Synthesis and biological characterization of novel hybrid 7-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol and their heterocyclic bioisosteric analogues for dopamine D2 and D3 receptors
Synthesis and biological characterization of novel hybrid 7-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol and their heterocyclic bioisosteric analogues for dopamine D2 and D3 receptors
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DOI：
10.1016/j.bmc.2004.06.019
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发表时间：
2004-08-15
影响因子：
3.5
通讯作者：
Reith, MEA
中科院分区：
文献类型：
--
作者：
Dutta, AK;Venkataraman, SK;Reith, MEA
在最近的一次初步交流中，我们描述了针对多巴胺 D2 和 D3 受体亚型的一系列混合分子的开发。这些化合物的设计基于将氨基四氢化萘的药效元件与衍生自已知多巴胺受体激动剂和拮抗剂分子的哌嗪分子片段相结合。从初步的[H-3]螺哌酮结合数据判断，通过这种方法开发的分子对 D3 受体表现出高亲和力和选择性。在本报告中，我们通过开发额外的新分子扩展了我们之前的发现，并另外评估了这些新分子在[H-3]胸苷掺入有丝分裂测定中的功能活性。结合结果表明生物等排苯并噻唑衍生物 N6-[2-(4-苯基-哌嗪-1-基)-乙基]-N6-丙基-4,5,6,7-四氢-苯并噻唑-2,6-二胺 (14) 对 D3 受体具有最高的选择性，而外消旋化合物7-({2-[4-(2,3-二氯-苯基)-哌嗪-1-基]-乙基}-丙基-氨基)-5,6,7,8-四氢-环烷-2-醇(10c)显示出最强的效力。评估功能活性的有丝分裂研究证明了这些新型衍生物对 D2 和 D3 受体具有有效的激动剂特性。在这方面，化合物7-{[4-(4-苯基-哌嗪-1-基)-丁基]-丙-2-炔基-氨基}-5,6,7,8-四氢-萘-2-醇(7b)对D3受体表现出最有效的激动剂活性，比喹吡罗强10倍，也是该系列中对D3受体最具选择性的化合物。外消旋化合物10a被拆分；然而，10a 的两种对映异构体之间几乎没有发现活性分离。使用 6-OH-DA 诱导的单侧损伤大鼠模型对活性稍高的对映体 (-)-10a 进行了体内检查，以评估其产生对侧旋转的活性。结果表明，与参考化合物阿扑吗啡相比，(-)-10a 在诱导对侧旋转方面相当有效，并且作用持续时间更长。 (C) 2004 Elsevier Ltd. 保留所有权利。
In a recent preliminary communication we described the development of a series of hybrid molecules for the dopamine D2 and D3 receptor subtypes. The design of these compounds was based on combining pharmacophoric elements of aminotetralin and piperazine molecular fragments derived from known dopamine receptor agonist and antagonist molecules. Molecules developed from this approach exhibited high affinity and selectivity for the D3 receptor as judged from preliminary [H-3]spiperone binding data. In this report, we have expanded our previous finding by developing additional novel molecules and additionally evaluated functional activities of these novel molecules in the [H-3]thymidine incorporation mitogenesis assay. The binding results indicated highest selectivity in the bioisosteric benzothiazole derivative N6-[2-(4-phenyl-piperazin-1-yl)-ethyl]-N6-propyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine (14) for the D3 receptor whereas the racemic compound 7-({2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-propyl-amino)-5,6,7,8-tetrahydro-naphthaten-2-ol (10c) showed the strongest potency. Mitogenesis studies to evaluate functional activity demonstrated potent agonist properties in these novel derivatives for both D2 and D3 receptors. In this regard, compound 7-{[4-(4-phenyl-piperazin-1-yl)-butyl]-prop-2-ynyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol (7b) exhibited the most potent agonist activity at the D3 receptor, 10 times more potent than quinpirole and was also the most selective compound for the D3 receptor in this series. Racemic compound 10a was resolved; however, little separation of activity was found between the two enantiomers of 10a. The marginally more active enantiomer (-)-10a was examined in vivo using the 6-OH-DA induced unilaterally lesioned rat model to evaluate its activity in producing contralateral rotations. The results demonstrated that in comparison to the reference compound apomorphine, (-)-10a was quite potent in inducing contralateral rotations and exhibited longer duration of action. (C) 2004 Elsevier Ltd. All rights reserved.