羧醯胺衍生物對於神經傳訊作用之探討

Studies of the effects of carboxamide derivatives on the neural transmission

黃冠章(Kuan-Chang Huang)

指導教授 ： 林明忠

中山醫學大學/醫學科技學院/生物醫學科學學系碩士班/碩士(2014年)

https://doi.org/10.6834/CSMU.2014.00107

摘要

有研究指出KCNQ開啟劑可使用來治療神經相關性疾病如癲癇、偏頭痛等等，本研究是探討利用已被發表的Kv7 (potassium channel, voltage-gated, KQT-like Subfamily) 鉀離子通道開啟藥劑ML213與retigabine，其中結構式2, 4 , 6 - (trimethylphenyl)acetamide來找尋其結構類似的新藥，林明忠老師利用從了藥物分析網站Hit2lead.com下去尋找了與retigabine與ML213結構相似的21種藥物來從事實驗，我們觀察到，對於以低頻率刺激神經引發肌肉張力，發現其中2-adamantyl-N~1~mesitylglycinamide hydrochloride (#0342) 具有明顯的抑制作用。而在高頻刺激中，#0342, 1-cyclohexyl-N- mesitylprolinamide hydrochloride (#0335), mesityl-2-piperidinecar boxamide hydrochloride (#0321) 和2-(1-azepanyl)-N-mesitylbutan amide (#0331)，這四種藥都有肌強直衰減的現象，除了#0342外其中#0335和#0321現象最為明顯。在神經末梢電流波型紀錄的實驗中(nerve-terminal spike recordings)，不論低頻率與高頻刺激，#0342、#0335和 #0321皆會明顯的抑制鈉離子電流波型。故推測造成 #0342、#0335和 #0321的抑制作用不同於其他KCNQ4開啟劑的作用，此可能是由於抑制鈉離子通道所造成的結果。原本計畫是為了尋找新的鉀離子通道開啟藥物，可是實驗結果卻意外找到了新類型的鈉離子通道阻斷劑。

關鍵字

羧醯胺衍生物

並列摘要

Recent studies have shown that KCNQ openers have potential for the treatment of several central nervous system disorders, eg., epilepsy, migraine. The purpose of this study was to find new compounds of KCNQ opener. We used the structure of KCNQ (potassium channel, voltage-gated, KQT-like Subfamily) openers ML213 and retigabine as the template to search the possible KCNQ openers. Dr. Min-Jon Lin used the website Hit2lead.com to compare the structure of KCNQ openers and found that 21 derivatives of KCNQ opener. In these experiments the nerve-evoked muscle tension is inhibited by the treatment 2-amantyl-N~1~mesitylglycinamide hydrochloride (#0342；50μM). Treatment with #0342, 1 -cyclohexyl -N- mesitylprolinamide hydrochloride (#0335), 2 - (1-azepanyl) -N- mesitylbutanamide (#0331) and mesityl -2-peridinecarbox amide hydrochloride (#0321) produced the significant effect of titanic failure (50 Hz stimulation). In terminal spike recordings, the treatment of #0342, #0321 and #0335 produced the significant inhibition effect of sodium spikes. Therefore, the effects of the #0342, #0335 and #0321 are not similar to the KCNQ openers. These data suggested that #0342, #0335 and #0321 are more likely to be the sodium channel blockers than KCNQ modulators. Our initial research planning is to screen of new KCNQ openers from the predicted compounds. However these unexpected results indicate that the effects of #0342, #0321, and #0335 on the blocked of nerve – muscle conduction are more likely through the inhibition of sodium channels.

並列關鍵字

carboxamide derivatives

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