Tuomisto J
Eur J Pharmacol. 1977 Mar 21;42(2):101-6. doi: 10.1016/0014-2999(77)90348-x.
An experimental antidepressive drug, nomifensine, was tested in simultaneous experiments as an inhibitor of the uptake of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) in rat brain synaptosomes. The drug was found to be a very potent inhibitor of NA (Ki 4.7 X 10(-9) M) and DA (Ki 2.6 X 10(-8) M) uptake, but relatively weak inhibitor of 5-HT uptake (Ki appr. 4 X 10(-6) M). 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 of nomifensine slightly decreased the potency, and addition of hydroxy and methoxy 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.
一种实验性抗抑郁药物——诺米芬辛，在同时进行的实验中作为大鼠脑突触体中去甲肾上腺素（NA）、多巴胺（DA）和5-羟色胺（5-HT）摄取抑制剂进行了测试。发现该药物是NA（Ki 4.7×10⁻⁹ M）和DA（Ki 2.6×10⁻⁸ M）摄取的非常有效的抑制剂，但对5-HT摄取的抑制作用相对较弱（Ki约为4×10⁻⁶ M）。根据对多巴胺摄取的动力学研究，这种抑制是竞争性的。时间进程研究表明，抑制百分比并不随时间增加。这一发现表明，该药物的作用机制是抑制膜摄取而非抑制储存。诺米芬辛的3种代谢产物也作为NA和DA摄取抑制剂进行了测试。在诺米芬辛的苯环上添加一个4-羟基会略微降低其效力，而在苯环的3位和4位添加羟基和甲氧基则明显降低其效力。将诺米芬辛的结构与氯米帕明的结构进行了比较。有人认为，对多巴胺和5-HT摄取机制选择性的差异可能归因于两种构象差异：诺米芬辛中的一个苯环可自由旋转，而氯米帕明中则不能；氯米帕明中的叔胺基团位于柔性侧链中，而在诺米芬辛中则刚性连接。
