Dopamine D2, D3, and D4 Selective Phenylpiperazines as Molecular Probes To Explore the Origins of Subtype Specific Receptor Binding
Dopamine D2, D3, and D4 Selective Phenylpiperazines as Molecular Probes To Explore the Origins of Subtype Specific Receptor Binding
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DOI：
10.1021/jm900690y
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发表时间：
2009-08-13
影响因子：
7.3
通讯作者：
Gmeiner, Peter
中科院分区：
文献类型：
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作者：
Ehrlich, Katharina;Gotz, Angela;Gmeiner, Peter
通过不同的间隔元件组装苯基哌嗪与7a-氮杂吲哚，我们开发了1a、c、2a和3a型亚型选择性多巴胺受体配体，分别优先与D-4、D-2和D-3相互作用。为了完成这一组，甲硫类似物2b和3b比2a和3a的亲和力高出一个数量级，并且结构 合成了中间体1b。这些化学上相似但生物学上不同的目标化合物可用作放射性配体置换实验、诱变以及基于β(2)-肾上腺素受体最新晶体结构的同源模型对接研究的分子探针。鉴定了与高度保守的氨基酸 ASP(3.32) 和 His(6.55) 以及位置 2.61、2,64、3.28 和 3.29 处不太保守的残基的特异性相互作用。仔细建模的细胞外环 2 的包含显示了 EL2 中的两个非保守残基，它们对配体结合有不同的贡献。显然，亚型选择性是由非保守氨基酸引起的，但通常由保守氨基酸介导。
Assembling phenylpiperazines with 7a-azaindole via different spacer elements, we developed subtype selective dopamine receptor ligands of types 1a,c,2a, and 3a preferentially interacting with D-4, D-2, and D-3, respectively, To complete this set, the methylthio analogues 2b and 3b exceeding the affinity of 2a and 3a by one order of magnitude and the structural intermediate 1b were synthesized. These chemically similar but biologically divergent target compounds served as molecular probes for radioligand displacement experiments, mutagenesis, and docking studies on homology models based on the recent crystal structure of the beta(2)-adrenergic receptor. Specific interactions with the highly conserved amino acids ASP(3.32) and His(6.55) and less conserved residues at positions 2.61, 2,64, 3.28, and 3.29 were identified. Inclusion of a carefully modeled extracellular loop 2 displayed two nonconserved residues in EL2 that differently contribute to ligand binding. Obviously, subtype selectivity is caused by nonconserved but frequently mediated by conserved amino acids.