Further structurally constrained analogues of cis-(6-benzhydrylpiperidin-3-yl)benzylamine with elucidation of bioactive conformation:: Discovery of 1,4-diazabicyclo[3.3.1]nonane derivatives and evaluation of their biological properties for the monoamine transporters
Further structurally constrained analogues of cis-(6-benzhydrylpiperidin-3-yl)benzylamine with elucidation of bioactive conformation:: Discovery of 1,4-diazabicyclo[3.3.1]nonane derivatives and evaluation of their biological properties for the monoamine transporters
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DOI：
10.1021/jm049796t
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发表时间：
2004-10-07
影响因子：
7.3
通讯作者：
Dutta, AK
中科院分区：
文献类型：
--
作者：
Kolhatkar, R;Cook, CD;Dutta, AK
我们对单胺转运体的哌啶类似物的构效关系（SAR）研究导致了一系列3,6-二取代哌啶衍生物的开发，这些衍生物是柔性哌啶类似物的结构约束版本，对多巴胺转运体（DAT）具有优先亲和力。我们试图进一步固化这种结构，以研究刚性对结合和体内活性的影响，我们开发了一系列4,8-二取代1,4-重氮杂环壬烷衍生物。所有合成的衍生物分别通过测定它们与[H-3] win35、428、[H-3]西酞普兰和[H-3]尼索西汀竞争结合的效力，来测试它们对脑内DAT、血清素转运体（SERT）和去甲肾上腺素转运体（NET）的亲和力。我们还测试了所选化合物抑制[H-3]DA摄取的能力。SAR研究发现了一种有效的先导化合物(-)- s,S-10c，对DAT具有高亲和力和选择性（IC50 = 22.5 nM; SERT/DAT = 384和NET/DAT > 444）。有趣的是，(-)-10c和3,6-二取代系列(-)-2的先导化合物在它们的（S，S）异构体中都表现出最高的活性，这表明对最大相互作用的区域特异性要求相似。总的来说，我们目前的SAR结果与这些分子较少约束的3,6-二取代版本的结果吻合得很好，尽管前一类分子对活性的分子结构要求更严格。然而，当前系列中的强效化合物与相应的3,6-二取代版本相比，对DAT表现出更大的选择性，这表明刚性在与转运蛋白的选择性相互作用中起作用。为了阐明其生物活性构象。在电流和3,6-二取代系列的引线分子结构中，进行了初步的分子建模研究，其中使用最刚性的衍生物(-)-10c作为模板结构。化合物(-)-2和(-)-10c在小鼠运动测试中表现出兴奋活性，其中(-)-2比(-)-10c表现出更慢的起效和更长的作用持续时间。这两种化合物在小鼠训练中产生完全的可卡因样反应，使其能够区分10 mg/kg的可卡因和对照物。
Our structure-activity relationship (SAR) study on piperidine analogues for monoamine transporters led to the development of a series of 3,6-disubstituted piperidine derivatives, structurally constrained versions of flexible piperidine analogues, with preferential affinity for the dopamine transporter (DAT). In our attempt to further rigidify this structure to study influence of rigidity on binding and in vivo activity, we have developed a series of 4,8-disubstituted 1,4-diazabicyclo[3.3.1]nonane derivatives. All synthesized derivatives were tested for their affinity at the DAT, serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in competing for the binding of [H-3]WIN 35, 428, [H-3]citalopram, and [H-3]nisoxetine, respectively. Selected compounds were also tested for their ability to inhibit uptake of [H-3]DA. The SAR study led to the discovery of a potent lead compound (-)-S,S-10c which exhibited high affinity and selectivity for the DAT (IC50 = 22.5 nM; SERT/DAT = 384 and NET/DAT > 444). It is interesting to note that both (-)-10c and the lead compound from the 3,6-disubstituted series (-)-2 exhibited highest activity in their (S,S) isomer indicating similar requirement of regiospecificity for maximum interaction. Overall, our current SAR results corresponded well with the results from less constrained 3,6-disubstituted versions of these molecules albeit the former class exhibited more stringent requirement in molecular structure for activity. However, the potent compounds in the current series exhibited greater selectivity for the DAT compared to their corresponding lesser constrained 3,6-disubstituted versions indicating an effect of rigidity in selective interaction with the transporter proteins. In an effort to elucidate the bioactive conformational. structure of the lead molecules in the current and the 3,6-disubstituted series, a preliminary molecular modeling study was carried out where the most rigid derivative (-)-10c was used,as a template structure. Compounds (-)-2 and (-)-10c exhibited stimulant activity in locomotor tests in mice in which (-)-2 exhibited a slower onset and longer duration of action compared to (-)-10c. Both compounds occasioned complete cocaine-like responding in mice trained to discriminate 10 mg/kg ip cocaine from vehicle.