臺灣博碩士論文加值系統

本研究主要是以異丁香醇為核心，進行結構的分子修飾及結構改變後
藥理活性之探討，所修飾的位置是在異丁香醇結構上第四位之酚基，合成
新型異丁香醇衍生物-Isoeugenolol: (1 - ( isopropylamino ) -3-( 4
- propenyl - 2 -methoxy -)phenoxy -ropanol)，並進一步利用活體和
離體之動物實驗探討isoeugenolol，對腎上腺激性乙型受體阻斷的特性。
在活體心臟血管實驗 : 由靜脈注射 isoeugenolol ( 1.0, 3.0, 5.0 mg/
kg )於pentobabital 麻醉之正常血壓的Wistar大鼠，可引起超過一小時
的心跳減慢及持續性血壓下降反應，此種化合物發現可以阻斷
(-)isoproterenol 在大鼠體內所引起的心跳加速作用，表示此化合物所
引起的心跳減緩作用與乙型腎上腺激性阻斷活性有關，且對於
phenylephrine 所引起的升壓作用幾乎不產生抑制，因此，證實它不具有
甲型受體阻斷作用。在離體組織實驗 : isoeugenolol 能抑制
(-)isoproterenol 引起之心房收縮力、跳動頻率累積性增加作用及氣管
鬆弛作用，並可使 (-)isoproterenol 的濃度反應曲線呈現劑量相關地由
左向右平行移動，其pA2值分別為 7.63 ±0.08，7.89 ±0.12 及 6.12
±0.05。此種離體實驗數據證實了此化合物具有競爭腎上腺激性乙型接受
體之活性，且顯示isoeugenolol 具備選擇性之乙一 型阻斷劑特性，其對
乙一型(β1)及乙二型(β2)接受體的選擇性比例為 32.4。以reserpine
前處理的離體天竺鼠心房及氣管來評估isoeugenolol是否具有內生性交感
活性，累積投予isoeugenolol，propranolol 及 atenolol 於離體天竺鼠
，其isoeugenolol 及 propranolol 在濃度為 10-5 M 時可產生心房跳
動頻率及收縮力降低現象。而 atenolol 幾乎不影響心房跳動頻率及收縮
力。另外，於天竺鼠離體氣管投予isoeugenolol 可產生劑量相關性的氣
管直接鬆弛作用，且可以抑制 carbachol 及 KCl( 75 mM ) 所引起的氣
管收縮反應。而以腎上腺激性乙二型受體阻斷劑 ICI 118,551 前處理，
不能抑制 isoeugenolol 對氣管所產生的直接魏弛作用，證實
isoeugenolol 不具有內生交感神經活性。在天竺鼠離體胸主動脈實驗中
，isoeugenolol 對 phenylephrine 引起的血管收縮之抑制作用較強，但
對高鉀溶液引起的血管收縮作用之抑制則較弱。此外，isoeugenolol 與
其它乙型阻斷劑競爭 [3H]CGP-12177 結合於老鼠心室，肺及脂肪組織膜
的次序為 (-)propranolol >> metoprolol > isoeugenolol > atenolol
。基於以上活體或離體組織實驗，及進一步放射性同位素乙型受體結合研
究，已經證實 isoeugenolol 具有選擇性乙一型腎上腺激性阻斷劑之特性
，並具血管及氣管鬆弛作用，而 isoeugenolol 所引起的血管及氣管鬆弛
作用可能與阻斷鈣離子流動有關。

Isoeugenolol was a newly synthesized compound derived
from isoeugenol.The beta-adrenoceptor blocking properties of
isoeugenolol were investigatedboth in vivo and in vitro
studies. Intravenous injection of isoeugenolol(1.0, 3.0, 5.0
mg/kg) in Wistar rats, anesthetized with pentobarbital sodium,
produced a dose-dependent bradycardia response and
decreased in bloodpressure. This compound inhibited the
tachycardia effects induced by (-)isoproterenol, but had no
blocking effect on the arterial pressor responsesinduced by
phenylephrine. These findings suggested that the compound
possessedbeta-adrenoceptor blocking activity, but was devoid of
α-adrenoceptor blockingacivity. In the isolated tissue of
guinea-pig, isoeugenolol attenuated (-)isoproterenol-induced
positive chronotropic and introtropic effects of theatria
and trachea relaxation responses in a concentration-dependent
manner.The parallel shift to the right of the concentration-
response curve of (-)isoproterenol suggested that this compound
was a beta-adrenoceptor competitiveantagonist. The effect of
isoeugenolol was more potent on the atria than ontracheal
tissues, indicating it had some β1-adrenoceptor selectivity.
On the other hand, isoeugenolol had a mild direct cardiac
depression at high concentrations and was without intrinsic
sympathomimetic activity (ISA). Inaddition, isoeugenolol
produced dose-dependently tracheal relaxant responsesof
carbachol-induced and KCl (75 mM)-induced contraction. In
isolated thoracicaorta of rat,isoeugenolol had potent effect on
the inhibition of phenylephrine-and high K+-induced
contraction. Furthermore, the binding characteristics
ofisoeugenolol were evaluated in [3H]CGP-12177 binding to rat
ventricle, lung,and interscapular brown adipose tissue
(IBAT) membranes. These resultsindicated that isoeugenolol is
a highly selective β1-adrenoceptor antagonistwith
vasorelaxant and tracheal relaxant activity and is devoid
of ISA.Isoeugenolol induced smooth muscle relaxation may
involve decrease entry ofca2+ from the extracellular fluid
and decrease release of ca2+ fromintracellular stores via a
receptor-linked calcium channel and a voltage-dependent
calcium channel.