Research Of New Molecules Of AMPK Agonist For The Exploration Of Improved Motor Performance

The key factors affecting modern military struggle are not only military equipment,but also the military quality of soldiers,such as physical strength and other influencing factors.Research and development of military operation capability enhancement technology,the use of functional molecules to directly or assist to achieve the purpose of physical enhancement,namely the development of rapid and efficient physical enhancement agent,has important military value.In this study,we focused on AMPK-PPAR-PGC-1αsignaling pathway,and systematically designed and evaluated new molecules with the characteristic structure of nucleosides.The main contents are as follows:1)28 nucleoside molecules were designed and synthesized using 5-aminimidazole-4-formamide nucleoside（AICAR）and adenosine as lead structures by group addition strategy.In the running wheel model of mice,the average exhaustion distance of mice in the experimental group with multiple compounds was significantly higher than that in the positive control group.The average exhaustion distance of the optimal compound B-002 was 4.8times that of AICAR,and 15.7 times that of the blank group.2)Based on the strategy of new use of old drugs,screening drugs with nucleoside structure or capable of activating AMPK,and evaluating their effect of improving physical performance.Among the five marketed drugs tested,c-003,the optimal compound,was 2.7 times higher than AICAR and 8.8 times higher than the control group.Studies on biochemical indices and mechanism of b-002/C-003 and other preferred compounds showed that the enhancement of physical strength was related to the reduction of lactic acid accumulation,the reduction of blood urea nitrogen level,the maintenance of glycogen level and the enhancement of p-AMPK protein expression,and did not involved in central excitatory effect.In addition,B-002/C-003 has good safety,and has the prospect of application in extreme cold,fatigue and exhaustion,and other military conditions.In addition,we also investigated the inhibitory effects of some new compounds on MCF-7 tumor cells based on AMPK activation.The IC₅₀ value of the optimal compound B-015 is 0.14 m M.The binding energy and action site of the compound and the target were further characterized by molecular docking experiments.This study focused on AMPK-PPAR-PGC-1αsignal pathway for the purpose of military physical fitness enhancement.The optimized compound obtained had significant rapid and efficient physical fitness improvement effect,and its efficiency was at the leading level in the field.This study is a research reserve for the development of special drugs for military,and it can also provide a new idea for the research of physical improvement.