Acyl-2-aminobenzimidazoles: a novel class of neuroprotective agents targeting mGluR5.

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TitleAcyl-2-aminobenzimidazoles: a novel class of neuroprotective agents targeting mGluR5.
Publication TypeJournal Article
Year of Publication2015
AuthorsHe, X, Lakkaraju, SK, Hanscom, M, Zhao, Z, Wu, J, Stoica, B, Mackerell, AD, Faden, AI, Xue, F
JournalBioorg Med Chem
Date Published2015 May 01
KeywordsAnimals, Benzimidazoles, Cell Survival, Cells, Cultured, Computer-Aided Design, Dose-Response Relationship, Drug, Excitatory Amino Acid Antagonists, Mice, Models, Molecular, Molecular Structure, Neuroprotective Agents, Nitric Oxide, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship

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, compound 22, showed promising activity with an IC₅₀ value of 6.4 μM, which is ∼20 fold more potent than that of DFB. Compound 22 represents a new lead for possible development as a treatment for TBI and related neurodegenerative conditions.

Alternate JournalBioorg. Med. Chem.
PubMed ID25801156
PubMed Central IDPMC4697443
Grant ListR01 CA107331 / CA / NCI NIH HHS / United States
R43 GM109635 / GM / NIGMS NIH HHS / United States
CA107331 / CA / NCI NIH HHS / United States