Toward multivalent GPCR signaling from poly(amidoamine) dendrimer conjugates

MEDI 275

Yoonkyung Kim, kimyoonk@niddk.nih.gov1, Athena M. Klutz1, Béatrice Hechler2, Christian Gachet2, and Kenneth A. Jacobson1. (1) Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, (2) INSERM U311, Etablissement Français du Sang-Alsace, Strasbourg, France
Adenosine receptors (ARs) are members of G-protein-coupled receptor (GPCR) family. A2A AR is one of the four identified AR subtypes and is relevant to various disease conditions including thrombosis, nervous system disorders, and ischemic reperfusion damage. In an effort to develop advanced therapeutics to act through ARs, PAMAM dendrimers were used to conjugate at the periphery varying numbers of receptor-selective nucleoside moieties for activation of the A2A AR and characterized spectroscopically. Dendrimers are treelike macromolecular architectures that possess unique size, shape, and physical properties. We envision that dendrimers may act as nanoscaffolds for attachment of multiple ligands for synergistic receptor binding and improved overall pharmacological profiles compared to the monovalent ligands. Indeed, PAMAM-nucleoside conjugates exhibited binding affinities at the human A2A AR with submicromolar Ki values. Furthermore, an enhanced antiaggregatory effect on ADP-induced platelet aggregation, characteristic of A2A AR agonists, was observed in our preliminary in vitro experiments.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007