IDENTIFICATION OF NADPH-INDEPENDENT GSH CONJUGATES OF ACETYLENE-CONTAINING POSITIVE ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 5

摘要

Compounds 1, 2and 3reacted with GSH at their acetylene moieties via Michael addition: 1. demonstrated to be NADPH-independent; 2. depend on the structures of adjacent aryl functional groups; 3. enhanced by actions of GST(s) in liver cytosol; 4. subject to species-related differences in the catalytic efficiency/capacity of the relevant GST(s). Compound 4did not exhibit the aforementioned reactivity, suggesting that the compound had a lower electron density at its acetylene group and/or was a poor substrate for GSTs. These results informed an ongoing drug-discovery effort to identify mGluR5 PAMs with drug-like properties and low risk of metabolism-related issues.