title: Acyl-2-aminobenzimidazoles: a novel class of neuroprotective agents targeting mGluR5.
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, 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.
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States.
authors: Xinhua
authors: X
authors: He
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States.
authors: Sirish K
authors: SK
authors: Lakkaraju
authors: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors: Marie
authors: M
authors: Hanscom
authors: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors: Zaorui
authors: Z
authors: Zhao
authors: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors: Junfang
authors: J
authors: Wu
authors: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors: Bogdan
authors: B
authors: Stoica
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States.
authors: Alexander D
authors: AD
authors: MacKerell
authors: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors: Alan I
authors: AI
authors: Faden
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States. Electronic address: fxue@rx.umaryland.edu.
authors: Fengtian
authors: F
authors: Xue
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D064529:Receptor, Metabotropic Glutamate 5; D009569:Nitric Oxide
keywords: Computer-aided drug design; Metabotropic glutamate receptor; Neuroprotection; Positive allosteric modulator; Traumatic brain injury