Application of the functionalized congener approach to dendrimer-based signaling agents acting through A2A adenosine receptors

Purinergic Signalling

Béatrice Hechler¹  Christian Gachet¹  Kenneth A. Jacobson²  Yoonkyung Kim²  Athena M. Klutz²  Zhan-Guo Gao² 

[1] INSERM U.311$$EFS-Alsace$$Université Louis Pasteur$$;National Institutes of Health$$

关键词: Nanotechnology;   

DOI  :  10.1007/s11302-008-9113-3

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

As a continued effort to develop multivalent ligands to enhance the pharmacological effects of monomeric drugs, DITC-APEC, a chemically reactive nucleoside A_2A 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 2008 19:406–411) by ca. 20 Å, potentially increasing the conformational flexibility of the appended ligands to achieve optimal geometry for efficient binding at A_2A 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 A_2A and A₃ ARs with submicromolar K_i values and selectivity in comparison to the human A₁ AR. Furthermore, these nucleoside-loaded dendrimers exhibited an A_2A 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.

【 授权许可】

Unknown