Shanghai Institute of Brain Functional Genomics, the Key Laboratories of Ministry of Education of China and Shanghai Municipality, East China Normal University, Shanghai 200062, China

Abstract 

Objective 
To characterize the function of a new xanomeline-derived M1 agonist, 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine Oxalate (EUK1001), the acute toxicity and the effects on synaptic plasticity and cognition of EUK1001 were evaluated. 
Methods 
To examine the median lethal dose (LD50) of EUK1001, a wide dose range of EUK1001 was administered by p.o. and i.p. in aged mice. Furthermore, novel object recognition task and in vitro electrophysiological technique were utilized to investigate the effects of EUK1001 on recognition memory and hippocampal synaptic plasticity in aged mice. 
Results 
EUK1001 exhibited lower toxicity than xanomeline, and improved the performance of aged mice in the novel object recognition test. In addition, bath application of 1 μmol/L EUK1001 directly induced long-term potentiation in the hippocampus slices. 
Conclusion 
We conclude that EUK1001 can improve the agerelated cognitive deficits.

Keywords

xanomeline; EUK1001; LD50; hippocampus; long-term potentiation; memory

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