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

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleCyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5.
Publication TypeJournal Article
Year of Publication2015
AuthorsLakkaraju, SK, Mbatia, H, Hanscom, M, Zhao, Z, Wu, J, Stoica, B, Mackerell, AD, Faden, AI, Xue, F
JournalBioorg Med Chem Lett
Date Published2015 Jun 01
KeywordsAnimals, Computer Simulation, Drug Design, Models, Chemical, Molecular Structure, Moles, Protein Conformation, Receptor, Metabotropic Glutamate 5

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.

Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID25937015
PubMed Central IDPMC4690453
Grant ListR43 GM109635 / GM / NIGMS NIH HHS / United States
R43GM109635 / GM / NIGMS NIH HHS / United States