Acyl-2-aminobenzimidazoles: A novel class of neuroprotective agents targeting mGluR5. Issue 9 (1st May 2015)

• Record Type: Journal Article
• Authors: He, Xinhua; Lakkaraju, Sirish K.; Hanscom, Marie; Zhao, Zaorui; Wu, Junfang; Stoica, Bogdan; MacKerell, Alexander D.; Faden, Alan I.; Xue, Fengtian
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 9(2015)
• Page Start: 2211
• Page End: 2220
• Publication Date: 2015-05-01
• Subjects: Traumatic brain injury -- Metabotropic glutamate receptor -- Neuroprotection -- Computer-aided drug design -- Positive allosteric modulator; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.02.054
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 5 (mGluR5) are promising therapeutic agents for treating traumatic brain injury (TBI). Using computational and medicinal methods, the structure–activity relationship of a class of acyl-2-aminobenzimidazoles (1 –26 ) is reported. The new compounds are designed based on the chemical structure of 3, 3′-difluorobenzaldazine (DFB), a known mGluR5 PAM. Ligand design and prediction of binding affinities of the new compounds have been performed using the site identification by ligand competitive saturation (SILCS) method. Binding affinities of the compounds to the transmembrane domain of mGluR5 have been evaluated using nitric oxide (NO) production assay, while the safety of the compounds is tested. One new compound found in this study, compound22, showed promising activity with an IC50 value of 6.4 μM, which is ∼20 fold more potent than that of DFB. Compound22 represents a new lead for possible development as a treatment for TBI and related neurodegenerative conditions.