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首页> 外文期刊>Bioorganic and medicinal chemistry >Investigation of various N-heterocyclic substituted piperazine versions of 5/7-{(2-(4-aryl-piperazin-1-yl)-ethyl)-propyl-amino}-5,6,7,8-tetrahydro-naphthale n-2-ol: effect on affinity and selectivity for dopamine D3 receptor.
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Investigation of various N-heterocyclic substituted piperazine versions of 5/7-{(2-(4-aryl-piperazin-1-yl)-ethyl)-propyl-amino}-5,6,7,8-tetrahydro-naphthale n-2-ol: effect on affinity and selectivity for dopamine D3 receptor.

机译：研究5/7-{（2-（4-芳基-哌嗪-1-基）-乙基）-丙基-氨基} -5,6,7,8-四氢萘n的各种N-杂环取代的哌嗪-2-ol：影响多巴胺D3受体的亲和力和选择性。

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摘要

Here we report on the design and synthesis of several heterocyclic analogues belonging to the 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthale n-2-ol series of molecules. Compounds were subjected to [(3)H]spiperone binding assays, carried out with HEK-293 cells expressing either D2 or D3 dopamine receptors, in order to evaluate their inhibition constant (K(i)) at these receptors. Results indicate that N-substitution on the piperazine ring can accommodate various substituted indole rings. The results also show that in order to maintain high affinity and selectivity for the D3 receptor the heterocyclic ring does not need to be connected directly to the piperazine ring as the majority of compounds included here are linked either via an amide or a methylene linker to the heterocyclic moiety. The enantiomers of the most potent racemic compound 10e exhibited differential activity with (-)-10e (K(i); D2=47.5 nM, D3=0.57 nM) displaying higher affinity at both D2 and D3 receptors compared to its enantiomer (+)-10e (K(i); D2=113 nM, D3=3.73 nM). Additionally, compound (-)-10e was more potent and selective for the D3 receptor compared to either 7-OH-DPAT or 5-OH-DPAT. Among the bioisosteric derivatives, the indazole derivative 10g and benzo[b]thiophene derivative 10i exhibited the highest affinity for D2 and D3 receptors. In the functional GTPgammaS binding study, one of the lead molecules, (-)-15, exhibited potent agonist activity at both D2 and D3 receptors with preferential affinity at D3.
机译：在这里，我们报告设计和合成属于5/7-{[2-（4-芳基-哌嗪-1-基）-乙基]-丙基-氨基} -5,6,7,8的几种杂环类似物-四氢萘n-2-ol系列分子。用表达D2或D3多巴胺受体的HEK-293细胞对化合物进行[（3）H]哌咯酮结合测定，以评估它们在这些受体上的抑制常数（K（i））。结果表明，哌嗪环上的N-取代可容纳各种取代的吲哚环。结果还表明，为了保持对D3受体的高亲和力和选择性，杂环不需要直接与哌嗪环相连，因为此处包含的大多数化合物都是通过酰胺或亚甲基接头与杂环部分。最有效的外消旋化合物10e的对映异构体与（-）-10e（K（i）; D2 = 47.5 nM，D3 = 0.57 nM）相比，其对映异构体（+）在D2和D3受体上均显示出更高的亲和力-10e（K（i）; D2 = 113 nM，D3 = 3.73 nM）。另外，与7-OH-DPAT或5-OH-DPAT相比，化合物（-）-10e对D3受体更有效且更具选择性。在生物立体异构体衍生物中，吲唑衍生物10g和苯并[b]噻吩衍生物10i对D2和D3受体表现出最高的亲和力。在功能性GTPgammaS结合研究中，先导分子之一（-）-15在D2和D3受体上均表现出强大的激动剂活性，并在D3上具有优先亲和力。

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