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Title: Functionalized Congeners of P2Y1 Receptor Antagonists:

Abstract

The P2Y{sub 1} receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y{sub 1} receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N{sup 6}-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates containing extended 2-alkynyl chains was designed, and binding affinity at the human (h) P2Y{sub 1} receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (K{sub i} 23 nM) and extended amine congener 15 (K{sub i} 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended {epsilon}-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y{sub 1} receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y{sub 1} receptor modeling and ligand docking. Attempted P2Y{sub 1}more » antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor antagonist to a PAMAM dendrimer to produce a multivalent conjugate exhibiting a desired biological effect, i.e., antithrombotic action.« less

Authors:
 [1];  [1];  [2];  [2];  [1];  [3];  [4];  [5];  [1]
  1. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
  2. ORNL
  3. University of Strasbourg
  4. EFS-Alsace, Strasbourg, France
  5. University of North Carolina School of Medicine
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Center for Nanophase Materials Sciences
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
988216
DOE Contract Number:  
DE-AC05-00OR22725
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioconjugate Chemistry; Journal Volume: 21; Journal Issue: 7
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; ADENINES; AFFINITY; ALKYNES; AMIDES; AMINES; BIOLOGICAL EFFECTS; BIOTIN; CHAINS; NUCLEOTIDES; PRESERVATION; RIBOSE; SIMULATION; SPACERS; TRIAZOLES

Citation Formats

de Castro, Sonia, Maruoka, Hiroshi, Hong, Kunlun, Kilbey, II, S Michael, Costanzi, Stefano, Hechler, Béatrice, Gachet, Christian, Harden, T. Kendall, and Jacobson, Kenneth A.. Functionalized Congeners of P2Y1 Receptor Antagonists:. United States: N. p., 2010. Web. doi:10.1021/bc900569u.
de Castro, Sonia, Maruoka, Hiroshi, Hong, Kunlun, Kilbey, II, S Michael, Costanzi, Stefano, Hechler, Béatrice, Gachet, Christian, Harden, T. Kendall, & Jacobson, Kenneth A.. Functionalized Congeners of P2Y1 Receptor Antagonists:. United States. doi:10.1021/bc900569u.
de Castro, Sonia, Maruoka, Hiroshi, Hong, Kunlun, Kilbey, II, S Michael, Costanzi, Stefano, Hechler, Béatrice, Gachet, Christian, Harden, T. Kendall, and Jacobson, Kenneth A.. Fri . "Functionalized Congeners of P2Y1 Receptor Antagonists:". United States. doi:10.1021/bc900569u.
@article{osti_988216,
title = {Functionalized Congeners of P2Y1 Receptor Antagonists:},
author = {de Castro, Sonia and Maruoka, Hiroshi and Hong, Kunlun and Kilbey, II, S Michael and Costanzi, Stefano and Hechler, Béatrice and Gachet, Christian and Harden, T. Kendall and Jacobson, Kenneth A.},
abstractNote = {The P2Y{sub 1} receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y{sub 1} receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N{sup 6}-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates containing extended 2-alkynyl chains was designed, and binding affinity at the human (h) P2Y{sub 1} receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (K{sub i} 23 nM) and extended amine congener 15 (K{sub i} 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended {epsilon}-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y{sub 1} receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y{sub 1} receptor modeling and ligand docking. Attempted P2Y{sub 1} antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor antagonist to a PAMAM dendrimer to produce a multivalent conjugate exhibiting a desired biological effect, i.e., antithrombotic action.},
doi = {10.1021/bc900569u},
journal = {Bioconjugate Chemistry},
number = 7,
volume = 21,
place = {United States},
year = {Fri Jan 01 00:00:00 EST 2010},
month = {Fri Jan 01 00:00:00 EST 2010}
}