Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists.
The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modification, found previously to enhance P2Y(2) receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y(2) receptor, in the form of Up(4)-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, alpha,beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1]glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P(1)-(uridine-5')-P(4)-(2'-deoxycytidine-5')tetraphosphate), a potent and selective P2Y(2) receptor agonist.
Ko
Hyojin
H
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-0810, USA.
Carter
Rhonda L
RL
Cosyn
Liesbet
L
Petrelli
Riccardo
R
de Castro
Sonia
S
Besada
Pedro
P
Zhou
Yixing
Y
Cappellacci
Loredana
L
Franchetti
Palmarisa
P
Grifantini
Mario
M
Van Calenbergh
Serge
S
Harden
T Kendall
TK
Jacobson
Kenneth A
KA
D006801:Humans; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D013329:Structure-Activity Relationship; D014500:Uracil Nucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
C546385:P2RY2 protein, human; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D014500:Uracil Nucleotides; C099845:purinoceptor P2Y6