Synthesis and antinociceptive properties of N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl) propionamide in the mouse tail-flick and hot-plate tests
Synthesis and antinociceptive properties of N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl) propionamide in the mouse tail-flick and hot-plate tests
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DOI：
10.1016/j.bmcl.2013.11.069
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发表时间：
2014-01-15
影响因子：
2.7
通讯作者：
DeRuiter, Jack
中科院分区：
文献类型：
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作者：
Andurkar, Shridhar V.;Reniguntala, Madhu Shaw J.;DeRuiter, Jack
本研究的目的是合成N-苯基-N-（1-（2-（噻吩-2-基）乙基）氮杂环庚烷-4-基）丙酰胺（1c）并测定其抗伤害活性。本文研究了可乐定对1c抗伤害作用的影响以及阿片受体、α 2肾上腺素受体和I-2咪唑啉受体参与1c抗伤害作用的情况。还研究了内皮素ETA受体拮抗剂对1c抗伤害性感受的影响。1c的合成是在两个步骤中完成的，使用以前报道的方法的修改。在用1c、拮抗剂+1c、可乐定+1c或拮抗剂+可乐定+1c处理的雄性Swiss韦伯斯特小鼠中测量抗伤害感受（甩尾和热板）潜伏期。用纳洛酮（阿片受体拮抗剂）、育亨宾（α（2）-肾上腺素受体拮抗剂）、咪唑克生（α（2）-肾上腺素受体/I-2-咪唑啉拮抗剂）、BU 224（I-2-咪唑啉拮抗剂）或BQ 123（内皮素ETA受体拮抗剂）预处理小鼠以研究这些受体的参与。化合物1c产生抗伤害性潜伏期的剂量依赖性增加;在甩尾和热板试验中，ED 50值分别为0.15 mg/kg和0.16 mg/kg。纳洛酮，但不是育亨宾，咪唑克生或BU 224，阻断1c抗伤害性。可乐定和BQ 123均不能增强1c的抗伤害作用。结果表明，1c的效力是吗啡的15倍。1c的抗伤害作用是通过阿片受体介导的。α（2）-肾上腺素能受体、I-2-咪唑啉受体和内皮素ETA受体不参与1c抗伤害感受。(C)2013爱思唯尔有限公司保留所有权利。
The goals of this study, were to synthesize N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propionamide (1c) and determine its antinociceptive properties. The effect of clonidine on 1c antinociception and the involvement of opioid, alpha(2)-adrenergic, and I-2 imidazoline receptors in 1c antinociception were studied. Also examined was the effect of an endothelin ETA receptor antagonist on 1c antinociception. Synthesis of 1c was accomplished in two steps using modifications of previously reported methods. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with 1c; antagonists + 1c; clonidine + 1c; or antagonists + clonidine + 1c. Mice were pretreated with naloxone (opioid antagonist), yohimbine (alpha(2)-adrenoceptor antagonist), idazoxan (alpha(2)-adrenoceptor/I-2-imidazoline antagonist), BU224 (I-2-imidazoline antagonist) or BQ123 (endothelin ETA receptor antagonist) to study the involvement of these receptors. Compound 1c produced a dose-dependent increase in antinociceptive latencies; ED50 values were 0.15 mg/kg and 0.16 mg/kg, respectively, in the tail flick and hot plate tests. Naloxone, but not yohimbine, idazoxan or BU224, blocked 1c antinociception. Neither clonidine nor BQ123 potentiated 1c antinociception. Results demonstrate that 1c is 15-times more potent than morphine. The antinociceptive effect of 1c is mediated through opioid receptors. The alpha(2)-adrenergic, I-2-imidazoline and endothelin ETA receptors are not involved in 1c antinociception. (C) 2013 Elsevier Ltd. All rights reserved.