Studies of flavin-adenine dinucleotide-requiring enzymes and phenothiazines. 3. Inhibition kinetics with highly purified D-amino acid oxidase.
Studies of flavin-adenine dinucleotide-requiring enzymes and phenothiazines. 3. Inhibition kinetics with highly purified D-amino acid oxidase.
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黄素腺嘌呤二核苷酸需求酶和吩噻嗪的研究。
DOI：
10.1016/0006-2952(67)90053-6
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发表时间：
1967
影响因子：
5.8
通讯作者：
S. R. Harris
中科院分区：
文献类型：
--
作者：
S. Gabay;S. R. Harris
研究了多种吩噻嗪衍生物对高纯度氨基酸氧化酶脱酶制剂（比活性300-330 μl O2/min/mg protein）的抑制作用。只有具有抗精神病活性的衍生物被发现是抑制剂。抑制是辅酶竞争性的，可以计算出以下Ki值：(1)氯丙嗪，5 × 10−5M;(2)三氟丙嗪，3 × 10−5M；(3)奋那嗪，2.7 × 10−5M；(4)氟非那嗪，2.4 × 10−5M；(5)三氟拉嗪，2.0 × 10−5M；(6)硫硝嗪，1.6 × 10−5M。这些化合物的抑制能力通常与它们在抗精神病治疗中的相对临床疗效和效力相一致。作为镇静剂的吩噻嗪类衍生物（丙嗪、三甲嗪、异丙嗪以及氯丙嗪和硫胺嘧啶的亚砜）即使在4 × 10−4M的浓度下也没有抑制氨基酸氧化酶的作用；丙咪嗪也是如此，它是一种抗抑郁药，结构上与吩噻嗪相似。然而，噻吩衍生物氯原噻烯在抗精神病治疗中具有明确的效用，也是一种辅酶竞争性抑制剂，其akiv为4 × 10−5M。由于ki的浓度低到足以代表体内可能遇到的浓度，吩噻嗪可以通过抑制黄酮类酶起作用的假设似乎获得了进一步的意义。
The inhibition of a very highly purifiedd-amino acid oxidase apoenzyme preparation (specific activity: 300–330 μl O2/min/mg protein) by a variety of phenothiazine derivatives has been studied. Only derivatives possessing antipsychotic activity were found to be inhibitors. The inhibition was coenzyme-competitive and the following Ki's could be calculated: (1) chlorpromazine, 5 × 10−5M, (2) triflupromazine, 3 × 10−5M; (3) perphenazine, 2.7 × 10−5M;(4) fluphenazine, 2.4 × 10−5M; (5) trifluoperazine, 2.0 × 10−5M; and (6) thioridazine, 1.6 × 10−5M. The inhibitory capacities of these compounds were generally in good agreement with their relative clinical efficacy and potency in antipsychotic therapy. Phenothiazine derivatives with little or no clinical efficacy as tranquilizing agents (promazine, trimeprazine, promethazine, and the sulfoxides of chlorpromazine and thioridazine) did not inhibitd-amino acid oxidase even in concentrations as high as 4 × 10−4M; neither did imipramine, an antidepressant which is structually similar to the phenothiazines. However, chlorprothixene, a thiaxanthene derivative with definite utility in antipsychotic management, was also a coenzymecompetitive inhibitor and had aKiof 4 × 10−5M. Since theKi′s were low enough to represent concentrations that might be encounteredin vivo, the hypothesis that phenothiazines could act by inhibiting flavoenzymes appears to gain further significance.