The Development of non-MPEP/MTEP mGluR5 Ligands Based on the Chromene Scaffold
Beauchamp, Blake D.
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Neurodegenerative diseases affect millions of individuals across the world. Glutamate excitotoxicity has been implicated as a common pathway leading to neuronal cell death in many neurodegenerative diseases. Glutamate excitotoxicity results from disruption in glutamate homeostasis leading to excessive glutamate within the synaptic space. This then leads to overstimulation of ionotropic glutamate receptors (iGluRs) resulting in neuronal death. Antagonism of iGluRs is effective short term; however, long- term antagonism of iGluRs also leads to neuronal cell loss and is therefore not a viable approach for treating glutamate excitotoxicity. Recently the metabotropic glutamate receptor 5 (mGluR5) antagonists MPEP showed protective activity against glutamate excitotoxicity. Despite these promising results, the alkyne linkage of MPEP renders it metabolically unstable in vivo; thus, the development of non-alkyne based mGluR5 antagonist would be beneficial. The hypothesis for this project was that the chromone scaffold could serve as a template for the development of non-MPEP mGluR5 antagonists. First, the energy minimized conformation of 7- methyl-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one (19) was compared to MPEP and showed the aryl groups of 19 and MPEP are in similar spatial orientations. Following this, ligand-docking studies using the available crystal structure of mGluR5 revealed a potential binding pocket common to both MPEP and 19. Furthermore, the relative binding energies calculated for MPEP (-6.5 kcal/mol) and 7-MPC (-7.5 kcal/mol) in this proposed binding pocket were encouraging. These in silico results supported the hypothesis that 7-MPC can be a scaffold for non-MPEP mGluR5 antagonists and 24 derivatives of 7-MPC were screened in silico. Those compounds showing significant improvements in binding energy over MPEP were then synthesized. These compounds are being screened for their binding affinities in vitro at mGluR5 and the results will be used to further refine the in silico model.