A novel derivative of xanomeline improves fear cognition in aged mice

The M1/M4 muscarinic acetylcholine receptor agonist xanomeline can significantly improve the cognitive function, but the intolerable side effects limit its clinical usefulness. Our recent study has reported a novel derivative of xanomeline, 3-[3-(3-(3-florophenyl)-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine oxalate (EUK1001), exhibited higher affinity of mAChRs and less side effects relative to xanomeline. In the present study, we further utilized behavioral and electrophysiological techniques to investigate the effects of EUK1001 on fear cognition and hippocampal long-term potentiation (LTP) in aged mice. Behavioral testing showed that 0.1, 0.5 or 1.0 mg/kg EUK1001 group, like 1.0 mg/kg xanomeline group, exhibited better performance in contextual fear conditioning and passive avoidance test than vehicle-controls. In the cued fear conditioning test, just 0.5 or 1.0, but not 0.1 mg/kg EUK1001, significantly enhanced the levels of freezing response. In addition, theta-burst stimulation (TBS) induced the significant larger hippocampal LTP in brain slices perfused with artificial cerebrospinal fluid (ACSF) containing 0.01 μM EUK1001 or in brain slices from aged mice injected intraperitoneally (i.p.) with EUK1001. This enhancing effect was blocked by 0.25 μM pirenzepine, a selective M1 antagonist. Together, these results show that EUK1001 can enhance fear cognition and synaptic plasticity via the activation of M1 muscarinic acetylcholine receptors. Thus, EUK1001 may possibly represent a promising lead compound for the treatment of Alzheimer's disease and age-related cognitive deficits.