【摘要】：毒蕈堿型乙酰膽堿受體(M受體)廣泛分布于外周組織和中樞神經(jīng)系統(tǒng),在體內(nèi)各器官組織的功能活動中起著重要的作用。為了尋找有效的M受體選擇性拮抗劑,我所合成了鹽酸苯環(huán)壬酯(CPG)及其類似物,本文主要通過其與大鼠腦蛋白M受體的放射性配體結(jié)合實驗及動物功能實驗(分別以中樞抑制作用、抗腺體分泌作用、抑制離體腸管平滑肌收縮作用及抑制氣管平滑肌收縮作用為觀察指標(biāo)),研究了它們的抗膽堿活性。研究結(jié)果如下: 1.CPG類似物抗膽堿活性: 對離體大鼠腦組織上的M受體親和性 我們運用放射性配體受體結(jié)合實驗方法,研究了CPG類似物與大鼠大腦皮層M受體的親和性。配體結(jié)合實驗表明:這些化合物均能抑制[~3H]QNB與大鼠腦組織M受體的結(jié)合,其與M受體的親和力高低順序為:031221最強,其抑制[~3H]QNB結(jié)合的IC_(50)為4.19×10~(-10)±3.19×10~(-10)M,031022及031124次之,分別為1.24×10~(-9)±9.46×10~(-10)M、2.22×10~(-9)±9.88×10~(-10)M,P010416、031122、031120其IC_(50)在10~(-8)M水平,(S)-SHRZ、8018-C_2H_5Br、SHRZ-CH_3Br、031121、031104在10~(-7)M水平,(R)-SHRZ、8018-CH_3Br、031110最弱,在10~(-6)M水平。 抑制Ach致氣管平滑肌收縮作用比較 溴甲基噻環(huán)壬酯作用較強,8018-C_2H_5Br、031022、8018-CH_3Br、031120次之,031124較弱,031121最弱。 031221、031022、031124抑制氧化震顫素致腺體分泌作用及抑制煙堿引起的小鼠驚厥作用比較 觀察其外周抑制氧化震顫素引起的腺體分泌能力順序為:031221031124031022。031022、031124對抗驚厥的ED_(50)±95%LC(M)分別為8.32±1.56,8.71±2.28。這時小鼠已經(jīng)出現(xiàn)了輕微的毒性反應(yīng)。031221在12mg/kg時仍不能對抗煙堿引起的驚厥。 以上我們可以看出031221、031022、031124等化合物表現(xiàn)出比較明顯的抗膽堿作用,但存不同組織、器官存存著藥效學(xué)上的差異。
[Abstract]:Muscarinic acetylcholine receptor (M receptor) is widely distributed in peripheral tissues and central nervous system (CNS) and plays an important role in the functional activities of organs and tissues in vivo. In order to find an effective selective antagonist for M receptor, I have synthesized diphenyl nonyl hydrochloride (CPG) and its analogues. In this paper, we mainly use the radioactive ligand binding test of rat brain protein M receptor and the animal function experiment (respectively with central inhibitory effect, anti-glandular secretion effect, etc.) Inhibition of contraction of isolated intestinal smooth muscle and inhibition of tracheal smooth muscle contraction were observed. The results are as follows: anticholine activity of 1.CPG analogues: effects of M on isolated rat brain tissue Receptor affinity we use the radioactive ligand receptor binding assay, The affinity of CPG analogues to M receptors in rat cerebral cortex was studied. The ligand binding assay showed that these compounds could inhibit the binding of [~ 3H] QNB to M receptor in rat brain tissue. The order of affinity between [~ 3H] QNB and M receptor was 031221, and the IC_ (50) of [~ 3H] QNB binding inhibition was 4.19 脳 10 ~ (-10) 鹵3.19 脳 10 ~ (-10) M031022 and 031124, respectively. The IC_ (50) was 1.24 脳 10 ~ (-9) 鹵9.46 脳 10 ~ (-10) M ~ (2.22 脳 10 ~ (-9) 鹵9.88 脳 10 ~ (-10) M) P010416031122 ~ (031120). The IC_ (50) level was 10 ~ (-8) M level, (S)-SHRZ,8018-C_2H_5Br,SHRZ-CH_3Br,031121,031104 level was 10 ~ (-7) M level, (R)-SHRZ,8018-CH_3Br,031110 level was the weakest, and it was at 10 ~ (-6) M level. The effect of inhibiting the contraction of tracheal smooth muscle induced by Ach was stronger than that of bromomethyl thiacyclic nonyl ester. 8018-C2H _ (5Br01022) 8018-Ch _ (3) Ch _ (03) 1120 was the second, 031124 was weaker and 031121 was the weakest. The effects of 031221C031022C031124 on the secretion of glandular gland induced by oxytremor and on the convulsion induced by nicotine in mice The order of glandular secretion induced by alltremlin was: 031221031124031022.0322.102222031124 ED_ (50 鹵95%LC (M) was 8.32 鹵1.56n8.71 鹵2.28. By this time the mice had developed a mild toxic reaction. 031221 was still unable to fight nicotine-induced convulsions at 12mg/kg. It can be seen that some compounds such as 031221C031022O031124 have obvious anticholine effect, but different tissues and organs have different pharmacodynamics.
【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2005
【分類號】：Q593.2

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相關(guān)期刊論文 前1條

1 何煦昌;手性藥物的發(fā)展[J];中國醫(yī)藥工業(yè)雜志;1997年11期

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本文編號：2277399