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Drug Discovery & Multifunctional Therapies

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Traumatic brain injury (TBI) is now known to causes progressive neurodegeneration associated with chronic microglial activation. These chronic changes occur over months to years, and appear to be pathologically different from chronic traumatic encephalopathy and likely far more frequent. The molecular mechanism of neurodegeneration is well understood and results show that the progressive neurodegeneration and neuroinflammation can be inhibited as late as 1 month after moderately severe TBI in animals by a novel strategy targeting the metabotropic glutamate receptor 5 (mGluR5) in microglia. This targeting can be performed using low-molecular weight mGluR5 agonists that target either the ligand binding domain (LBD) or a positive allosteric modulator (PAM) site on mGluR5. However, while chemical agents that perform these functions are known, there are known limitations in their pharmacology that disallow their clinical use. We are directly addressing the clinical limitations to develop drug candidates for future clinical trials.

Recent experimental evidence showed that a single dose administration of the mGluR5 agonist (R/S)-2-chloro-5-hydroxy-phenylglycine (CHPG) is highly neuroprotective after experimental TBI, even with highly delayed intervention, markedly facilitating recovery of cognitive and motor function, and halting the progressive degeneration. However, CHPG, which is the only available well-defined selective mGluR5 agonist, is a partial agonist with only modest potency. In addition, CHPG does not readily cross the blood-brain barrier (BBB), thus requiring central administration, which limits its clinical application. Alternatively, PAMs that target the 7-helical transmembrane domain of mGluR5 appear to be neuroprotective after experimental TBI, is shown in our preliminary studies. We are undertaking a two-pronged approach whereby ligands targeting the LBD or the PAM that have acceptable pharmacological properties will be rationally developed using a combination of computer-aided drug design, synthetic chemistry and pharmacology