Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2007 May 3;50(9):2030-9.
doi: 10.1021/jm061222w. Epub 2007 Apr 4.

Structure-activity relationship of uridine 5'-diphosphoglucose analogues as agonists of the human P2Y14 receptor

Hyojin Ko  1 , Ingrid Fricks, Andrei A Ivanov, T Kendall Harden, Kenneth A Jacobson
Affiliations

Structure-activity relationship of uridine 5'-diphosphoglucose analogues as agonists of the human P2Y14 receptor

Hyojin Ko et al. J Med Chem. .

Abstract

UDP-glucose (UDPG) and derivatives are naturally occurring agonists of the Gi protein-coupled P2Y14 receptor, which occurs in the immune system. We synthesized and characterized pharmacologically novel analogues of UDPG modified on the nucleobase, ribose, and glucose moieties, as the basis for designing novel ligands in conjunction with modeling. The recombinant human P2Y14 receptor expressed in COS-7 cells was coupled to phospholipase C through an engineered Galpha-q/i protein. Most modifications of the uracil or ribose moieties abolished activity; this is among the least permissive P2Y receptors. However, a 2-thiouracil modification in 15 (EC50 49 +/- 2 nM) enhanced the potency of UDPG (but not UDP-glucuronic acid) by 7-fold. 4-Thio analogue 13 was equipotent to UDPG, but S-alkylation was detrimental. Compound 15 was docked in a rhodposin-based receptor homology model, which correctly predicted potent agonism of UDP-fructose, UDP-mannose, and UDP-inositol. The hexose moiety of UDPG interacts with multiple H-bonding and charged residues and provides a fertile region for agonist modification.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Activation by potent agonists 13 (A) and 15 (B) of phospholipase C in COS-7 cells expressing both the human P2Y14 receptor and an engineered Gα-q/i protein that allows the Gi-coupled receptor to stimulate inositol phosphate hydrolysis by phospholipase C.
Figure 1
Figure 1
Activation by potent agonists 13 (A) and 15 (B) of phospholipase C in COS-7 cells expressing both the human P2Y14 receptor and an engineered Gα-q/i protein that allows the Gi-coupled receptor to stimulate inositol phosphate hydrolysis by phospholipase C.
Figure 2
Figure 2
Possible conformations of the hexose ring of UDPG.
Figure 3
Figure 3
The molecular model of the human P2Y14 receptor obtained after 20 ns of molecular dynamics simulation. A centroid of Lys171, Arg253, and Lys277 (red sphere) was used as a center of the box for molecular docking of UDPG.
Figure 4
Figure 4
Molecular model of the P2Y14-compound 15 complex. A rhodopsin-based molecular model of the human P2Y14 receptor, was refined using 20 ns molecular dynamics (MD) simulation in the phospholipid bilayer. The complex obtained after the automatic docking of 15 was used as a starting point for a Monte Carlo Multiple Minimum (MCMM) conformational search analysis of the ligand inside the putative binding site of the P2Y14 receptor.
Figure 5
Figure 5
The fructose moiety of 26 docked within the binding site of the human P2Y14 receptor.
Scheme 1
Scheme 1
Synthesis of UDPG analogues substituted on the ribose moiety or the 2 position of the uracil moiety. Reagents and conditions: (a) (i) POCl3, Proton Sponge, PO(OMe)3, 0 °C, (ii) 0.2 M triethylammonium bicarbonate, rt; (b) CF3CO2Et, DIEA, DMF, rt; (c) (i) 1,1′-carbonyldiimidazole, DMF, rt, (ii) Et3N 5% in H2O/MeOH 1/1, rt, (iii) glucose-1-monophosphate tributylammonium salt, DMF, rt; (d) H2, Pd/C, MeOH, rt; (e) (i) morpholine, DCC, t-BuOH, H2O, reflux, (ii) glucose-1-monophosphate tributylammonium salt, DMF, rt.
Scheme 2
Scheme 2
Synthesis of UDPG analogues substituted on the 4 or 5 position of the uracil moiety. Reagents and conditions: (a) (i) 1,1′-carbonyldiimidazole, DMF, rt, (ii) Et3N 5% in H2O/MeOH 1/1, rt, (iii) glucose-1-monophosphate tributylammonium salt, DMF, rt; (b) (i) 0.25 M NaOH, H2O, MeOH, rt, (ii) iodomethane, DMF, rt.
Scheme 3
Scheme 3
Synthesis of an (S)-methanocarba analogue of 2′-deoxy-UDPG. Reagents and conditions: (a) (i) 1,1′-carbonyldiimidazole, DMF, rt, (ii) Et3N 5% in H2O/MeOH 1/1, rt, (iii) glucose-1-monophosphate tributylammonium salt, DMF, rt.
Chart 1
Chart 1
Structures of three naturally-occurring UDP-sugars (1, 2, and 4a) and related derivatives that activate the P2Y14 receptor.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Fredholm BB, Abbracchio MP, Burnstock G, Dubyak GR, Harden TK, Jacobson KA, Schwabe U, Williams M. Towards a revised nomenclature for P1 and P2 receptors. Trends Pharmacol. Sci. 1997;18:79–82. - PMC - PubMed
    1. North RA, Barnard EA. Nucleotide receptors. Curr. Opin. Neurobiol. 1997;7:346–357. - PubMed
    1. Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Fumagalli M, King BF, Gachet C, Jacobson KA, Weisman GA. International Union of Pharmacology. Update of the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol. Rev. 2006;58:281–341. - PMC - PubMed
    1. Jacobson KA, Costanzi S, Ohno M, Joshi BV, Besada P, Xu B, Tchilibon S. Molecular recognition at purine and pyrimidine nucleotide (P2) receptors. Curr. Top. Med. Chem. 2004;4:805–819. - PMC - PubMed
    1. von Kügelgen I. Pharmacological profiles of cloned mammalian P2Y-receptor subtypes. Pharmacology Therapeutics. 2006;110:415–432. - PubMed

Publication types

Substances

LinkOut - more resources