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研究生:李誌雄
研究生(外文):Chih-Hsiung Lee
論文名稱:二氫吡啶型鈣通道阻斷劑具有鉀通道打開及甲型腎上腺受體阻斷特性之研究
論文名稱(外文):A new dihydropyridine type calcium channel blocker displaying potassium channel opening and adrenoceptor blocking activities
指導教授:陳英俊陳英俊引用關係
指導教授(外文):Ing-Jun Chen
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:92
中文關鍵詞:二氫吡鉀通道打開
外文關鍵詞:14-dihydropyridinepotassium channel open
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對於現今高血壓藥物的治療,甲型腎上腺激性阻斷劑、乙型腎上腺激性阻斷劑和鈣離子通道阻斷劑皆有不錯的治療效果。本研究主要是以化學方法合成新化合物,進行結構的分子修飾及官能基的改變,希望同一個化合物上同時具有腎上腺激性甲型、乙型和鈣離子通道阻斷的藥理活性。並對新合成的化合物 KMUP 890330 和最終具有1,4-dihydropyridine 架構的衍生物 KMUP 890418,進一步利用活體、離體及放射性同位素受體結合之動物實驗,對腎上腺激性甲型、乙型受體及鈣離子通道阻斷的藥理特性進行探討。
在活體心臟血管實驗:由靜脈注射 KMUP 890330(1.0、2.0、3.0 mg/kg) 和 KMUP 890418 (0.5、1.0、3.0 mg/kg)於 pentobarbital 麻醉之正常血壓的Wistar 系大鼠,或以口服投予 KMUP 890330 和 KMUP 890418 (5、10、25 mg/kg)皆可引起血壓下降及心跳減慢反應。
在離體組織實驗:KMUP 890330 和 KMUP 890418(10-7、10-6、10-5 M)能競爭性拮抗 (-)isoproterenol 引起之心房收縮力、跳動頻率累積性增加作用和氣管鬆弛作用,以及抑制 phenylephrine 引起之血管收縮作用,此種離體實驗數據證實了此化合物具有競爭腎上腺性甲型/乙型受體之活性。累積投予 KMUP 890330 和 KMUP 890418 於大鼠離體心房發現不會產生顯著性的心房跳動頻率及收縮力降低現象。另外,於天竺鼠離體氣管投予 KMUP 890330 和 KMUP 890418 也不會產生顯著性的氣管直接鬆弛作用,證實 KMUP 890330 和 KMUP 890418 應不具有內生性交感神經活性。
KMUP 890330 和 KMUP 890418的血管鬆弛作用會因去除內皮或以一氧化氮合成酶 (nitric oxide synthase; NOS) 抑制劑 L-NAME (10-4 M), soluble guanylyl cyclase (sGC) 抑制劑methylene blue (10-5 M) 和 ODQ (10-5 M), 鉀離子通道阻斷劑tetraethylammonium chloride (TEA, 10-2 M)、glibenclamide (10-6 M)、4-aminopyridine (4-AP, 10-4 M) 、 apamine (10-6 M) 和 charybotoxin (CHTX; 10-7 M) 前處理而變弱。
在大鼠離體胸主動脈, KMUP 890418 (10-8、10-7、10-6 M) 也可競爭細胞外累積投予鈣離子所引起的血管收縮作用,可使 CaCl2 的濃度反應曲線呈現劑量相關地由左向右平行移動。KMUP 890418 能抑制高鉀溶液 (80 mM ) 所引起的血管收縮作用,另外 KMUP 890418 對 phenylephrine 引起之快速血管收縮期及持續性血管收縮期也都有抑制作用。以上實驗證實了 KMUP 890418 具有鈣離子拮抗劑之活性。
KMUP 890330 和 KMUP 890418 在乙型受體結合競爭的實驗中,以 [3H]CGP-12177 分別結合於老鼠心室和肺細胞膜上;在甲型受體結合競爭的實驗中,以 [3H]prazosin 結合於老鼠大腦組織膜上;另外,KMUP 890418 在鈣離子通道結合競爭實驗中,以 [3H]nitrendipine 結合於老鼠大腦皮質細胞膜來進一步評估其細胞膜結合的特性。
基於以上活體或離體組織實驗,以及進一步放射性同位素甲型與乙一、乙二型受體結合研究,可得知 KMUP 890330 具有甲型、乙型腎上腺性阻斷劑及鉀離子通道開啟之特性,而 KMUP 890418 是一個化合物中同時具有腎上腺激性甲型、乙型受體阻斷、鉀離子通道開啟及鈣離子通道阻斷之藥理活性。

Today a-adrenoceptor blockers, b-adrenoceptor blockers and calcium entry blockers have good therapeutical effects in hypertensive patients. The goal of this study is by using chemical methods to synthesize compounds with the pharmacological properties of a-adrenoceptor blocking, b-adrenoceptor blocking with and without calcium entry blocking activities. Two compounds KMUP 890418 with and KMUP 890330 without 1,4-dihydropyridine base, were synthesized and evaluated in vivo or in vitro in isolated preparations or by radioligand binding studies. Intravenous injection of KMUP 890330 (1.0, 2.0, 3.0 mg/kg) and KMUP 890418 (0.5, 1.0, 3.0 mg/kg) in anethetized Wistar rats, or oral administration of KMUP 890330 and KMUP 890418 (5, 10, 25 mg/kg) in conscious spontaneously hypertensive rats, produced dose-dependent hypotension and bradycardia. In the isolated Wistar rat right atria, left atria and guinea-pigs tracheal strips, KMUP 890330 and KMUP 890418 (10-7, 10-6, 10-5 M) competitively antagonized (-)isoproterenol-induced positive chronotropic and inotropic effects and tracheal relaxant responses in a concentraction-dependent manner. The parallel shift to the right of the concentration-response curves of (-)isoproterenol suggested that KMUP 890330 and KMUP 890418 were b1/b2-adrenoceptor competitive antagonists. In isolated artria of reserpinized rats, cumulative additions of KMUP 890330 and KMUP 890418 did not produce significantly cardiodepressant responses at high concentrations. On tracheal strips of reserpinized guinea-pigs, cumulative doses of KMUP 890330 and KMUP 890418 did not produce significantly relaxant responses, indicating that KMUP 890330 and KMUP 890418 might not have intrinsic sympathomimetic activity (ISA). In thoracic aorta, KMUP 890330 and KMUP 890418 (10-7,10-6, 10-5 M) competitively antagonized the phenylephrine-induced vasocontraction in a concentration-dependent manner. The parallel shift to the right of the concentration-response curves of phenylephrine suggested that KMUP 890330 and KMUP 890418 were a-adrenoceptor competitive antagonists. Furthermore, KMUP 890330 and KMUP 890418, in a equal antagonist activity, inhibitted phenylephrine-induced phasic and tonic contraction. In phenylephrine-preconstricted endothelium—intact or denuded rat aortic rings, KMUP 890330 and KMUP 890418 produced a concentration-dependent relaxation. KMUP 890330 and KMUP 890418-induced aortic relaxation was reduced by endothelium removal or by the presence of L-NAME (10-4 M), a nitric oxide synthase inhibitor. In addition, the vasorelaxant effects of KMUP 890330 and KMUP 890418 were inhibited by pretreatment with soluble guanylyl cyclase inhibitors methylene blue (10-5 M) and ODQ (10-5 M), a non-selective K+ channels blocker TEA (10-2 M), a KATP channels blocker glibenclamide (10-6 M), a votage-dependent potassium channels blocker 4-aminopyridine (4-AP, 10-4 M), a slow-conductance Ca2+-activated potassium chnnel blocker apamine (10-6 M), a high-conductance Ca2+-activated potassium chnnel blocker charybotoxin (10-7 M). In the isolated rat aorta, KMUP 890418 also competitively antagonized CaCl2-induced contractions, and made the parallel shift to the right of the concentration-response curves of CaCl2. The tonic contraction elicited by KCl (80 mM) was also relaxed by the addition of KMUP 890418. The binding characteristics of KMUP 890330 and KMUP 890418 were evaluated in [3H]CGP-12177 binding to ventricle and lung and [3H]prazosin binding to brain membranes in rats. KMUP 890418 also was evaluated in [3H]nitrendipine binding to brain membranes in rats. These results indicated that KMUP 890330 was a a/b-adrenoceptor antagonist and potassium channel opener; KMUP 890418 possesses a-adrenoceptor blocking, b-adrenoceptor blocking, potassium channel opening and calcium entry blocking activities in one compound.

1.摘要------------------------------------------------------1
2.英文摘要--------------------------------------------------3
3縮寫表-----------------------------------------------------6
4.緒論------------------------------------------------------7
5.研究材料--------------------------------------------------12
6.研究方法--------------------------------------------------18
7.研究結果--------------------------------------------------33
8.討論------------------------------------------------------42
9.參考文獻--------------------------------------------------------51
10.附表與附圖----------------------------------------------------59

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