A novel derivative of xanomeline improved memory function in aged mice

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.

Effects of Selective Activation of M₁ and M₄ Muscarinic Receptors on Object Recognition Memory Performance in Rats

“…Although there is substantial evidence that enhancing mAChR signaling can benefit recognition memory [17], the relative efficacy of VU0364572, BQCA and VU0152100 to improve recognition memory performance has yet to be investigated. The task to evaluate drug effects on memory was based on the rats' spontaneous preference for novel objects [18], involved little in terms of rule learning, and permitted each rat to be tested on all drug conditions.…”

The M1/M4 agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain

“…Xanomeline is a functionally-selective M1 and M4 muscarinic agonist that has been investigated as a potential pro-cognitive cholinergic stimulant in Alzheimer disease (Avery et al, 1997;Bodick et al, 1997;Cui et al, 2008;Si et al, 2010;Wang et al, 2011), as well as a putative antipsychotic agent, based on the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia (Hyde and Crook, 2001;Lucas-Meunier et al, 2003;Mirza et al, 2003;NR et al, 2003;Sarter, 2005;Raedler et al, 2006;Lisman et al, 2008). The primary original contributions of this report are the demonstration that xanomeline acutely reduces functional connectivity in a widespread set of mouse brain networks and reverses the hyperconnectivity induced by PCP, but focally increasing connectivity in terminals of the mesolimbic pathway in both conditions.…”

“…An increasing body of preclinical and clinical evidence has highlighted a potential beneficial effect of cholinergic stimulation on brain disorders characterized by cognitive dysfunction or psychosis, including neurodegenerative conditions such as Alzheimer disease or neuropsychiatric diseases such as schizophrenia (Felder et al, 2018;Verma et al, 2018;Erskine et al, 2019). These properties have prompted clinical investigations into the use of this drug to improve cognitive function and behavioral disturbance in Alzheimer's disease patients, with encouraging results but dose-limiting peripheral cholinergic side effects (Avery et al, 1997;NC et al, 1997;Cui et al, 2008;Si et al, 2010;Wang et al, 2011;Melancon et al, 2013). Interestingly, a parallel set of clinical observations have linked recreational use of betel nut with fewer positive and negative symptoms in schizophrenia (Sullivan et al, 2000), a finding that has been linked to the observation of decreased M1/M4 mAChR density in the brains of schizophrenia patients (for review, see Scarr & Dean 2008).…”

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…In tests with rodents, it showed an improvement in memory and cognition;h owever,i tf ailed phase II clinical trials due to an umber of side effects generally of gastrointestinal nature.T hese effectsw ere possibly due to the simultaneous activation of both receptor subtypes. [96][97][98][99] In fact, this is an example of ac ase that has raised doubts about the importance of the quest for selectivity.T his is because Alt et al [100] have shown, in anotheri nvivo study,t hat selectivec ompounds,s pecifically those for the M1 receptor, also elicit the same side effects. That is, even compounds that interacts electively with the M1 receptor were found to show side effects similar to those of xanomeline, which interacts with the M1 andM 3r eceptors.…”