title: Boranophosphate isoster controls P2Y-receptor subtype selectivity and metabolic stability of dinucleoside polyphosphate analogues.
abstract: Dinucleoside polyphosphates, Np(n)N', exert their physiological effects via P2 receptors (P2Rs). Np(n)N' 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(n)N', 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(1)R and P2Y(6)R 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(n)N' 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(n)N' 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.
authors: Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors: Shir
authors: S
authors: Yelovitch
authors: Jean
authors: J
authors: Camden
authors: Gary A
authors: GA
authors: Weisman
authors: Bilha
authors: B
authors: Fischer
mesh_terms: D000818:Animals; D001880:Boranes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D015226:Dinucleoside Phosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D008968:Molecular Conformation; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry; D058912:Purinergic P2Y Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011755:Pyrophosphatases / Q000737:chemistry; D058470:Receptors, Purinergic P2Y / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014421:Turkey
chemical_list: D001880:Boranes; D015226:Dinucleoside Phosphates; D058912:Purinergic P2Y Receptor Agonists; D058470:Receptors, Purinergic P2Y; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; D002118:Calcium