SOME DIFFERENTIAL-EFFECTS OF 4-DIPHENYLACETOXY-N-(2-CHLOROETHYL)-PIPERIDINE HYDROCHLORIDE ON GUINEA-PIG ATRIA AND ILEUM
SOME DIFFERENTIAL-EFFECTS OF 4-DIPHENYLACETOXY-N-(2-CHLOROETHYL)-PIPERIDINE HYDROCHLORIDE ON GUINEA-PIG ATRIA AND ILEUM
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DOI：
10.1111/j.2042-7158.1990.tb06581.x
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发表时间：
1990-06-01
影响因子：
3.3
通讯作者：
VEALE, MA
中科院分区：
文献类型：
--
作者：
BARLOW, RB;SHEPHERD, MK;VEALE, MA
4-二苯基乙酰氧基-N-（2-氯乙基）-哌啶盐酸盐（I）在中性pH下环化形成氮丙啶鎓盐。盐的形成和分解取决于温度（在25至37 ℃的范围内）。C）。在30 ℃的溶液中，C，peal水平，对应于60-80%的转化率，达到约60分钟后，半衰期超过100分钟。在0.9%NaCl的存在下，转化率降低到45- 60%。I不可逆地阻断豚鼠回肠和心房的毒蕈碱受体，并且在回肠上用10 nM I产生的剂量比可能是心房上的剂量比的约100倍。在暴露于I的溶液（预先制备15-20分钟，以充分建立氮丙啶离子的形成）约30分钟后，log（剂量比）对时间的图是线性的，并且用两种不同的激动剂卡巴胆碱和乙氧基乙基三甲基铵获得类似的图。对于回肠的结果，线的外推表明它不是从零开始（剂量比=1）：这是因为初始相对快速的可逆阻滞。该早期阶段类似于使用10 nM 4DAMP甲溴化物在回肠上观察到的，4DAMP甲溴化物是一种竞争性拮抗剂，因此可能是由氮丙啶离子的竞争性阻断引起的，氮丙啶离子与4DAMP甲盐非常相似。随后的不可逆相应该是由受体的烷基化引起的。I易于制备，应该是研究毒蕈碱受体的有价值的工具。
4-Diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride (I) cyclizes at neutral pH to form an aziridinium salt. The formation and breakdown of the salt depend on the temperature (in the range 25 to 37.degree. C). In solution at 30.degree. C, peal levels, corresponding to 60-80% conversion, are reached after around 60 min and half-life exceeds 100 min. In the presence of 0.9% NaCl conversion was reduced to 45-60%. I blocks muscarinic receptors in guinea-pig ileum and atria irreversibly and it is possible to produce dose-ratios on ileum with 10 nM I which are about 100 times those on atria. After about 30 min exposure to solutions of I (prepared 15-20 min previously so that formation of aziridinium ions is well-established) the graph of log (dose-ratio) against time is linear and similar plots were obtained with two different agonists, carbachol and ethoxyethyltrimethylammonium. With results for the ileum, extrapolation of the line suggests that it does not start from zero (dose-ratio =1): this is because of an initial relatively rapid reversible block. This early phase is similar to that seen on ileum with with 10 nM 4DAMP methobromide, which is a competitive antagonist, so is probably caused by competitive block by the aziridinium ion, which closely resembles 4DAMP metho-salts. The subsequent irreversible phase should be caused by alkylation of the receptors. I is easy to make and should be a valuable tool for the study of muscarinic receptors.