High affinity hydroxypiperidine analogues of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the dopamine transporter: Stereospecific interactions in vitro and in vivo
High affinity hydroxypiperidine analogues of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the dopamine transporter: Stereospecific interactions in vitro and in vivo
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DOI：
10.1021/jm020275k
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发表时间：
2003-03-27
影响因子：
7.3
通讯作者：
Dutta, AK
中科院分区：
文献类型：
--
作者：
Ghorai, SK;Cook, C;Dutta, AK
在我们努力开发可能用作可卡因药物的多巴胺转运蛋白的高亲和力配体的过程中，将极性羟基取代基引入到我们的衍生自1-[2-（二苯基甲氧基）乙基] -4-（3-苯基丙基）哌嗪（GBR 12935）的二取代的铅类似物之一的哌啶环中。合成了顺式和反式3-羟基衍生物，并将外消旋反式异构体（+/-）-5进一步拆分为两种对映异构体。新合成的化合物的特征是它们对大鼠大脑中多巴胺、血清素和去甲肾上腺素转运蛋白系统的结合亲和力。两种对映体（+）-5和（-）-5在多巴胺转运蛋白上表现出明显的亲和力差异，（+）-5在抑制放射性标记可卡因类似物结合方面的效力是（-）-5的122倍（IC 50; 0.46 vs 56.7 nM），抑制多巴胺摄取的活性是（-）-5的9倍（IC 50; 4.05 vs 38.0 nM）。此外，与标准GBR 12909相比，最具活性的（+）-5在多巴胺转运蛋白方面的效力高22倍。通过X-射线结构分析明确确定了其中一种对映异构体的绝对构型。在体内运动活性研究中，对映体（+）-5和外消旋体（+）-5，但不是（-）-5，表现出刺激活性，具有长的作用持续时间。在测试的剂量范围内，所有三种化合物（+）-5、（-）-5和（-）-5在经训练以区分10 mg/kg ip可卡因与媒介物的小鼠中部分（50%）但不完全（80%）产生可卡因样反应。化合物（-）-5在这方面的独特之处在于，与（+）-5和（+/-）-5不同，它还不影响运动活性，但与它们类似，能够产生（尽管不完全）可卡因样反应。
In our effort to develop high-affinity ligands for the dopamine transporter which might find potential use as cocaine medication, a polar hydroxy substituent was introduced into the piperidine ring of one of our disubstituted lead analogues derived from 1-[2-(diphenylmethoxy)ethyl] -4-(3-phenylpropyl)piperazine (GBR 12935). Both cis- and trans-3-hydroxy derivatives were synthesized and the racemic trans isomer, (+/-)-5, was further resolved into two enantiomers. Newly synthesized compounds were characterized for their binding affinity at the dopamine, serotonin, and norepinephrine transporter systems in rat brain. The two enantiomers (+)-5 and (-)-5 exhibited marked differential affinities at the dopamine transporter with (+)-5 being 122-fold more potent than (-)-5 in inhibiting radiolabeled cocaine analogue binding (IC50; 0.46 vs 56.7 nM) and 9-fold more active for inhibiting dopamine uptake (IC50; 4.05 vs 38.0 nM). Furthermore, the most active (+)-5 was 22-fold more potent at the dopamine transporter compared to the standard GBR 12909. Absolute configuration of one of the enantiomers was determined unambiguously by X-ray structural analysis. In in vivo locomotor activity studies, the enantiomer (+)-5 and the racemic ()-5, but not (-)-5, exhibited stimulant activity with a long duration of effect. All three compounds, (+)-5, (-)-5, and ()-5, within the dose range tested, partially (50%) but incompletely (80%) produced cocaine-like responses in mice trained to discriminate 10 mg/kg ip cocaine from vehicle. Compound (-)-5 was distinctive in this regard in that, unlike (+)-5 and (+/-)-5, it did not affect locomotor activity yet, but similar to them, was able to engender (albeit incompletely) cocaine-like responses.