UCP1-inspired mitochondrial uncouplers: Design, synthesis and thermogenic activity studies

Given that uncoupling protein 1 (UCP1) serves as the principal thermogenic effector in adipose tissue, and motivated by recent breakthroughs in its structural characterization, we tried to obtain the precursor compounds with optimal docking mode, tryptophan compounds, by virtual screening. Following the initial structural refinement of these derivatives, we synthesized a series of tryptophan-based compounds aimed at enhancing their functional properties. Notably, the tryptophan-derived compound ZGL-18 was found to effectively induce lipid consumption without causing toxicity in brown adipocytes at a concentration of 100 μmol/L. In addition, administration of ZGL-18 stimulates brown adipocytes, trigger a reduction in mitochondrial membrane potential. In vivo experiments showed that ZGL-18 at a dose of 100 mg/kg significantly enhanced thermogenesis and cold tolerance in mice with preserving core and skin temperature. ZGL-18 was found to efficiently enhance respiration as well as energy expenditure in cold environments, in addition to passing, and was non-toxic at a dose of 1000 mg/kg. Furthermore, we preliminarily confirmed the binding mode of ZGL-18 to UCP1 by molecular docking and molecular dynamics simulation. These results suggest that ZGL-18 might be a promising candidate for drug development targeting UCP1.