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首页> 外文期刊>Journal of Medicinal Chemistry >Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors.
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Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors.

机译：基于哌啶的可卡因类似物的进一步SAR研究。 2.有效的多巴胺和5-羟色胺再摄取抑制剂。

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The synthesis and monoamine transporter activity of additional members of a series of 3,4-disubstituted piperidines (truncated analogues of the WIN series) are described. All members of this series were prepared from arecoline hydrobromide in optically pure form and were evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds prepared in this series are reasonably potent DAT inhibitors (K(i) values of 4-400 nM) and have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to the DAT ( approximately 25-fold). In the present series, (-)-methyl 1-methyl-4beta-(2-naphthyl)piperidine-3beta-carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting K(i)'s of 21 nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6 is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in their stereochemistry, show different degrees of selectivity for the three transporters. Consistent with results reported in the literature for the tropane analogues, removal of the methyl group from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the in vivo effects of these piperidines, preliminary behavioral screening was carried out on piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was found to be about 2. 5-fold less potent in increasing distance traveled in mice. However, consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based ligands may provide valuable insights into the pharmacological mechanisms underlying the enhancement in distance traveled versus stereotypic movements. The present results have important implications for better understanding the structural motifs required in the design of agents with specific potency and selectivity at monoamine transporters.
机译：描述了一系列3,4-二取代哌啶（WIN系列的截短类似物）的其他成员的合成和单胺转运活性。该系列的所有成员均由氢溴酸槟榔碱以光学纯净形式制备，并对其抑制多巴胺（DA），5-羟色胺（5-HT）和去甲肾上腺素（NE）进入大鼠脑神经末梢（突触小体）的抑制能力进行了评估。 。该系列中制备的大多数化合物都是相当有效的DAT抑制剂（K（i）值为4-400 nM），并且相对于NE转运蛋白（3-9倍）和相对于NE转运蛋白，对5-HT转运蛋白具有选择性。 DAT（约25倍）。在本系列中，发现（-）-甲基1-甲基-4β-（2-萘基）哌啶-3β-羧酸盐（6）是最有效的哌啶基配体，其K（i）为21 DAT和5-HTT分别为nM和7.6 nM。尽管化合物6的5-HTT活性与抗抑郁药氟西汀相当，但选择性较低。从提供的数据显而易见，萘取代的哌啶6-9，其立体化学不同，对三种转运蛋白显示出不同程度的选择性。与文献中有关托烷类似物的报道结果一致，从9的氮原子上除去甲基会进一步提高5-HTT活性。为了检查这些哌啶的体内作用，对哌啶14进行了初步的行为筛选。尽管哌啶14的DAT活性是可卡因的2.5倍，但哌啶14的有效距离却降低了约5倍。在小鼠中。然而，与其DAT活性一致，发现哌啶14在增强定型运动方面的效力比可卡因高约2.5倍。这些基于哌啶的配体的进一步研究可为深入研究行进距离与定型运动之间的药理机制提供有价值的见解。本结果对更好地理解在单胺转运蛋白上具有特定效力和选择性的试剂设计中所需的结构基序具有重要意义。

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