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研究生:呂宜蓉
研究生(外文):Leu, Yi-Rong
論文名稱:Flavone類衍生物之氣管鬆弛作用及其結構-活性的關係
論文名稱(外文):Tracheal relaxant effects of flavone derivatives and their structure-activity relationships
指導教授:柯文昌柯文昌引用關係
指導教授(外文):Ko Wun-Chang
學位類別:碩士
校院名稱:台北醫學院
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:1997
畢業學年度:85
語文別:中文
論文頁數:57
中文關鍵詞:構造-活性關係作用機轉外鈣內流內鈣釋放
外文關鍵詞:flavone 類衍生物phosphodiesteraseflavone derivativesstflavone derivativesstructure-activity relationshipaction mechanismcalcium influxcalcium releasephosphodiesterase
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我們分析十二種 flavone 類衍生物,包括 6-hydroxyflavone,
7-hydroxyflavone, chrysin, baicalein, luteolin,
5-methoxyflavone, 6-methoxyflavone, diosmetin, diosmin,
acacetin, tangeretin 及 luteolin-7-glucoside 對 histamine (30 μ
M) 預縮的離體天竺鼠氣管,產生劑量依存性的鬆弛作用,由其 IC50 得
知其活性大致依序為6-hydroxyflavone, 7-hydroxyflavone, luteolin,
tangeretin > chrysin, 5-methoxyflavone, > baicalein, acacetin,
luteolin-7-glucoside > 6-methoxyflavone, diosmetin, diosmin.,
其 structure-activity relationship (SAR) 如下: (a) 第 7 位之 OH
接上 sugar,如 luteolin 變成 luteolin-7-glucoside﹔及diosmetin 變
成 diosmin, 則活性顯著下降; (b) 第 6 或 3' 及位之 H 被 OH 取代,
如 flavone 變成 6-hydroxyflavone 或 apigenin 變成 luteolin 活性
皆明顯增加,但第 7 位之 H 被 OH 取代,如 flavone 變成
7-hydroxyflavone 則活性不變,若第 5 及第 7 位之 H 同時被 OH 取代
,如 flavone 變成 chrysin 亦然,反觀第5, 6 及 7 位之 H 被 OH 取
代,如 flavone 變成 baicalein, 或原先已在第 5 或 7 位有 OH 只單
獨在第 6 位以 OH 取代 H 如 chrysin 變成 baicalein 則活性會下降;
(c) 第 5 位之 H 被 OCH3 取代﹐如 flavone 變成 5-methoxyflavone
或進一步多位 H 被 OCH3 取代如 5-methoxyflavone 變成 tangeretin
活性不變,但然而第 6 位之 H 被 OCH3 取代,如 flavone 變成
6-methoxyflavone 則活性明顯下降﹔(d) 第 6 位之 OH 被 OCH3 取代如
6-hydroxyflavone 變成 6-methoxyflavone;或第 4' 位之 OH 被 OCH3
取代,如 luteolin 及 apigenin 分別變成 diosmetin 及 acacetin﹐
活性會明顯下降。上述十二種flavone類衍生物中較強的六種,包括
6-hydroxyflavone, 7-hydroxyflavone, chrysin, luteolin,
5-methoxyflavone 及 tangeretin 預處理均能非競爭性地對抗累加
histamine, carbachol 或 KCl 引起的收縮,它們的 pD2'值大致上均有
意義地小於它們的 -logIC50 值, 顯示他們抑制內鈣釋放的能力小於抑
制外鈣內流的能力。在高鉀 (60 mM)無鈣溶液中,它們也能非競爭性地抑
制累加外鈣引起的收縮,也對 histamine (30 μM)預縮而nifedipine
(10 μM) 引起的最大鬆弛產生更進一步的鬆弛,表示除了能抑制
voltage (VOC) 及/或 receptor operated calcium channels (ROC) 外
,尚有其他的鬆弛機轉。然而除了下列三點外,這六種flavone 類衍生物
的鬆弛反應並不因上皮細胞去除或 propranolol (1 μM)、
glibenclamide (10 μM)、methylene blue (25 μM) 及
2',5'-dideoxyadenosine (10 (M) 存在的影響,(一) 6-hydroxyflavone
在 2',5'-dideoxyadenosine (10 μM) 存在下,能使 6-hydroxyflavone
的對數濃度-反應曲線向右平行移動,表示 6-hydroxyflavone 可能會活
化 adenylate cyclase ;(二) luteolin 在 methylene blue (25 μM)
存在下,能使 luteolin 的對數濃度-反應曲線向右移動,表示 luteolin
可能會活化 guanylate cyclase,(三) 5-methoxyflavone 在
glibenclamide (10 μM) 存在下,能使 5-methoxyflavone 的對數濃度-
反應曲線向左平行移動,原因不明。6-hydroxyflavone (20 μM) 及
luteolin (20 μM) 能使 forskolin 的對數濃度-反應曲線向左平行移動
,而使 forskolin 的 pD2 值增加, 6-hydroxyflavone (10, 20 μM),
luteolin (20 μM) ,5-methoxyflavone (20 μM) 及 tangeretin (20
μM)能使 nitroprusside 的對數濃度-反應曲線向左平行移動,而使
nitroprusside 的 pD2 值增加。顯示6-hydroxyflavone, luteolin,
5-methoxyflavone 及 tangeretin 可能有抑制 phosphodiesterase
(PDE) 的作用,由 PDE 的直接測定得知,luteolin 在 100 μM 及 300
μM 會大大地抑制 cAMP-PDE 及 cGMP-PDE 的活性,而抑制 cGMP-PDE 之
程度有意義地大於抑制 cAMP-PDE;其他 flavone 如 6-hydroxyflavone,
7-hydroxyflavone, chrysin, 5-methoxyflavone, 及tangeretin 雖能抑
制 cAMP-PDE 及 cGMP-PDE, 但並不強,即使 300 μM, 尚不完全 ( <
70 % ); 然而 6-hydroxyflavone 100 μM 抑制 cAMP-PDE 之程度有意
義地大於抑制 cGMP-PDE 以及 tangeretin 300 μM 抑制 cGMP-PDE 之程
度有意義地大於抑制 cAMP-PDE。綜觀以上,luteolin 的鬆弛機轉大部份
來自對 PDE 的抑制,特別對 cGMP-PDE的抑制較具選擇性,6-
hydroxyflavone 可能來自活化 adenylate cyclase 及輕微的 PDE 抑制
作用,其他四種對 PDE 僅具輕微的抑制作用; 以上六種均能抑制外鈣流
入及內鈣釋放,除 leteolin 外,對外鈣流入的抑制均比對內鈣釋放的抑
制較具選擇性。

The tracheal relaxant activities and action mechanisms of
flavone derivatives, including 6-hydroxyflavone,
7-hydroxyflavone, chrysin, baicalein, luteolin,
5-methoxyflavone, 6-methoxyflavone, diosmetin, diosmin,
acacetin, tangeretin and luteolin-7-glucoside were analyzed to
understand their structure-activity relationships (SAR). The
above tweleve flavones concentration-dependently relaxed the
histamine (30 μM)-, carbachol (0.2 μM)-, and KCl (30 mM)-
induced precontractions of isolated guinea-pig trachea. Roughly,
according to their IC50 values, the order of their relaxant
potency was 6-hydroxyflavone, 7-hydroxyflavone, luteolin,
tangeretin > chrysin, 5-methoxyflavone, > baicalein, acacetin,
luteolin-7-glucoside > 6-methoxyflavone, diosmetin, diosmin. The
SAR was concluded as follows: (a) The substitution of sugar
group at position 7, such as luteolin to luteolin-7-glucoside
and diosmetin to diosmin, reduced their relaxant activities ;
(b) The substitution of OH group at position 6 or 3', such as
flavone to 6-hydroxyflavone or apigenin to luteolin,
respectively, increased their relaxant activity, but at position
7 , such as flavone to 7-hydroxyflavone, and even at both
positions 5 and 7, such as flavone to chrysin did not change its
relaxant activity. On the contrary, substitution of OH group at
positions 5, 6, and 7, such as flavone to baicalein, or at
position 6 of 5, 7-dihydroxyflavone compound, such as chrysin to
baicalein decreased their relaxant activities. (c) The
substitution of OCH3 group at position 5, such as flavone to
5-methoxyflavone, or further substitution at many other
positions, such as 5-methoxyflavone to tangeretin, did not
change its relaxant activity, whereas at position 6, such as
flavone to 6-methoxyflavone attenuate its relaxant activity. (d)
The substitution of OCH3 to OH group at position 6, such as
6-hydroxyflavone to 6-methoxyflavone or at position 4', such as
luteolin and apigenine to diosmetin and acacetin, respectively,
markedly decreased their relaxant activity. The preincubation of
the six more potent flavones, 6-hydroxyflavone,
7-hydroxyflavone, chrysin, luteolin, 5-methoxyflavone or
tangeretin among the above twelve compounds, non-competitively
inhibited contraction induced by cumulatively adding histamine,
carbachol or KCl in isolated guinea-pig trachea. In general,
their pD2' values were significantly less than their -logIC50
values. Therefore, their abilities of inhibition on calcium
release from intracellular calcium stores may be less potent
than those of suppression on calcium influx from extracellular
fluid. They also non-competitively inhibited contractions of the
trachealis induced by cumulatively adding calcium into high
potassium (60 mM)-Ca2+ free medium in the trachealis. After
maximal relaxation on histamine (30 μM)-induced precontraction
by nifedipine (10 μM), they caused further relaxation of the
trachealis. The result suggests that they may have other
relaxing mechanisms in addition to inhibiting voltage (VOC) and/
or receptor operated calcium channels (ROC) in the trachealis.
With exception of the following three flavones, their relaxant
responses were not affected by the removal of epithelial cells
or by the preincubation of propranolol (1 μM), glibenclamide
(10 μM), methylene blue (25 μM) or 2',5'-dideoxyadenosine (10
μM), suggesting their relaxing effects may not be related to
epithelium derived relaxing factor(s), activation of β-
adrenoreceptor, opening of ATP-sensitive potassium channels, or
activation of guanylate cyclase or adenylate cyclase. First,
2',5'-dideoxyadenosine (10 μM) parallelly rightward shifted the
log concentration-response curve of 6-hydroxyflavone, suggesting
that 6-hydroxyflavone may activate adenylate cyclase. Secondary,
methylene blue (25 μM) parallelly to the rightward shifted the
log concentration-response curve of luteolin, suggesting that
luteolin may activate guanylate cyclase. Third, glibenclamide
(10 μM) parallelly leftward shifted the log concentration-
response curve of 5-methoxyflavone with unknown mechanism.
6-hydroxyflavone (20 μM) and luteolin (20 μM) parallelly
leftward shifted the log concentration-response curve of
forskolin, and enhance the pD2 value of forskolin.
6-hydroxyflavone (10, 20 μM), luteolin (20 μM),
5-methoxyflavone (20 μM) and tangeretin (20 μM) also
parallelly leftward shifted the log concentration-response curve
of nitroprusside and enhanced the pD2 value of nitroprusside. It
seems that 6-hydroxyflavone, luteolin, 5-methoxyflavone, and
tangeretin may inhibit phosphodiesterase (PDE) activity. From
determination of PDE activity, we found that luteolin (100 and
300 μM) markedly inhibited cAMP-PDE and cGMP-PDE activity and
that the inhibition on cGMP-PDE activity was significantly
larger than on that of cAMP-PDE. Other flavone derivatives, such
as 6-hydroxyflavone, 7-hydroxyflavone, chrysin,
5-methoxyflavone, and tangeretin partially inhibited cAMP-PDE
and cGMP-PDE activities. Even at a high concentration such as
300 μM the inhibition was less than 70%. However, the
inhibition on cAMP-PDE activity by 6-hydroxyflavone (100 μM)
was significantly larger than that on cGMP-PDE, but the
inhibition on cGMP-PDE activity by tangeretin (300 μM) was
significantly larger than that on cAMP-PDE. These results
suggest that the relaxant mechanism of luteolin is mainly the
inhibition on PDE activity, especially on cGMP-PDE activity.
6-Hydroxyflavone may activate adenylate cyclase and slightly
inhibit PDE activity. 7-Hydroxyflavone, chrysin,
5-methoxyflavone and tangeretin only slightly inhibit the
activity of PDE. The above six flavones inhibit both calcium
influx and calcium release from calcium store. In addition to
luteolin, these six flavones may inhibit calcium influx more
markedly than that on calcium release.

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