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研究生： 黃國倫
Huang, Kuo-Lun
論文名稱： 設計與開發疼痛治療新藥
Design and development of new drugs for pain management
指導教授： 葉茂榮
Yeh, Mou-Yung
共同指導教授: 王志中
Wang, Jhi-Joung
學位類別： 博士
Doctor
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2013
畢業學年度： 101
語文別： 中文
論文頁數： 185
中文關鍵詞： 局部麻醉劑 、抗心律不整藥物 、脊椎麻醉 、結構與活性相對關係 、阿米替林 、長效製劑 、神經病理性疼痛
外文關鍵詞： Local anesthetic, Antiarrhythmic, Spinal anesthesia, Structure-activity relationship, Amitriptyline, Long-acting formulation, Neuropathic pain
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    • 疼痛是一種不舒服的感覺，也為一種心理的感覺經驗。雖然已有多種止痛劑供臨床上使用，然而除副作用外尚有藥效作用不強或藥物作用時間較短的缺陷。本論文的目的為研發一系列新型局部麻醉劑與長效止痛劑，作為治療疼痛之用。本論文研究主要分為三大部分，第一部分研究為第一類抗心律不整藥物於大白鼠皮膚止痛與脊椎麻醉之藥效研究。第二部分為設計與合成新型具局部麻醉作用之化合物及其結構與活性相對關係之探討。第三部分為設計與製備長效阿米替林(amitriptyline)及其治療熱痛覺敏感(thermal hyperalgesia)藥效之研究。本論文研究成果為，第一部分，證實第一類抗心律不整藥物奎尼丁(quinidine)、每息禮延(mexiletine)及氟卡奈(flecainide)不管於大白鼠皮膚或脊椎均產生止痛及麻醉的效果。在皮膚或脊椎其藥物強弱排名依序為氟卡奈>奎尼丁>每息禮延。第二部分，完成新類型局部麻醉作用之化合物的設計與合成，以及在大白鼠脊椎麻醉之效用評估。結果發現局部麻醉劑化學結構之鍵鏈部分為碳鏈亦可產生局部麻醉作用，以5或6個碳鏈長具有較佳的脊椎麻醉活性。另外，新合成化合物N,N-二乙基-3-(2,6-二甲基苯基)丙胺和N,N-二乙基-5-(2,6-二甲基苯基)戊胺，在動物實驗中完成其皮膚止痛強度(ED50)、致死劑量(LD50)測試及安全指數(safety indices)的評估。證實N,N-二乙基-3-(2,6-二甲基苯基)丙胺有較高的系統安全指數。第三部分研究成果為完成阿米替林長效製劑之設計及製備，並評估其治療熱痛覺敏感之藥效。長效阿米替林鹼儲存型(depot)之新劑型，於大白鼠誘發熱痛覺敏感後測試在相同劑量下(100 umol/kg)，可產生長效之止痛作用，約為阿米替林鹽酸鹽(溶於生理食鹽水)的4.8倍(24小時：5小時)。於大白鼠誘發熱痛覺敏感手術前1小時皮下注射一劑劑量200 umol/kg，則可對大白鼠所誘發熱痛覺敏感產生預防性的作用。總結，本論文應用老藥新用、新合成化合物及劑型改良三種方式，研發出一系列用於治療疼痛之局部麻醉劑與長效止痛劑。

    Pain is an unpleasant sensory and psychological experience. Although many analgesics have been used in clinical medicine, they have some side effects, such as low potency and relatively short duration of action. The aim of this dissertation was to design and develop a series of new local anesthetics and novel long-acting formulations of amitriptyline base for the treatment of pain and thermal hyperalgesia. The research efforts of this study included: evaluating the cutaneous local anesthetic actions and spinal anesthetic effect of three Class I antiarrhythmic drugs in rats, designing new local anesthetic compounds and analyzing the chemical structure-activity relationships and pharmacodynamics of these new synthetic compounds in rats, and developing a novel long-acting formulation of amitriptyline base for the treatment of thermal hyperalgesia in rats. The results of the research included: the first, all three Class I antiarrhythmic drugs (quinidine, mexiletine and flecainide) produced a dose-related cutaneous analgesia and spinal anesthesia in rats. The potencies of these drugs in producing cutaneous and spinal effects were, in ascending order, flecainide (class IC) > quinidine (class IA) > mexiletine (class IB). The second, new local anesthetic compounds were synthesized, developed, and evaluated the spinal anesthetic effects in rats. The intermediate chain of chemical structure of local anesthetic was carbon chain that also produced local anesthetic effect in rats, and a 5- or 6- carbon chain, indicating that their effects of spinal anesthesia were more potent. In addition, compounds N,N-diethyl-3-(2,6-dimethylphenyl)propylamine (6) and N,N-diethyl-5-(2,6-dimethylphenyl)pentylamine (17), their potencies (ED50), lethal doses (LD50), and safety indices were calculated in rats. Compound N,N-diethyl-3-(2,6-dimethylphenyl)propylamine was safer than lidocaine. The third, a novel, long-acting formulation of amitriptyline base for the treatment of thermal hyperalgesia was designed and developed. In rats, the novel depot of amitriptyline-base (100 umol/kg s.c.) had significantly longer antinociception than amitriptyline-HCl (100 umol/kg s.c.) (24 h vs. 5 h, 4.8 times longer). A single subcutaneous injection of amitriptyline-base (200 umol/kg) 1 h before spinal nerve ligation completely prevented thermal hyperalgesia in rats. In conclusion, we applied the new application of old medcations, new synthetic compounds and the improvement of dosage form to develop a series local anesthetics and long-acting analgesic for pain management.

    目 錄 中文摘要 ---------------------------------------------------------------------------- I 英文摘要 -------------------------------------------------------------------------- III 誌謝 --------------------------------------------------------------------------------- V 導言 ---------------------------------------------------------------------------------- 1 第一篇 設計與開發新型局部麻醉劑及其藥效之研究 -------------------- 6 第一章 第一類抗心律不整藥物於大白鼠皮膚止痛之藥效研究 -------- 6 第一節 緒言 ----------------------------------------------------------------------- 6 第二節 材料與方法 -------------------------------------------------------------- 8 壹、動物 ----------------------------------------------------------------------------- 8 貮、藥物 ----------------------------------------------------------------------------- 9 参、大白鼠皮膚局部止痛模式 -------------------------------------------------- 9 肆、資料分析與統計 ------------------------------------------------------------- 11 第三節 結果 ---------------------------------------------------------------------- 12 第四節 討論 ---------------------------------------------------------------------- 12 第五節 結論 ---------------------------------------------------------------------- 18 第二章 第一類抗心律不整藥於大白鼠脊椎麻醉之藥效研究 ---------- 19 第一節 緒言 ---------------------------------------------------------------------- 19 第二節 材料與方法 ------------------------------------------------------------- 20 壹、動物 --------------------------------------------------------------------------- 20 貮、藥物 --------------------------------------------------------------------------- 20 参、動物模式 --------------------------------------------------------------------- 21 肆、50%最大有效反應之劑量(ED50) ----------------------------------------- 24 伍、資料分析與統計 ------------------------------------------------------------ 24 第三節 結果 ---------------------------------------------------------------------- 24 第四節 討論 ---------------------------------------------------------------------- 30 第五節 結論 ---------------------------------------------------------------------- 32 第三章 設計與合成新類型局部麻醉作用之化合物 ---------------------- 33 第一節 緒言 ---------------------------------------------------------------------- 33 壹、局部麻醉劑歷史之簡介 --------------------------------------------------- 33 貳、具局部麻醉作用化合物結構設計之思維 ------------------------------ 34 参、設計化合物製備之流程 --------------------------------------------------- 42 第二節 實驗材料與方法 ------------------------------------------------------- 46 壹、實驗儀器 --------------------------------------------------------------------- 46 貮、實驗藥品 --------------------------------------------------------------------- 46 参、實驗步驟及光譜資料 ------------------------------------------------------ 48 第三節 結果 ---------------------------------------------------------------------- 76 第四節 結論 ---------------------------------------------------------------------- 76 第四章 合成新型局部麻醉劑其結構與活性相對關係之探討 ---------- 79 第一節 緒言 ---------------------------------------------------------------------- 79 第二節 材料與方法 ------------------------------------------------------------- 80 壹、動物 --------------------------------------------------------------------------- 80 貮、藥物 --------------------------------------------------------------------------- 81 参、動物模式 --------------------------------------------------------------------- 82 肆、資料分析與統計 ------------------------------------------------------------ 83 第三節 結果 ---------------------------------------------------------------------- 84 壹、新型化合物其鍵鏈種類與其局部麻醉活性之相對關係 ------------ 84 貳、新型化合物其鍵鏈長度與其局部麻醉活性之相對關係 ------------ 89 参、新型化合物苯環取代基與局部麻醉活性之相對關係 --------------- 92 第四節 討論 ---------------------------------------------------------------------- 95 壹、新型化合物其鍵鏈種類與其局部麻醉活性之相對關係探討 ------ 95 貳、新型化合物其鍵鏈長度與其局部麻醉活性之相對關係探討 ------ 98 参、新型化合物苯環取代基與局部麻醉活性之相對關係探討 --------- 98 第五節 結論 ---------------------------------------------------------------------- 99 第五章 設計與合成新型長效局部麻醉作用之化合物 ----------------- 100 第一節 緒言 -------------------------------------------------------------------- 100 壹、新型長效局部麻醉作用化合物結構設計之思維 ------------------- 100 貳、設計化合物製備之流程 ------------------------------------------------- 103 第二節 實驗材料與方法 ----------------------------------------------------- 104 壹、實驗儀器 ------------------------------------------------------------------- 104 貮、實驗藥品 ------------------------------------------------------------------- 105 参、實驗步驟及光譜資料 ---------------------------------------------------- 105 第三節 結果與結論 ----------------------------------------------------------- 111 第六章 新化合物之長效局部麻醉作用及急性毒性之評估 ----------- 113 第一節 緒言 -------------------------------------------------------------------- 113 第二節 材料與方法 ----------------------------------------------------------- 114 壹、動物 ------------------------------------------------------------------------- 114 貮、藥物 ------------------------------------------------------------------------- 115 参、大白鼠皮膚局部止痛模式 ---------------------------------------------- 115 肆、藥物作用強度(potency)及作用時間(duration)評估 ---------------- 116 伍、藥物急性毒性評估 ------------------------------------------------------- 117 陸、藥物安全指標 ------------------------------------------------------------- 118 柒、電腦軟體輔助計算 ------------------------------------------------------- 118 捌、資料分析與統計 ---------------------------------------------------------- 119 第三節 結果 -------------------------------------------------------------------- 120 壹、皮下注射利度卡因鹽酸鹽、化合物6鹽酸鹽和化合物 17鹽酸鹽之藥物作用強度(potency)及作用持續時間 (duration)評估 ------------------------------------------------------------- 120 貳、大白鼠腹腔注射利度卡因鹽酸鹽、化合物6鹽酸鹽和 化合物17鹽酸鹽之致死劑量評估------------------------------------- 124 参、利度卡因鹽酸鹽、化合物6鹽酸鹽和化合物17鹽酸鹽 之安全指數評估 ---------------------------------------------------------- 124 肆、利度卡因、化合物6和化合物17分子嵌合之結合能及 分配係數估算 ------------------------------------------------------------- 124 第四節 討論 -------------------------------------------------------------------- 128 壹、皮下注射利度卡因鹽酸鹽、化合物6鹽酸鹽和化合物 17鹽酸鹽之藥物作用強度(potency)及作用持續時間 (duration)評估 ------------------------------------------------------------- 128 貳、大白鼠腹腔注射利度卡因鹽酸鹽、化合物6鹽酸鹽和 化合物17鹽酸鹽之致死劑量及安全指數評估 -------------------- 130 第五節 結論 -------------------------------------------------------------------- 131 第二篇 設計與製備長效阿米替林及其藥效之研究 -------------------- 132 第一章 長效阿米替林治療熱痛覺敏感之藥效研究 -------------------- 132 第一節 緒言 -------------------------------------------------------------------- 132 第二節 材料與方法 ----------------------------------------------------------- 135 壹、動物 ------------------------------------------------------------------------- 135 貮、藥物 ------------------------------------------------------------------------- 136 参、動物模式 ------------------------------------------------------------------- 136 肆、熱痛覺敏感(thermal hyperalgesia)行為測試 ------------------------- 137 伍、實驗設計 ------------------------------------------------------------------- 138 陸、資料分析與統計 ---------------------------------------------------------- 140 第三節 結果 -------------------------------------------------------------------- 140 壹、動物模式建立之誘發熱痛覺敏感之結果 ---------------------------- 140 貳、皮下注射阿米替林鹽酸鹽水劑對大白鼠誘發熱痛覺敏感 之抑制效果 ---------------------------------------------------------------- 142 参、皮下注射阿米替林鹼油劑對大白鼠誘發熱痛覺敏感之 抑制效果 ------------------------------------------------------------------- 142 第四節 討論 -------------------------------------------------------------------- 146 第五節 結論 -------------------------------------------------------------------- 147 第二章 阿米替林以preemptive給藥對預防熱痛覺敏感之研究 ----- 148 第一節 緒言 -------------------------------------------------------------------- 148 第二節 材料與方法 ----------------------------------------------------------- 150 壹、動物 ------------------------------------------------------------------------- 150 貮、藥物 ------------------------------------------------------------------------- 150 参、動物模式 ------------------------------------------------------------------- 151 肆、熱痛覺敏感(thermal hyperalgesia)行為測試 ------------------------- 152 伍、實驗設計 ------------------------------------------------------------------- 152 陸、資料分析與統計 ---------------------------------------------------------- 155 第三節 結果 -------------------------------------------------------------------- 155 壹、動物模式建立之誘發熱痛覺敏感之結果 ---------------------------- 155 貳、阿米替林鹽酸鹽(水劑)在預防熱痛覺敏感產生之 劑量-反應關係研究 ------------------------------------------------------ 155 参、阿米替林鹽酸鹽(水劑)於不同給藥時間長度下其 預防熱痛覺敏感產生之研究 ------------------------------------------- 157 肆、阿米替林鹼(油劑)在預防熱痛覺敏感產生之研究 ---------------- 157 伍、阿米替林鹽酸鹽(水劑)與阿米替林鹼(油劑)在抑制 或預防熱痛覺敏感產生之綜合比較 ---------------------------------- 160 第四節 討論 -------------------------------------------------------------------- 160 第五節 結論 -------------------------------------------------------------------- 166 總 結 ----------------------------------------------------------------------------- 167 參考文獻 ------------------------------------------------------------------------- 170 附錄、已發表之相關著作(Publication List) --------------------------------- 185 表目錄 表I-1-1、藥物於皮膚止痛模式下50 %最大有效反應之劑量(ED50) --- 15 表I-2-1、三個代表性第一類抗心律不整藥物與布比卡因於大白鼠 神經阻斷其ED25、ED50和ED75劑量一覽表 ------------------- 28 表I-3-1、合成新類型局部麻醉作用之化合物 ----------------------------- 77 表I-4-1、合成新型局部麻醉作用之化合物在27 mM劑量下於大鼠 測試脊椎麻醉作用強度與作用時間一覽表 ------------------- 87 表I-5-1、合成新型長效局部麻醉作用之化合物 ------------------------- 112 表I-6-1、藥物或化合物於大白鼠利用up-and-down method測試 評估化合物其50%有效劑量 ----------------------------------- 121 表I-6-2、藥物或化合物於大白鼠利用up-and-down method測試 評估化合物其50%致死劑量 ----------------------------------- 125 表I-6-3、藥物或化合物之50%有效劑量ED50S、50%致死劑量LD50S 及安全指數(LD50/ED50)及ED50劑量下之作用時間 ------- 126 表I-6-4、藥物或化合物與離子通道受體之結合能(binding energy)、 分配係數(log P)之估計值 --------------------------------------- 127 表II-1-1、阿米替林鹽酸鹽及其鹼在大白鼠中抑制熱痛覺敏感 之效果一覽表 ----------------------------------------------------- 144 表II-2-1、阿米替林鹽酸鹽及其鹼在大白鼠中抑制熱痛覺敏感 之效果一覽表 ----------------------------------------------------- 162 圖目錄 圖I-1-1、第一類抗心律不整藥物奎尼丁、每息禮延、利度卡因 和氟卡奈之化學結構式 -------------------------------------------- 7 圖I-1-2、皮下注射第一類抗心律不整藥與利度卡因對大白鼠皮膚 trunci肌肉反射之抑制時間圖 ----------------------------------- 13 圖I-1-3、氟卡奈、奎尼丁、每息禮延與利度卡因於大白鼠皮膚止痛 模式之劑量-反應曲線圖 ------------------------------------------ 14 圖I-1-4、氟卡奈、奎尼丁、每息禮延與利度卡因於大白鼠皮膚止痛 模式於ED50劑量下之阻斷持續時間圖 ------------------------ 16 圖I-2-1、5%葡萄糖水溶液、氟卡奈與布比卡因於大白鼠脊椎神經 阻斷(% PE)時間圖 ------------------------------------------------- 26 圖I-2-2、三個代表性第一類抗心律不整藥物與布比卡因於大白鼠 脊椎神經阻斷之劑量-反應曲線圖 ------------------------------ 27 圖I-2-3、三個代表性第一類抗心律不整藥物與布比卡因於大白鼠 脊椎神經阻斷持續時間圖 ---------------------------------------- 29 圖I-3-1、例舉局部麻醉劑之化學結構式 ----------------------------------- 35 圖I-3-2、例舉三環抗憂鬱藥之化學結構式 -------------------------------- 37 圖I-3-3、例舉第一類抗心律不整藥物之化學結構式 -------------------- 38 圖I-3-4、例舉止咳藥之化學結構式 ----------------------------------------- 39 圖I-3-5、設計局部麻醉作用之化學結構 ----------------------------------- 40 圖I-4-1、藥物利度卡因鹽酸鹽及化合物6鹽酸鹽於27 mM濃度下， 大白鼠脊椎神經麻醉作用之最大阻斷效用(%MPE)圖 ------ 85 圖I-4-2、藥物利度卡因鹽酸鹽及化合物6鹽酸鹽於27 mM濃度下， 大白鼠脊椎神經麻醉作用持續時間圖 ------------------------- 86 圖I-4-3、藥物利度卡因鹽酸鹽及化合物8a, 8b, 11a-11f鹽酸鹽於 27 mM濃度下，大白鼠脊椎神經麻醉作用之最大阻斷 效用(% MPE)圖 ---------------------------------------------------- 90 圖I-4-4、藥物利度卡因鹽酸鹽及化合物8a, 8b, 11a-11f鹽酸鹽於 27 mM濃度下，大白鼠脊椎神經麻醉作用持續時間圖 ---- 91 圖I-4-5、藥物利度卡因鹽酸鹽、化合物16a、16b和16c鹽酸鹽 於27 mM濃度下，大白鼠脊椎神經麻醉作用之最大 阻斷效用(%MPE)圖 ----------------------------------------------- 93 圖I-4-6、藥物利度卡因鹽酸鹽、化合物16a、16b和16c鹽酸鹽 於27 mM濃度下，大白鼠脊椎神經麻醉作用之持續 時間圖 ---------------------------------------------------------------- 94 圖I-4-7、藥物利度卡因鹽酸鹽、化合物8b、6和16a鹽酸鹽於 27 mM濃度下，大白鼠脊椎神經麻醉作用之最大阻斷 效用(%MPE)圖 ----------------------------------------------------- 96 圖I-4-8、藥物利度卡因鹽酸鹽、化合物8b、6和16a鹽酸鹽於 27 mM濃度下，大白鼠脊椎神經麻醉作用之持續時 間圖 ------------------------------------------------------------------- 97 圖I-5-1、設計新型長效局部麻醉作用化合物N,N-二乙基-5-(2,6-二 甲基苯基)戊胺(17)之化學結構 -------------------------------- 102 圖I-6-1、同為ED50的劑量下，皮下注射利度卡因鹽酸鹽、化合 物6和17鹽酸鹽對大白鼠皮膚trunci肌肉反射之抑制 時間圖 -------------------------------------------------------------- 122 圖I-6-2、利度卡因鹽酸鹽、化合物6和17鹽酸鹽於大白鼠皮膚 止痛模式之阻斷持續時間圖 ----------------------------------- 123 圖II-1-1、阿米替林(amitriptyline)之化學結構式 ------------------------- 134 圖II-1-2、大白鼠誘導熱痛覺敏感時間圖 ---------------------------------- 141 圖II-1-3、大白鼠皮下注射一劑阿米替林鹽酸鹽(AMT-HCl) (溶於 生理食鹽水)對熱痛覺敏感抑制效果圖 ---------------------- 143 圖II-1-4、大白鼠皮下注射一劑阿米替林鹼(AMT-Base) (溶於芝 麻油)對熱痛覺敏感抑制效果圖 ------------------------------- 145 圖II-2-1、大白鼠誘導熱痛覺敏感長期觀測時間圖 --------------------- 156 圖II-2-2、大白鼠皮下注射六劑阿米替林鹽酸鹽(AMT-HCl)後對 預防熱痛覺敏感效果劑量-反應關係圖 ---------------------- 158 圖II-2-3、阿米替林鹽酸鹽(AMT-HCl)於不同給藥時間長度下對 預防熱痛覺敏感效果圖 ----------------------------------------- 159 圖II-2-4、大白鼠於手術前1小時皮下注射一劑阿米替林鹽酸鹽 (AMT-HCl)或阿米替林鹼(AMT-Base)後對預防熱痛覺 敏感產生之效果圖 ----------------------------------------------- 161 圖II-2-5、藥物阿米替林鹽酸鹽(AMT-HCl)及其阿米替林鹼(AMT- Base)經由皮下注射後，對熱痛覺敏感抑制效果之藥物 作用時間綜合比較圖 -------------------------------------------- 163 流程 3-1 --------------------------------------------------------------------------- 42 流程 3-2 --------------------------------------------------------------------------- 43 流程 3-3 --------------------------------------------------------------------------- 45 流程 5-1 -------------------------------------------------------------------------- 103

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