六氢苄基福达平对M2和M3毒蕈碱受体的选择性阻断作用及其与扎米芬净的比较。

Selective blockade of M2 and M3 muscarinic receptors by hexahydrobenzyl-fourdapine and a comparison with zamifenacin.

作者信息

Barlow R B, Bond S M, Branthwaite A G, Jackson O, McQueen D S, Smith K M, Smith P J

机构信息

University Department of Pharmacology, Edinburgh.

出版信息

Br J Pharmacol. 1995 Dec;116(7):2897-902. doi: 10.1111/j.1476-5381.1995.tb15942.x.

DOI:10.1111/j.1476-5381.1995.tb15942.x

PMID:8680722

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1909210/

Abstract

4-Diphenylacetoxy-N-cyclohexylmethyl-piperidine HCl (hexahydro-benz-4DAP) is more active as an antagonist of carbachol at receptors in guinea-pig isolated ileum, log K (pA2) = 6.64 +/- 0.14 (s.e. 7 results), than at receptors in guinea-pig isolated atria, log K = 5.43 +/- 0.14 (7). In the presence of neostigmine bromide (0.2 microM) the value for atria was 5.62 +/- 0.19 (4), so the lower activity on atria cannot be attributed to hydrolysis of the compound by cholinesterases present in this tissue. 2. The limit of solubility of the free base in Krebs solution (pH 7.6) is about 50 microM for both hexahydrobenz-4DAP and benzyl-fourdapine (benz-4DAP). 3. In experiments on guinea-pig isolated ileum with hexahydro-benz-4DAP given together with 4-DAMP methobromide, the combined dose-ratio was consistent with competition: similar results were obtained with benz-4DAP. 4. In rats anaesthetized with pentobarbitone, hexahydro-benz-4DAP antagonized the effects of bethanechol on blood-pressure in doses that had little effect on heart rate or airflow. There was a limit to the effect which could be obtained, however, and the slopes of the Schild plots were less than one. The effects on rat blood-pressure had a half-life of at least 30 min. 5. In similar experiments with zamifenacin the slopes of the Schild plots were close to 1 and the compound was 10 to 20 times as active on blood-pressure at it was on heart-rate. 6. The limited solubility of the base probably accounts for the flat Schild plots obtained with hexahydro-benz-4DAP, which had about 10 fold selectivity for effects on blood-pressure and was more active than expected from tests on isolated ileum.

摘要

4-二苯基乙酰氧基-N-环己基甲基哌啶盐酸盐（六氢苯-4DAP）作为豚鼠离体回肠中卡巴胆碱受体的拮抗剂比在豚鼠离体心房受体上更具活性，log K（pA2）= 6.64±0.14（标准误，7次结果），而在豚鼠离体心房受体上log K = 5.43±0.14（7次结果）。在新斯的明溴化物（0.2微摩尔）存在下，心房的值为5.62±0.19（4次结果），所以在心房上较低的活性不能归因于该组织中存在的胆碱酯酶对化合物的水解。2. 对于六氢苯-4DAP和苄基-4DAP（苯-4DAP），游离碱在克雷布斯溶液（pH 7.6）中的溶解度极限约为50微摩尔。3. 在豚鼠离体回肠实验中，将六氢苯-4DAP与4-二甲基氨基吡啶甲溴化物一起给药，联合剂量比符合竞争关系：苯-4DAP也得到了类似结果。4. 在戊巴比妥麻醉的大鼠中，六氢苯-4DAP拮抗氨甲酰甲胆碱对血压的影响，所用剂量对心率或气流影响很小。然而，所能获得的效果存在限度，并且希尔曲线的斜率小于1。对大鼠血压的影响半衰期至少为30分钟。5. 在使用扎非那新的类似实验中，希尔曲线的斜率接近1，并且该化合物对血压的活性比对心率的活性高10至20倍。6. 碱的有限溶解度可能解释了用六氢苯-4DAP得到的平坦希尔曲线，该化合物对血压影响具有约10倍的选择性，并且比在离体回肠试验中预期的更具活性。