Polyamidoamine (PAMAM) Dendrimer Conjugates of “Clickable” Agonists of the A3 Adenosine Receptor and Coactivation of the P2Y14 Receptor by a Tethered Nucleotide

We previously synthesized a series of potent and selective A3 adenosine receptor (AR) agonists (North-methanocarba nucleoside 5′-uronamides) containing dialkyne groups on extended adenine C2 substituents. We coupled the distal alkyne of a 2-octadiynyl nucleoside by Cu(I)-catalyzed “click” chemistry...

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Bibliographic Details
Published in:Bioconjugate chemistry 2010-02, Vol.21 (2), p.372-384
Main Authors: Tosh, Dilip K, Yoo, Lena S, Chinn, Moshe, Hong, Kunlun, Kilbey, S. Michael, Barrett, Matthew O, Fricks, Ingrid P, Harden, T. Kendall, Gao, Zhan-Guo, Jacobson, Kenneth A
Format: Article
Language:English
Subjects:
ADENINES
ADENOSINE
Adenosine - chemistry
Adenosine A3 Receptor Agonists
AFFINITY
ALKYNES
Alkynes - chemistry
Amides - chemistry
Animals
BASIC BIOLOGICAL SCIENCES
CARBOXYLIC ACIDS
Catalysis
Cell Line, Tumor
CHEMISTRY
CHO Cells
Copper - chemistry
Cricetinae
Cricetulus
Dendrimers - chemistry
DISEASES
GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
Humans
Ligands
Neuroimmunomodulation - drug effects
NUCLEOSIDES
NUCLEOTIDES
Receptors, Purinergic P2 - metabolism
TRIAZOLES
Triazoles - chemistry
Uridine Diphosphate Glucose - chemistry
Uridine Diphosphate Glucose - pharmacology
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Summary:We previously synthesized a series of potent and selective A3 adenosine receptor (AR) agonists (North-methanocarba nucleoside 5′-uronamides) containing dialkyne groups on extended adenine C2 substituents. We coupled the distal alkyne of a 2-octadiynyl nucleoside by Cu(I)-catalyzed “click” chemistry to azide-derivatized G4 (fourth-generation) PAMAM dendrimers to form triazoles. A3AR activation was preserved in these multivalent conjugates, which bound with apparent K i of 0.1−0.3 nM. They were substituted with nucleoside moieties, solely or in combination with water-solubilizing carboxylic acid groups derived from hexynoic acid. A comparison with various amide-linked dendrimers showed that triazole-linked conjugates displayed selectivity and enhanced A3AR affinity. We prepared a PAMAM dendrimer containing equiproportioned peripheral azido and amino groups for conjugation of multiple ligands. A bifunctional conjugate activated both A3 and P2Y14 receptors (via amide-linked uridine-5′-diphosphoglucuronic acid), with selectivity in comparison to other ARs and P2Y receptors. This is the first example of targeting two different GPCRs with the same dendrimer conjugate, which is intended for activation of heteromeric GPCR aggregates. Synergistic effects of activating multiple GPCRs with a single dendrimer conjugate might be useful in disease treatment.
ISSN:1043-1802
1520-4812
DOI:10.1021/bc900473v