Sp-2-propylthio-ATP-α-B and Sp-2-propylthio-ATP-α-B,b-g- dichloromethylene are novel potent and specific agonists of the human P2Y 11 receptor

Michael Haas, Idan Ben-Moshe, Bilha Fischer, Georg Reiser

Research output: Contribution to journalArticlepeer-review


The human P2Y11 nucleotide receptor mRNA was found in virtually all human tissues, and the receptor serves many physiological roles, such as immune response regulation. The Ala-87-Thr-P2Y11 receptor single nucleotide polymorphism was linked to increased risk for acute myocardial infarction. To facilitate the development of new therapeutic applications involving cells expressing several P2 receptor subtypes, the availability of specific and potent agonists is mandatory. Here, we synthesized a series of novel adenine nucleotide derivatives, based upon the potent P2Y11 receptor agonists AR-C67085. Features of the novel nucleotide derivatives are a propylthio substitution at C2-adenine and a Pα-borano or Pα-thio substitution of non-bridging oxygen atom. The latter substitutions introduce a chiral center at the a-phosphate. Sp-isomers of Pα-borano- and Rp-isomers of Pa-thio-substituted nucleotides are preferred by the P2Y11 receptor. As recently reported by us, diastereoselectivity of the P2Y 11 receptor is opposite to that of the P2Y1 receptor. Therefore, we exploit this characteristic to increase nucleotide selectivity. At the P2Y11 receptor, the Sp-isomers of 2-propylthio-ATP-α-B (2B) and 2-propylthio-ATP-α- B,β-γ-dichloromethylene (4B) were the most potent of the novel nucleotide series, with EC50 values of 0.03 mM for both, being ca. 80-fold more potent than 2-propylthio-ATP and ATP (EC50 = 2.6 μM). We conclude that the borano-substitution at the a-phosphate of 2-propylthio-ATP enhances nucleotide potency at the P2Y11 receptor. The combination with a Pβ-Pγ-dichloromethylene group in 4B results in a nucleotide, which shows higher selectivity for the P2Y11 receptor over the P2Y1 receptor than 2B making it the most promising of the novel P2Y11 receptor agonists.

Original languageEnglish
Pages (from-to)645-655
Number of pages11
JournalBiochemical Pharmacology
Issue number5
StatePublished - 2013
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by a Grant from the German-Israeli Foundation for Scientific Research and Development (GIF Grant 958 ) to GR and BF.


  • AR-C67085
  • ATP
  • Nucleotide receptor
  • P2Y receptor
  • Purinergic agonist

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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