TY - JOUR
T1 - 5-OMe-UDP is a Potent and Selective P2Y6-Receptor Agonist
AU - Ginsburg-Shmuel, Tamar
AU - Haas, Michael
AU - Schumann, Marien
AU - Reiser, Georg
AU - Kalid, Ori
AU - Stern, Noa
AU - Fischer, Bilha
PY - 2010/2/25
Y1 - 2010/2/25
N2 - P2Y nucleotide receptors (P2Y-Rs) play important physiological roles. However, most of the P2Y-R subtypes are still lacking potent and selective agonists and antagonists. Based, on data mining analysis of binding interactions in 44 protein-uridine nucleos(t)ides complexes, we designed uracil nucleotides, substituted at the C5/C6 position. All Co-substituted derivatives were inactive at the P2Y2,4,6-Rs, while out of the C5-substituted analogues, only 5-OMe-UD(T)P showed activity. To rationalize the data, the ionization and conformation of these analogues were evaluated. The pKa values of most analogues substituted at the C5/C6 positions were unaltered compared to UTP (pKa 9.42), except for 5-F-UTP nucleotide (pKa 7.85). Co-substituted analogues adopt the syn or high-syn conformations, which are disfavored by the receptors, while 5-OMe-UD(T)P adopt the favored anti conformation. Furthermore, 5-OMe-UDP adopts the S sugar puckering, which is the conformation preferred by the P2Y6-R, but not the P2Y2- or P2Y4-Rs. 5-OMe-UDP fulfills the conformational and H-bonding requirements of P2Y6-R, thus, making a potent P2Y6-R agonist, (EC50 0.08 μM), more than UDP (EC50 0.14μM).
AB - P2Y nucleotide receptors (P2Y-Rs) play important physiological roles. However, most of the P2Y-R subtypes are still lacking potent and selective agonists and antagonists. Based, on data mining analysis of binding interactions in 44 protein-uridine nucleos(t)ides complexes, we designed uracil nucleotides, substituted at the C5/C6 position. All Co-substituted derivatives were inactive at the P2Y2,4,6-Rs, while out of the C5-substituted analogues, only 5-OMe-UD(T)P showed activity. To rationalize the data, the ionization and conformation of these analogues were evaluated. The pKa values of most analogues substituted at the C5/C6 positions were unaltered compared to UTP (pKa 9.42), except for 5-F-UTP nucleotide (pKa 7.85). Co-substituted analogues adopt the syn or high-syn conformations, which are disfavored by the receptors, while 5-OMe-UD(T)P adopt the favored anti conformation. Furthermore, 5-OMe-UDP adopts the S sugar puckering, which is the conformation preferred by the P2Y6-R, but not the P2Y2- or P2Y4-Rs. 5-OMe-UDP fulfills the conformational and H-bonding requirements of P2Y6-R, thus, making a potent P2Y6-R agonist, (EC50 0.08 μM), more than UDP (EC50 0.14μM).
UR - http://www.scopus.com/inward/record.url?scp=77649207345&partnerID=8YFLogxK
U2 - 10.1021/jm901450d
DO - 10.1021/jm901450d
M3 - Article
C2 - 20095577
AN - SCOPUS:77649207345
SN - 0022-2623
VL - 53
SP - 1673
EP - 1685
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -