Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5. Issue 11 (1st June 2015)

• Record Type: Journal Article
• Authors: Lakkaraju, Sirish K.; Mbatia, Hannah; Hanscom, Marie; Zhao, Zaorui; Wu, Junfang; Stoica, Bogdan; MacKerell, Alexander D.; Faden, Alan I.; Xue, Fengtian
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 11(2015)
• Page Start: 2275
• Page End: 2279
• Publication Date: 2015-06-01
• Subjects: Traumatic brain injury -- Metabotropic glutamate receptor -- Neuroprotection -- Computer-aided drug design -- Positive allosteric modulator; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.04.042
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.