brain (Gasparini et al, 2008;Rodriguez et al, 2010). However, the recent development of new negative allosteric modulators of mGluR5 that offer better pharmacokinetic properties for this purpose may provide the necessary tools to further assess the clinical relevance of these drugs in humans (Gasparini et al, 2008;Zhou et al, 2009;Rodriguez et al, 2010;Nicoletti et al, 2011).…”

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

“…84,85 These PAMs contained a basic acetylene core with either a benzamide or nicotinamide or related isoquinolinone and naphthridinone bicyclic ring systems. Several PAMs 47À49 were disclosed as being active in reversal of amphetamine induced hyperlocomotion (Figure 7).…”