1 research outputs found
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 ActivityS⃞
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