Indirect parasympathomimetic activity of metoclopramide: reversible inhibition of cholinesterases from human central nervous system and blood.
Indirect parasympathomimetic activity of metoclopramide: reversible inhibition of cholinesterases from human central nervous system and blood.
复制标题
甲氧氯普胺的间接拟副交感活性：可逆地抑制人中枢神经系统和血液中的胆碱酯酶。
DOI：
10.1006/phrs.1996.9999
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发表时间：
1996
影响因子：
9.3
通讯作者：
R. Zech
中科院分区：
文献类型：
--
作者：
J. Chemnitius;K. H. Haselmeyer;B. Gonska;H. Kreuzer;R. Zech
用分光光度法研究了多巴胺D2受体拮抗剂甲氧氯普胺（MCP）对人红细胞和尾状核乙酰胆碱酯酶（AChE; EC 3.1.1.7）同工酶及人血清胆碱酯酶（ChE; EC 3.1.1.8）的抑制作用。MCP浓度在试验中变化从0.30 μ M到0.15 mM。所有研究的同工酶抑制甲氧氯普胺在浓度依赖性的方式。MCP抑制AChE和胆碱酯酶同工酶是不依赖于时间和可逆的类型。双倒数图的反应速度对不同的ASCh浓度显示，红细胞和尾状核的AChE同工酶，MCP降低最大反应速度（Vmax）和底物亲和力（表观米氏常数，KM，增加）。因此，MCP抑制AChE同工酶的混合竞争/非竞争型。可逆竞争性（Ki）和非竞争性（Ki）抑制MCP常数可以确定为红细胞乙酰胆碱酯酶（Ki = 10 μ M; Ki = 70 μ M）和尾状核乙酰胆碱酯酶（Ki = 9.3 μ M; Ki = 82 μ M）。相反，MCP抑制AChE同工酶，可逆的MCP抑制人血清胆碱酯酶的类型依赖于底物浓度。如果底物浓度超过0.2 mM，则MCP抑制为竞争性/非竞争性混合型（Ki = 0.19 μ M; Ki = 1.4 μ M）。如果底物浓度低于0.2 mM（Ki（u）= 1.0 μ M），则MCP抑制为非竞争性类型。混合型MCP抑制胆碱酯酶同工酶，因为它的非竞争性成分，只能部分克服增加浓度的胆碱能递质乙酰胆碱（ACh）。由于静脉输注，MCP在人体内的血浆峰浓度达到4 μ M，MCP在体内对ACh水解的抑制可能有助于该物质的促动力和止吐作用及其锥体外系副作用。
Inhibitory effects of the dopamine D2-receptor antagonistic benzamide compound metoclopramide (MCP) on acetylcholinesterase (AChE; EC 3.1.1.7) isoenzymes of both erythrocytes and human caudate nucleus and on human serum cholinesterase (ChE; EC 3.1.1.8) were studied in vitro using a spectrophotometric assay with acetylthiocholine (ASCh) as substrate. MCP concentrations in the assays varied from 0.30 microM to 0.15 mM. All isoenzymes studied were inhibited by metoclopramide in a concentration-dependent manner. MCP inhibition of AChE and ChE isoenzymes was not time-dependent and of the reversible type. Double reciprocal plots of the reaction velocity against varying ASCh concentrations revealed that, for AChE isoenzymes of erythrocytes and of the caudate nucleus, MCP reduced both maximal reaction velocity (Vmax) and substrate affinity (apparent Michaelis constant, KM, increased). Thus, MCP inhibition of both AChE isoenzymes was of mixed competitive/non-competitive type. MCP constants for reversible competitive (Ki) and non-competitive (Ki) inhibition could be determined for erythrocyte AChE (Ki = 10 microM; Ki = 70 microM) and caudate nucleus AChE (Ki = 9.3 microM; Ki = 82 microM). In contrast to MCP inhibition of AChE isoenzymes, the type of reversible MCP inhibition of human serum ChE depended on substrate concentration. If substrate concentration exceeded 0.2 mM, MCP inhibition was of mixed competitive/non-competitive type (Ki = 0.19 microM; Ki = 1.4 microM). MCP inhibition was of uncompetitive type, if substrate concentration was below 0.2 mM (Ki(u) = 1.0 microM). The mixed-type MCP inhibition of cholinesterase isoenzymes, because of its non-competitive component, can only partially be overcome by increased concentrations of the cholinergic transmitter acetylcholine (ACh). Since, with intravenous infusions, peak MCP plasma concentrations in humans reach 4 microM, MCP inhibition of ACh hydrolysis in vivo may contribute both to prokinetic and anti-emetic actions of the substance and to its extrapyramidal side effects.