Nomifensine and its derivatives as possible tools for studying amine uptake.
Nomifensine and its derivatives as possible tools for studying amine uptake.
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诺米芬辛及其衍生物作为研究胺吸收的可能工具。
DOI：
10.1016/0014-2999(77)90348-x
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发表时间：
1977
影响因子：
5
通讯作者：
J. Tuomisto
中科院分区：
文献类型：
--
作者：
J. Tuomisto
在同步实验中，测试了一种实验性抗抑郁药nomifensive作为大鼠脑突触体摄取非肾上腺素（NA）、多巴胺（DA）和5-羟色胺（5-HT）的抑制剂。研究发现该药物是一种非常有效的Na（Ki4.7 × 10 - 9 M）和DA（Ki2.6 × 10 - 8 M）吸收抑制剂，但对5-HT吸收的抑制剂相对较弱（Kiappr. 4 × 10−6M）。根据多巴胺摄取动力学研究，抑制是竞争性的。时程研究表明，抑制百分比不随时间增加。这一发现表明，抑制膜摄取而不是抑制储存是这种药物的作用机制。诺米芬辛的3种代谢产物也被测试为NA和Da摄取的抑制剂。在苯环或诺米芬辛上添加4-羟基略微降低了效力，并且在苯环的3位和4位上添加羟基和甲氧基明显降低了效力。诺米芬辛的结构与氯丙咪嗪的结构进行了比较。有人建议，多巴胺和5-HT摄取机制的选择性的差异可能是由于2构象的差异：苯环之一是自由旋转的诺米芬辛，但不是在氯丙咪嗪，叔胺基团是在一个灵活的侧链氯丙咪嗪，但严格绑定在诺米芬辛。
An experimental antidepressive drug, nomifensive, was tested in simultaneous experiments as an inhibitor of the uptake of nonradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) in rat brain synaptosomes. The drug was found to be a very potent inhibitor of Na (Ki4.7 × 10−9M) and DA (Ki2.6 × 10−8M) uptake, but relatively weak inhibitor of 5-HT uptake (Kiappr. 4 × 10−6M). According to kinetic studies on dopamine uptake, the inhibition was competitive. Time course studies indicated that the percentage inhibition did not increase with time. This finding suggests that inhibition of membrane uptake rather than inhibition of storage is the mechanism of action of this drug. 3 metabolites of nomifensine were also tested as inhibitors of NA and Da uptake. The addition of a 4-hydroxy group to the phenyl ring or nomifensine slightly decreased the potency, and addition of hydroxyl and methoxyl groups to the positions 3 and 4 in the phenyl ring, clearly decreased the potency. The structure of nomifensine is compared to that of chlorimipramine. It is suggested that the differences in selectivity as to dopamine and 5-HT uptake mechanisms might be due to 2 conformational differences: one of the phenyl rings is freely rotating in nomifensine but not in chlorimipramine, and the tertiary amine group is in a flexible side chain in chlorimipramine but rigidly tied in nomifensine.