Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5

Abstract

Positive allosteric modulators (PAM) 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 lipopolysachharide (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.

Estimation of relative free energies of binding using pre‐computed ensembles based on the single‐step free energy perturbation and the site‐identification by Ligand competitive saturation approaches

“…Contributing to this is that the studied transformations are largely limited to a single non‐hydrogen atom such that energetic contributions associated with connectivity of ligands, interaction with the protein and configurational entropy changes, cancel to a large extent, leading to the quality of the prediction for the present datasets. However, when the SILCS LGFE approach is applied to a more varied set of p38 MAP kinase inhibitors, the results are competitive with published FEP values (Table ), indicating the potential utility of the method with larger chemical transformations, as have been reported for Factor Xa, thrombin, Mcl‐1/Bcl‐xl, ERK2, nuclear receptors, and the β 2 adrenergic and mGluR5 GPCRs . More generally, the results indicate the range of conformational changes in the protein and the sampling of the solutes in and around the protein obtained from the SILCS simulations are representative of the structural perturbations and functional group distributions in full ligands.…”

Driving Structure-Based Drug Discovery through Cosolvent Molecular Dynamics

“…26. 48 While promising, the low correlations underscore the need for further development in this area.…”

A CO2-Catalyzed Transamidation Reaction

“…The synthetic utility of CO 2 -catalyzed transamidation reaction was further demonstrated by accessing various bioactive and drug-like scaffolds from a single Weinreb amide source ( 3m , Figure b), while avoiding the use of coupling reagents or acyl chlorides. − Under practical reaction conditions, various amine nucleophiles were employed, and the Weinreb amides were smoothly converted to the desired drug-like structures with modest to high yields ( 4ma – 4mh , 25–91% isolated yields). It is noteworthy here that a CO 2 atmosphere prevents the evaporation of amine nucleophiles with low-boiling points (e.g., cyclopropyl amine and allylamine), therefore preserving the concentration of reagents throughout the progress of reactions.…”