期刊
BIOCHEMICAL PHARMACOLOGY
卷 80, 期 2, 页码 188-196出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2010.03.020
关键词
Cardioprotection; Nucleoside; G protein-coupled receptor; Dendrimers; Polymeric drugs; HL-1 cells
资金
- NIH, National Institute of Diabetes and Digestive and Kidney Diseases
Multivalent dendrimeric conjugates of GPCR ligands may have increased potency or selectivity in comparison to monomeric ligands, a phenomenon that was tested in a model of cytoprotection in mouse HL-1 cardiomyocytes. Quantitative RT-PCR indicated high expression levels of endogenous A(1) and A(2A) adenosine receptors (ARs), but not of A(2B) and A(3)ARs. Activation of the heterologously expressed human A(3)AR in HL-1 cells by AR agonists significantly attenuated cell damage following 4 h exposure to H2O2 (750 mu M) but not in untransfected cells. The A(3) agonist IB-MECA (EC50 3.8 mu M) and the non-selective agonist NECA (EC50 3.9 mu M) protected A(3) AR-transfected cells against H2O2 in a concentration-dependent manner, as determined by lactate dehydrogenase release. A generation 5.5 PAMAM (polyamidoamine) dendrimeric conjugate of a N-6-chain-functionalized adenosine agonist was synthesized and its mass indicated an average of 60 amide-linked nucleoside moieties out of 256 theoretical attachment sites. It non-selectively activated the A3AR to inhibit forskolin-stimulated cAMP formation (IC50 66 nM) and, similarly, protected A(3)-transfected HL-1 cells from apoptosis-inducing H2O2 with greater potency (IC50 35 nM) than monomeric nucleosides. Thus, a PAMAM conjugate retained AR binding affinity and displayed greatly enhanced cardioprotective potency. Published by Elsevier Inc.
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