2. Academic Validation
  3. Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5

Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5

  • Bioorg Med Chem Lett. 2015 Jun 1;25(11):2275-9. doi: 10.1016/j.bmcl.2015.04.042.
Sirish K Lakkaraju 1,  Hannah Mbatia 1,  Marie Hanscom 2,  Zaorui Zhao 2,  Junfang Wu 2,  Bogdan Stoica 2,  Alexander D MacKerell Jr 1,  Alan I Faden 2,  Fengtian Xue 3
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States.
  • 2 Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
  • 3 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States. Electronic address: fxue@rx.umaryland.edu.
PMID: 25937015 DOI: 10.1016/j.bmcl.2015.04.042
Abstract

Positive allosteric modulators (PAMs) binding to the transmembrane (TM) domain of metabotropic glutamate receptor 5 (mGluR5) are promising therapeutic agents for psychiatric disorders and traumatic brain injury (TBI). Novel PAMs based on a trans-2-phenylcyclopropane amide scaffold have been designed and synthesized. Facilitating ligand design and allowing estimation of binding affinities to the mGluR5 TM domain was the novel computational strategy, site identification by ligand competitive saturation (SILCS). The potential protective activity of the new compounds was evaluated using nitric oxide (NO) production in BV2 microglial cell cultures treated with lipopolysaccharide (LPS), and the toxicity of the new compounds tested using a cell viability assay. One of the new compounds, 3a, indicated promising activity with potency of 30 μM, which is 4.5-fold more potent than its lead compound 3,3'-difluorobenzaldazine (DFB), and showed no detectable toxicity with concentrations as high as 1000 μM. Thus this compound represents a new lead for possible development as treatment for TBI and related neurodegenerative disorders.

Keywords

Computer-aided drug design; Metabotropic glutamate receptor; Neuroprotection; Positive allosteric modulator; Traumatic brain injury.

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