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 A(3) 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. A(3)AR 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 A(3)AR affinity. We prepared a PAMAM dendrimer containing equiproportioned peripheral azido and amino groups for conjugation of multiple ligands. A bifunctional conjugate activated both A(3) and P2Y(14) 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.
Tosh
Dilip K
DK
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Yoo
Lena S
LS
Chinn
Moshe
M
Hong
Kunlun
K
Kilbey
S Michael
SM
Barrett
Matthew O
MO
Fricks
Ingrid P
IP
Harden
T Kendall
TK
Gao
Zhan-Guo
ZG
Jacobson
Kenneth A
KA
D000241:Adenosine / Q000737:chemistry; D058909:Adenosine A3 Receptor Agonists; D000480:Alkynes / Q000737:chemistry; D000577:Amides / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D002384:Catalysis; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry; D006224:Cricetinae; D003412:Cricetulus; D050091:Dendrimers / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D015213:Neuroimmunomodulation / Q000187:drug effects; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D014230:Triazoles / Q000737:chemistry; D014532:Uridine Diphosphate Glucose / Q000737:chemistry* / Q000494:pharmacology*
D058909:Adenosine A3 Receptor Agonists; D000480:Alkynes; D000577:Amides; D050091:Dendrimers; D008024:Ligands; C518528:P2Y14 receptor, human; C104700:PAMAM Starburst; D018048:Receptors, Purinergic P2; D014230:Triazoles; D003300:Copper; D000241:Adenosine; D014532:Uridine Diphosphate Glucose