Functionalized Congeners of P2Y1 Receptor Antagonists:

de Castro, Sonia; Maruoka, Hiroshi; Hong, Kunlun; Costanzi, Stefano; Hechler, Béatrice; Gachet, Christian; Harden, T. Kendall; Jacobson, Kenneth A.

doi:10.1021/bc900569u

Title: Functionalized Congeners of P2Y1 Receptor Antagonists:

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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 »« less

Authors:

de Castro, Sonia ^[1]; Maruoka, Hiroshi ^[1]; Hong, Kunlun ^[2]; Costanzi, Stefano ^[1]; Hechler, Béatrice ^[3]; Gachet, Christian ^[4]; Harden, T. Kendall ^[5]; Jacobson, Kenneth A. ^[1]

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
ORNL
University of Strasbourg
EFS-Alsace, Strasbourg, France
University of North Carolina School of Medicine

Publication Date:: Fri Jan 01 00:00:00 EST 2010

Research Org.:: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Nanophase Materials Sciences (CNMS)

Sponsoring Org.:: USDOE Office of Science (SC)

OSTI Identifier:: 988216

DOE Contract Number:: DE-AC05-00OR22725

Resource Type:: Journal Article

Journal Name:: Bioconjugate Chemistry

Additional Journal Information:: Journal Volume: 21; Journal Issue: 7; Journal ID: ISSN 1043-1802

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.

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                    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.  https://doi.org/10.1021/bc900569u

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                    de Castro, Sonia, Maruoka, Hiroshi, Hong, Kunlun, Kilbey, II, S Michael, Costanzi, Stefano, Hechler, Béatrice, Gachet, Christian, Harden, T. Kendall, and Jacobson, Kenneth A. 2010.  
        "Functionalized Congeners of P2Y1 Receptor Antagonists:".  United States.  https://doi.org/10.1021/bc900569u.

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@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},

  url          = {https://www.osti.gov/biblio/988216},
  journal      = {Bioconjugate Chemistry},

  issn         = {1043-1802},

  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}

}

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