Design, synthesis and characterization of novel gamma-aminobutyric acid type A receptor ligands

Antinociceptive ligand HZ-166 is a GABA(A) alpha 2/alpha 3 receptor subtype-selective potentiator. It has been shown to exhibit anxiolytic-like effects in rodent and rhesus monkeys, as well as reduced sedative/ataxic liabilities. In order to improve the metabolic stability of HZ-166, the ethyl ester moiety was bioisosterically replaced with 2,4-disubstituted oxazoles and oxazolines. The new analogs of HZ-166 were synthesized, characterized, and evalutated for their biological activity and docked in the human full-length heteromeric alpha 1 beta 3 gamma 2L GABA(A) receptor subtype CyroEM structure (6HUO). Importantly no sedation nor ataxia was observed on the rotorod for LKG-I-70 (6) or KPP-III-51 (6c) at 100 and 120 mg/kg, respectively. There was also no loss of righting response for either ligand. [GRAPHICS] .