A novel derivative of xanomeline improved memory function in aged mice.
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 micromol/L EUK1001 directly induced long-term potentiation in the hippocampus slices.


CONCLUSIONS
We conclude that EUK1001 can improve the age-related cognitive deficits.
Cui
Yi-Hui
YH
Shanghai Institute of Brain Functional Genomics, the Key Laboratories of Ministry of Education of China and Shanghai Municipality, East China Normal University, Shanghai, China.
Si
Wen
W
Yin
Liang
L
An
Shu-Ming
SM
Jin
Jing
J
Deng
Shi-Ning
SN
Cao
Xiao-Hua
XH
D000375:Aging / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D007928:Lethal Dose 50; D017774:Long-Term Potentiation / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D018721:Muscarinic Agonists / Q000008:administration & dosage* / Q000009:adverse effects*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry; D013830:Thiadiazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry
C533736:3-(3-(3-florophenyl-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6- tetrahydro-1-methylpyridine oxalate; D018721:Muscarinic Agonists; D011725:Pyridines; D013830:Thiadiazoles; C075257:xanomeline