Selective Agonists for Dopamine/Neurotensin Receptor Heterodimers
Selective Agonists for Dopamine/Neurotensin Receptor Heterodimers
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DOI：
10.1002/cmdc.201100499
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发表时间：
2012-03-05
期刊：
影响因子：
3.4
通讯作者：
Gmeiner, Peter
中科院分区：
文献类型：
--
作者：
Koschatzky, Susanne;Gmeiner, Peter
神经调节肽神经降压素已被描述为与人脑的多巴胺能通路发生功能性相互作用。我们采用放射性配体结合研究来研究共表达的多巴胺 D2L 或 D3 与神经降压素 NTS1 或 NTS2 受体之间的物理相互作用。在神经降压素存在的情况下，检测到两种受体亚型 NTS1 和 NTS2 对 D2L 或 D3 激动剂结合的显着交叉抑制作用。为了识别配体特异性调节和亚型依赖性差异，合成了带有 7-OH-DPAT 药效团的新型多巴胺受体激动剂 5 和 6。 D3NTS2 共表达观察到异常的配体特异性，在神经降压素存在的情况下，联苯甲酰胺 5 的亲和力降低了 20 倍。比较神经降压素存在下多巴胺能化合物的结合特性，观察到神经降压素交叉抑制作用的多巴胺受体亚型选择性谱。
The neuromodulatory peptide neurotensin has been described to functionally interact with dopaminergic pathways of the human brain. We employed radioligand binding studies to investigate the physical interaction between co-expressed dopamine D2L or D3 and neurotensin NTS1 or NTS2 receptors. Substantial cross-inhibitory effects of both receptor subtypes NTS1 and NTS2 on the agonist binding of D2L or D3 were detected in the presence of neurotensin. To identify ligand-specific modulation and subtype-dependent differences, the novel dopamine receptor agonists 5 and 6 bearing the 7-OH-DPAT pharmacophore were synthesized. Exceptional ligand specificity was observed for D3NTS2 co-expression, which gave a 20-fold decrease in affinity for biphenylcarboxamide 5 in the presence of neurotensin. Comparing the binding properties of dopaminergic compounds in the presence of neurotensin, dopamine receptor subtype-selective profiles of the cross-inhibitory effect of neurotensin were observed.