Boranophosphate isoster controls P2Y-receptor subtype selectivity and metabolic stability of dinucleoside polyphosphate analogues

Shir Yelovitch, Jean Camden, Gary A. Weisman, Bilha Fischer

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Dinucleoside polyphosphates, Np nN′, exert their physiological effects via P2 receptors (P2Rs). Np nN′ are attractive drug candidates as they offer better stability and specificity compared to nucleotides, the most common P2R ligands. To further improve the agonist properties of Np nN′, we synthesized novel isosters of dinucleoside polyphosphates where N and N′ are A or U and where the Pα or Pβ phosphate groups are replaced by boranophosphate, denoted as Np n(α-B)N′ or Np n(β-B)N′ (n = 3, 4), respectively. The potency of Np n(α/β-B)N′ analogues was evaluated at tP2Y 1, hP2Y 2, hP2Y 4, and rP2Y 6 receptors. The most potent P2Y 1R and P2Y 6R agonists were the Up 4(β-B)A (A isomer, EC 50 of 0.5 μM vs 0.004 μM for 2-SMe-ADP) and Up 3(α-B)U (B isomer, EC 50 of 0.3 μM vs 0.2 μM for UDP), respectively. The receptor subtype selectivity is controlled by the position of the borano moiety on the Np nN′ polyphosphate chain and the type of the nucleobase. In addition, Np n(α/β-B) N′ proved ∼22-fold more resistant to hydrolysis by e-NPP1, as compared to the corresponding Np nN′ analogues. In summary, Up 4(β-B)A and Up 3(α-B)U are potent, stable, and highly selective P2Y 1 and P2Y 6 receptor agonists, respectively.

Original languageEnglish
Pages (from-to)437-448
Number of pages12
JournalJournal of Medicinal Chemistry
Volume55
Issue number1
DOIs
StatePublished - 12 Jan 2012

Funding

FundersFunder number
National Institute of Dental and Craniofacial ResearchR01DE007389

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