CPG及其类似物抗胆碱作用研究
发布时间：2018-10-17 17:21
【摘要】：毒蕈碱型乙酰胆碱受体(M受体)广泛分布于外周组织和中枢神经系统,在体内各器官组织的功能活动中起着重要的作用。为了寻找有效的M受体选择性拮抗剂,我所合成了盐酸苯环壬酯(CPG)及其类似物,本文主要通过其与大鼠脑蛋白M受体的放射性配体结合实验及动物功能实验(分别以中枢抑制作用、抗腺体分泌作用、抑制离体肠管平滑肌收缩作用及抑制气管平滑肌收缩作用为观察指标),研究了它们的抗胆碱活性。研究结果如下: 1.CPG类似物抗胆碱活性: 对离体大鼠脑组织上的M受体亲和性 我们运用放射性配体受体结合实验方法,研究了CPG类似物与大鼠大脑皮层M受体的亲和性。配体结合实验表明:这些化合物均能抑制[~3H]QNB与大鼠脑组织M受体的结合,其与M受体的亲和力高低顺序为:031221最强,其抑制[~3H]QNB结合的IC_(50)为4.19×10~(-10)±3.19×10~(-10)M,031022及031124次之,分别为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致气管平滑肌收缩作用比较 溴甲基噻环壬酯作用较强,8018-C_2H_5Br、031022、8018-CH_3Br、031120次之,031124较弱,031121最弱。 031221、031022、031124抑制氧化震颤素致腺体分泌作用及抑制烟碱引起的小鼠惊厥作用比较 观察其外周抑制氧化震颤素引起的腺体分泌能力顺序为:031221031124031022。031022、031124对抗惊厥的ED_(50)±95%LC(M)分别为8.32±1.56,8.71±2.28。这时小鼠已经出现了轻微的毒性反应。031221在12mg/kg时仍不能对抗烟碱引起的惊厥。 以上我们可以看出031221、031022、031124等化合物表现出比较明显的抗胆碱作用,但存不同组织、器官存存着药效学上的差异。
[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) 卤3.19 脳 10 ~ (-10) M031022 and 031124, respectively. The IC_ (50) was 1.24 脳 10 ~ (-9) 卤9.46 脳 10 ~ (-10) M ~ (2.22 脳 10 ~ (-9) 卤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 卤95%LC (M) was 8.32 卤1.56n8.71 卤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.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：硕士
【学位授予年份】：2005
【分类号】：Q593.2
本文编号：2277399
[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) 卤3.19 脳 10 ~ (-10) M031022 and 031124, respectively. The IC_ (50) was 1.24 脳 10 ~ (-9) 卤9.46 脳 10 ~ (-10) M ~ (2.22 脳 10 ~ (-9) 卤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 卤95%LC (M) was 8.32 卤1.56n8.71 卤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.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：硕士
【学位授予年份】：2005
【分类号】：Q593.2
【参考文献】
相关期刊论文 前1条
1 何煦昌;手性药物的发展[J];中国医药工业杂志;1997年11期
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