莫达非尼类似物的合成及在小鼠体内的精神生物学评价。

Synthesis and psychobiological evaluation of modafinil analogs in mice.

机构信息

Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.

出版信息

Daru. 2013 Dec 19;21(1):67. doi: 10.1186/2008-2231-21-67.

DOI:10.1186/2008-2231-21-67

PMID:24355111

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3897940/

Abstract

BACKGROUND AND THE PURPOSE OF THE STUDY

Modafinil, a novel wake-promoting agent with low potential for abuse and dependence, has a reliable structure to find some novel derivatives with better activity and lower potential for abuse and risk of dependency. This study was designed to evaluate psychobiological activity of some novel N-aryl modafinil derivatives.

METHODS

Seven novel N-aryl modafinil derivatives were synthesized through three reactions: a) preparation of benzhydrylsulfanyl acetic acid through reaction of benzhydrol with thioglycolic acid, b) formation of desired amide by adding the substituted aniline to activated acid with EDC (1-ethyl-3-(3-dimethyl amino propyl) carbodiimide). This reaction was catalyzed by HOBt (N- hydroxylbenzotriazole), and c) oxidation of sulfur to sulfoxide group with H2O2. Then, their psychobiological effect on the performance of male albino mice were compared to that of modafinil as following: wakefulness by determining the effects of derivatives on phenobarbital-induced loss of the righting reflex (LOPR); exploratory activity by measuring activity in the open field test (OFT); depression by measuring immobility time (IT) during forced swimming test (FST) and the anxiogenic and anxiolytic like effects by using elevated plus-maze test (EPM). All tests were videotaped and analyzed for the frequency and duration of the behaviors during the procedures.

CONCLUSIONS

2-(Benzhydrylsulfonyl)-N-(4-chlorophenyl)acetamide (4c) showed comparable result in LOPR test. However, all analogs were found to be stimulant except 2-(benzhydrylsulfinyl)-N-phenylacetamide (4a). Also 4c led the most exploratory activity in mice among derivatives. FST results showed that 4a had the longest IT while modafinil, 2-(benzhydrylsulfinyl)-N-(3-chlorophenyl) acetamide (4b) and 2-(benzhydrylsulfinyl)-N-(4-ethylphenyl) acetamide (4d) had the shortest IT. In EPM, all derivatives showed anxiogenic-like behavior since they decreased open arms time and open arms entries and simultaneously increased close arms time.

摘要

背景与研究目的

莫达非尼是一种新型的促觉醒药物，具有较低的滥用和依赖潜力，其结构可靠，有望找到一些活性更好、滥用潜力和依赖性风险更低的新型衍生物。本研究旨在评估一些新型 N-芳基莫达非尼衍生物的心理生物学活性。

方法

通过三种反应合成了 7 种新型 N-芳基莫达非尼衍生物：a）通过苯甲醇与硫代乙醇酸反应制备苯甲硫基乙酸；b）通过 EDC（1-乙基-3-（3-二甲基氨基丙基）碳二亚胺）将取代苯胺加入到活化酸中形成所需酰胺。该反应由 HOBt（N-羟基苯并三唑）催化；c）用过氧化氢将硫氧化为亚砜基。然后，将它们对雄性白化小鼠的行为表现的影响与莫达非尼进行比较，具体方法如下：通过测定衍生物对苯巴比妥诱导的翻正反射（LOPR）丧失的影响来确定觉醒作用；通过测量开放式场试验（OFT）中的活动来确定探索性作用；通过测量强迫游泳试验（FST）中的不动时间（IT）来确定抑郁作用；通过使用高架十字迷宫试验（EPM）来确定焦虑和抗焦虑样作用。所有测试均进行录像，并在程序过程中分析行为的频率和持续时间。

结论

2-（苯甲硫基）-N-（4-氯苯基）乙酰胺（4c）在 LOPR 试验中表现出相似的结果。然而，除 2-（苯甲硫基）-N-苯甲酰胺（4a）外，所有类似物均表现出兴奋剂作用。此外，4c 在衍生物中诱导出最多的探索性活动。FST 结果表明，4a 的 IT 最长，而莫达非尼、2-（苯甲硫基）-N-（3-氯苯基）乙酰胺（4b）和 2-（苯甲硫基）-N-（4-乙基苯基）乙酰胺（4d）的 IT 最短。在 EPM 中，所有衍生物均表现出焦虑样行为，因为它们减少了开放臂时间和进入次数，同时增加了封闭臂时间。