Dopamine-sensitive adenylate cyclase in mammalian brain: a possible site of action of antipsychotic drugs.
Dopamine-sensitive adenylate cyclase in mammalian brain: a possible site of action of antipsychotic drugs.
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哺乳动物大脑中的多巴胺敏感腺苷酸环化酶：抗精神病药物的可能作用位点。
DOI：
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发表时间：
1974
影响因子：
11.1
通讯作者：
P. Greengard
中科院分区：
文献类型：
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作者：
Y. Clement;J. Kebabian;G. Petzold;P. Greengard
腺苷酸环化酶（EC 4.6.1.1）在一些哺乳动物的嗅结节、伏隔核和尾状核中被发现有选择性地受到低浓度多巴胺的刺激。几种不同类型的治疗精神分裂症的有效药物（抗精神病药物）是有效抑制多巴胺对这些不同区域的酶的刺激。研究的药物包括吩噻嗪、丁苯酮和二苯二氮卓类药物的代表。这些抗精神病药物对多巴胺的抑制是竞争性的。测试中最有效的抗精神病药物是氟非那嗪，其计算出的抑制常数（K(i)）约为5 x 10(-9) m。对于测试的几种药物中的每一种，来自嗅结节的酶的K(i)与来自尾状核的酶的K(i)相似。一些化合物在结构上与精神活性吩噻嗪类药物密切相关，但在临床上几乎没有抗精神病或锥体外系作用，它们作为多巴胺刺激的腺苷酸环化酶活性抑制剂的相对效力较低。这些结果，连同其他数据一起考虑，提出了这样一种可能性，即这些抗精神病药物的治疗效果以及锥体外系副作用，可能至少部分归因于它们能够阻断多巴胺对人脑中特定多巴胺敏感的腺苷酸环化酶的激活。
Adenylate cyclase (EC 4.6.1.1), selectively stimulated by low concentrations of dopamine, has been found in the olfactory tubercle, the nucleus accumbens, and the caudate nucleus of several mammalian species. Several different classes of drugs effective in the treatment of schizophrenia (antipsychotic drugs) were potent inhibitors of the stimulation by dopamine of the enzyme from these various regions. The drugs studied included representatives of the phenothiazine, butyrophenone, and dibenzodiazepine classes. The inhibition by these antipsychotic drugs was competitive with respect to dopamine. The most potent of the antipsychotic agents tested was fluphenazine, which had a calculated inhibition constant (K(i)) of about 5 x 10(-9) M. For each of several drugs tested, the K(i) for the enzyme from the olfactory tubercle was similar to that for the enzyme from the caudate nucleus. Several compounds closely related structurally to the psychoactive phenothiazines, but which have little or no antipsychotic or extrapyramidal actions clinically, had low relative potencies as inhibitors of dopamine-stimulated adenylate cyclase activity. The results, considered together with other data, raise the possibility that the therapeutic effects, as well as the extrapyramidal side effects, of these antipsychotic agents may be attributable, at least in part, to their ability to block the activation by dopamine of specific dopamine-sensitive adenylate cyclases in the human brain.