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首页> 外文期刊>Journal of Medicinal Chemistry >5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activity: a new approach toward efficient antidepressants.
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5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activity: a new approach toward efficient antidepressants.

机译：具有5-HT（1B / 1D）拮抗活性的5-HT再摄取抑制剂：一种有效的抗抑郁药的新方法。

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As part of our research program toward new, potential antidepressants, a series of unsymmetrical ureas has been prepared and evaluated as 5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activities. The design of these compounds was based on coupling of various indole derivatives, previously shown to inhibit 5-HT reuptake, to three different aniline moieties, which are part of known 5-HT(1B/1D) ligands. Binding experiments in rat frontal cortex using [(125)I]iodocyanopindolol, in calf striatum using [(3)H]5-HT, and in rat hippocampus using [(3)H]8-OH-DPAT as radioligands, respectively, revealed significantly higher affinity at the 5-HT(1B) receptor as compared to the affinities for the 5-HT(1A) and 5-HT(1D) receptors for a number of compounds, among them 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (5), the corresponding 4-fluoro-1H-indol-3-yl analogue 21a, and the corresponding 6-fluoro-1H-indol-3-yl analogue 21b. Conformational restriction of the aniline moiety in 5 only slightly enhanced the 5-HT(1B) affinity, whereas introduction of an aniline moiety with higher conformational flexibility resulted in a less potent 5-HT(1B) receptor ligand as compared to 5. The functional 5-HT(1B/1D) antagonistic activity was investigated using the rabbit saphenous vein model as well as the [(3)H]5-HT release from guinea pig cortical slices. All new compounds tested in the rabbit saphenous vein model were shown to antagonize the sumatriptan-evoked contractile responses with pA(2) values ranging from 7.3 to 8.7. These observations were consistent with the results of the cortical slice model, in which the ureas were found to block the sumatriptan-induced inhibition of potassium-evoked [(3)H]5-HT release. The 5-HT reuptake inhibition of the ureas determined in rat brain synaptosomes was found to be either increased or decreased as compared to the uncoupled indole derivatives indicating that the reuptake inhibition shown by the ureas is not only due to the indole part but also affected by the aniline moiety of the molecule. Among this series of compounds described the ureas 5, 21a, and 21b seem to be the most interesting candidates showing both 5-HT reuptake inhibition and 5-HT(1B/1D) antagonism in vitro. This dual pharmacological profile should in theory lead to a pronounced enhancement in serotonergic neurotransmission and consequently to a more efficient treatment of depression.
机译：作为我们针对新型潜在抗抑郁药的研究计划的一部分，已制备了一系列不对称尿素，并将其评估为具有5-HT（1B / 1D）拮抗活性的5-HT再摄取抑制剂。这些化合物的设计基于各种吲哚衍生物（先前已显示出抑制5-HT再摄取的作用）与已知的5-HT（1B / 1D）配体的三个不同的苯胺部分偶联的基础。分别在大鼠额叶皮层中使用[（125）I]碘氰基吲哚醇，在小腿纹状体中使用[（3）H] 5-HT以及在大鼠海马体中使用[（3）H] 8-OH-DPAT作为放射性配体的结合实验，与5-HT（1A）和5-HT（1D）受体对许多化合物的亲和力相比，其中5-HT（1B）受体的亲和力显着更高，其中包括4-（5-fluoro-1H -吲哚-3-基）哌啶-1-甲酸[4-甲氧基-3-（4-甲基哌嗪-1-基）苯基]酰胺（5），相应的4-氟-1H-吲哚-3-基类似物21a，和相应的6-氟-1H-吲哚-3-基类似物21b。苯胺部分在5中的构象限制仅略微增强了5-HT（1B）亲和力，而与5相比，引入具有更高构象柔性的苯胺部分导致了效力更弱的5-HT（1B）受体配体。研究了5-HT（1B / 1D）的拮抗活性，使用了兔大隐静脉模型以及从豚鼠皮层切片中释放的[（3）H] 5-HT。在兔大隐静脉模型中测试的所有新化合物均显示与舒马曲坦诱发的收缩反应拮抗，pA（2）值范围为7.3至8.7。这些观察结果与皮质切片模型的结果一致，在该模型中，尿素被发现阻止舒马曲坦诱导的钾诱发的[（3）H] 5-HT释放抑制。发现与未偶合的吲哚衍生物相比，在大鼠脑突触体中测定的尿素对5-HT的再摄取抑制作用增加或减少，这表明尿素显示的再摄取抑制作用不仅是由于吲哚部分引起的，而且还受到分子的苯胺部分。在描述的这一系列化合物中，脲5、21a和21b似乎是最有趣的候选物，在体外显示出5-HT再摄取抑制和5-HT（1B / 1D）拮抗作用。从理论上讲，这种双重药理学特征应导致血清素能神经传递的明显增强，因此可更有效地治疗抑郁症。

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