Application of the functionalized congener approach to dendrimer-based signaling agents acting through A(2A) adenosine receptors.
Application of the functionalized congener approach to dendrimer-based signaling agents acting through A(2A) adenosine receptors.
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DOI：
10.1007/s11302-008-9113-3
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发表时间：
2009-03
影响因子：
3.5
通讯作者：
Jacobson, Kenneth A.
中科院分区：
文献类型：
--
作者：
Kim, Yoonkyung;Klutz, Athena M.;Hechler, Beatrice;Gao, Zhan-Guo;Gachet, Christian;Jacobson, Kenneth A.
关键词：
为了继续开发多价配体以增强单体药物的药理作用，采用化学反应性核苷A2A腺苷受体（AR）激动剂DITC-APEC对第三代（G3）聚氨基胺（PAMAM）树状大分子表面进行衍生化。所得到的偶联物携带了通过硫脲连接的激动剂的多个拷贝，并且在连接的数量和是否存在荧光团或额外的表面修饰方面有所不同。计算机模拟研究表明，这些负载dtc - apec的树状大分子将先前报道的PAMAM-CGS21680树状大分子衍生物（Kim等人，Bioconjugate Chem 19:406-411）的总直径延长了约20 Å，潜在地增加了附加配体的构象灵活性，以实现在A2A ARs上有效结合的最佳几何形状。与CGS21680偶联物相比，由于存在扩展的连接物，即二硫脲基功能，预计其结合的亲和力和选择性将增加。体外放射性配体竞争实验表明，与人类A1 AR相比，PAMAM-DITC-APEC树状大分子偶联物在人类A2A和A3 AR上具有亚微摩尔Ki值和选择性。此外，这些核苷负载的树状大分子对adp诱导的人类血小板聚集表现出A2A AR介导的抑制作用。本研究证明了应用功能化同源物概念来设计基于树突的G蛋白偶联受体多价配体的潜力。本文的在线版本（doi:10.1007/ s111302 -008-9113-3）包含补充资料，仅供授权用户使用。
As a continued effort to develop multivalent ligands to enhance the pharmacological effects of monomeric drugs, DITC-APEC, a chemically reactive nucleoside A2A adenosine receptor (AR) agonist, was employed to derivatize the surface of third-generation (G3) polyamidoamine (PAMAM) dendrimers. The resulting conjugates carried multiple copies of the agonist attached through a thiourea linkage and differed in the number of attachments and in the presence of a fluorophore or additional surface modification. Computer modeling studies suggested that these DITC-APEC-loaded dendrimers extended the overall diameter of the previously reported PAMAM-CGS21680 dendrimer derivatives (Kim et al., Bioconjugate Chem 19:406–411) by ca. 20 Å, potentially increasing the conformational flexibility of the appended ligands to achieve optimal geometry for efficient binding at A2A ARs. Increased affinity and selectivity in binding in comparison to the CGS21680 conjugate were envisioned, due to the presence of an extended linker, i.e., a dithioureylenephenyl functionality. In vitro radioligand competition experiments showed effective binding of these PAMAM-DITC-APEC dendrimer conjugates at the human A2A and A3 ARs with submicromolar Ki values and selectivity in comparison to the human A1 AR. Furthermore, these nucleoside-loaded dendrimers exhibited an A2A AR-mediated inhibitory effect on ADP-induced aggregation of human platelets. The present study demonstrates the potential of applying the functionalized congener concept to engineer dendrimer-based multivalent ligands for G protein-coupled receptors. The online version of this article (doi:10.1007/s11302-008-9113-3) contains supplementary material, which is available to authorized users.
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