Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines.: Implications for the binding mode of heterocyclic dopamine D3 receptor agonists
Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines.: Implications for the binding mode of heterocyclic dopamine D3 receptor agonists
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DOI：
10.1021/jm0503805
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发表时间：
2005-09-08
影响因子：
7.3
通讯作者：
Gmeiner, P
中科院分区：
文献类型：
--
作者：
Elsner, J;Boeckler, F;Gmeiner, P
利用基于3D-QSAR的药效团假说，描述了多巴胺能5-氨基四氢吡唑[1,5-a]吡啶的合成和生物学评价。数据显示，当对映体(S)-1与D3结合（K-i高= 4.0 nM）时，杂环测试化合物（）-1与D3受体有明显的选择性亲和性。(S)-1表现出与我们之前描述的D3激动剂fac 54相当的结合亲和力和配体功效，当亚型选择性可以显着提高时。结果表明，多巴胺能(S)-1和普拉克索的吡唑环和噻唑环上的sp(2)氮分别是重要的药效元素。为了提供(S)-1高亲和力的推测性解释，采用活性状态D3模型进行了计算研究。
Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound ()-l when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K-i high = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.