Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 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.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States.
Sirish K
SK
Lakkaraju
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States.
Hannah
H
Mbatia
Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Marie
M
Hanscom
Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Zaorui
Z
Zhao
Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Junfang
J
Wu
Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Bogdan
B
Stoica
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States.
Alexander D
AD
MacKerell
Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Alan I
AI
Faden
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States. Electronic address: fxue@rx.umaryland.edu.
Fengtian
F
Xue
D000818:Animals; D003198:Computer Simulation; D015195:Drug Design; D008956:Models, Chemical; D015394:Molecular Structure; D008971:Moles; D011487:Protein Conformation; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*
D064529:Receptor, Metabotropic Glutamate 5
Computer-aided drug design; Metabotropic glutamate receptor; Neuroprotection; Positive allosteric modulator; Traumatic brain injury