Bioisosteric heterocyclic versions of 7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol: Identification of highly potent and selective agonists for dopamine D3 receptor with potent in vivo activity
Bioisosteric heterocyclic versions of 7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol: Identification of highly potent and selective agonists for dopamine D3 receptor with potent in vivo activity
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DOI：
10.1021/jm701524h
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发表时间：
2008-05-22
影响因子：
7.3
通讯作者：
Dutta, Aloke K.
中科院分区：
文献类型：
--
作者：
Biswas, Swati;Hazeldine, Stuart;Dutta, Aloke K.
在目前的报告中，我们进一步扩展了对我们的杂化结构7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5，6，7，8-tetrahydronaphthalen-2-ol的合成孔径雷达研究，包括杂环生物等立体类似物。用表达D2或D3受体的HEK-293细胞与氚螺环酮进行结合实验，计算抑制常数(K)。用表达人D2受体的CHO细胞和表达人D3受体的ATT-20细胞评价了所选化合物刺激GTP-γ-S结合的功能活性。(-)-34对D3受体的结合亲和力和选择性最高(K-I=0.92nM，D2/D3=253)。在功能GTP-γS结合实验中，(-)-34对D3受体具有皮摩尔亲和力的完全激动剂活性，且选择性高(EC_(50)=0.08 nM，D_2/D_3=248)。在体内旋转实验中，(-)-34在6-OH-DA单侧损毁大鼠体内表现出很强的旋转活性，作用时间长，这表明它在帕金森病的神经保护治疗中具有潜在的应用价值。
In the current report, we extend the SAR study on our hybrid structure 7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol further to include heterocyclic bioisosteric analogues. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (K). Functional activity of selected compounds in stimulating GTP gamma S binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. The highest binding affinity and selectivity for D3 receptors were exhibited by (-)-34 (K-i = 0.92 nM and D2/D3 = 253). In the functional GTP gamma S binding assay, (-)-34 exhibited full agonist activity with picomolar affinity for D3 receptor with high selectivity (EC50 = 0.08 nM and D2/D3 = 248). In the in vivo rotational study, (-)-34 exhibited potent rotational activity in 6-OH-DA unilaterally lesioned rats with long duration of action, which indicates its potential application in neuroprotective treatment of Parkinson's disease.