Pharmacokinetics and pharmacodynamics of a novel Acetylcholinesterase Inhibitor, DMNG-3

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Acta Neurobiologiae Experimentalis

Nencki Institute of Experimental Biology

Polish Neuroscience Society

Subject: Behavioral Sciences , Biomedical Sciences & Nutrition , Life Sciences , Medicine , Neurosciences

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ISSN: 0065-1400
eISSN: 1689-0035

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VOLUME 76 , ISSUE 2 (June 2016) > List of articles

Advertisement Pharmacokinetics and pharmacodynamics of a novel Acetylcholinesterase Inhibitor, DMNG-3

Xin-Guo Zhang * / Fei Kou / Guo-Di MA / Peng Tang / Zhong-Duo Yang

Keywords : DMNG-3, step-down passive avoidance test, HPLC, pharmacokinetics, tissue distribution

Citation Information : Acta Neurobiologiae Experimentalis. Volume 76, Issue 2, Pages 117-124, DOI: https://doi.org/10.21307/ane-2017-011

License : (CC BY 4.0)

Received Date : 04-January-2016 / Accepted: 13-April-2016 / Published Online: 25-July-2017

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ABSTRACT

DMNG-3 (3β-Methyl-[2-(4-nitrophenoxy)ethyl]-amino]con-5-enine), is a new and the potentially most potent acetylcholinesterase inhibitor recently obtained from conessine by N-demethylation and nucleophilic substitution reaction. In the present study, a step‑down passive avoidance test was used to investigate whether DMNG-3 could modulate impairment of learning and memory induced by scopolamine, and a high performance liquid chromatography (HPLC) method for the determination of DMNG-3 in biological samples was applied to study its pharmacokinetics and tissues distribution. Separation was achieved on C18 column using a mobile phase consisting methanol‑water (70:30, v/v) at a flow rate of 1.0 ml/min. The intra- and inter-day precisions were good and the RSD was all lower than 1.30%. The mean absolute recovery of DMNG-3 in plasma ranged from 88.55 to 96.45%. Our results showed oral administration of DMNG-3 (10, 25, 50 mg/kg/day) can significantly improve the latency and number of errors and had a positive effect of improvement of learning and memory in mice in passive avoidance tests. The elimination half-life (T1/2) was 14.07±1.29, 15.87±1.03 h, and the total clearance (CL) values were 0.70±0.11, 0.78±0.13 L/h/kg, respectively. The pharmacokinetic studies showed that DMNG-3 has a slowly clearance and large distribution volume in experimental animals, and its disposition is linear over the range of doses tested. The liver, small intestine, stomach, and large intestine were the major distribution tissues of DMNG-3 in mice. It was found that DMNG-3 could be detected in brain, suggesting that DMNG-3 can cross the blood-brain barrier. The present study shows that DMNG-3 can be possible developed as a new drug for the treatment of Alzheimer’s disease in the future.

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