Selective High-Affinity P2Y14 Receptor Antagonist
49
Hirschberg CB, Robbins PW, and Abeijon C (1998) Transporters of nucleotide sugars,
ATP, and nucleotide sulfate in the endoplasmic reticulum and Golgi apparatus.
Annu Rev Biochem 67:49–69.
Jacobson KA, Jayasekara MPS, and Costanzi S (2012) Molecular structure of P2Y
receptors: mutagenesis, modelling and chemical probes. Wiley Interdiscip Rev
Membr Transp Signal 1:815–827.
Kreda SM, Okada SF, van Heusden CA, O’Neal W, Gabriel S, Abdullah L, Davis CW,
Boucher RC, and Lazarowski ER (2007) Coordinated release of nucleotides and
mucin from human airway epithelial Calu-3 cells. J Physiol 584:245–259.
Lazarowski ER, Shea DA, Boucher RC, and Harden TK (2003) Release of cellular
UDP-glucose as a potential extracellular signaling molecule. Mol Pharmacol 63:
1190–1197.
Authorship Contributions
Participated in research design: Barrett, Jacobson, Lazarowski,
Harden.
Conducted experiments: Barrett, Sesma, Ball.
Contributed new reagents or analytic tools: Jayasekara, Jacobson.
Performed data analysis: Barrett, Sesma, Ball.
Wrote or contributed to the writing of the manuscript: Barrett,
Sesma, Jacobson, Lazarowski, Harden.
Lazarowski ER, Sesma JI, Seminario-Vidal L, and Kreda SM (2011) Molecular mech-
anisms of purine and pyrimidine nucleotide release. Adv Pharmacol 61:221–261.
Lecut C, Frederix K, Johnson DM, Deroanne C, Thiry M, Faccinetto C, Marée R,
Evans RJ, Volders PG, and Bours V et al. (2009) P2X1 ion channels promote
neutrophil chemotaxis through Rho kinase activation. J Immunol 183:2801–2809.
Lee BC, Cheng T, Adams GB, Attar EC, Miura N, Lee SB, Saito Y, Olszak I,
Dombkowski D, and Olson DP et al. (2003) P2Y-like receptor, GPR105 (P2Y14),
identifies and mediates chemotaxis of bone-marrow hematopoietic stem cells.
Genes Dev 17:1592–1604.
Moore DJ, Murdock PR, Watson JM, Faull RL, Waldvogel HJ, Szekeres PG, Wilson
S, Freeman KB, and Emson PC (2003) GPR105, a novel Gi/o-coupled UDP-glucose
receptor expressed on brain glia and peripheral immune cells, is regulated by
immunologic challenge: possible role in neuroimmune function. Brain Res Mol
Brain Res 118:10–23.
Nicholas RA, Watt WC, Lazarowski ER, Li Q, and Harden K (1996) Uridine nucle-
otide selectivity of three phospholipase C-activating P2 receptors: identification of
a UDP-selective, a UTP-selective, and an ATP- and UTP-specific receptor. Mol
Pharmacol 50:224–229.
Okada SF, Zhang L, Kreda SM, Abdullah LH, Davis CW, Pickles RJ, Lazarowski ER,
and Boucher RC (2011) Coupled nucleotide and mucin hypersecretion from goblet-
cell metaplastic human airway epithelium. Am J Respir Cell Mol Biol 45:253–260.
Qi AD, Kennedy C, Harden TK, and Nicholas RA (2001) Differential coupling of the
human P2Y11 receptor to phospholipase C and adenylyl cyclase. Br J Pharmacol
132:318–326.
Ralevic V and Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol
Rev 50:413–492.
Robichaud J, Fournier JF, Gagné S, Gauthier JY, Hamel M, Han Y, Hénault M,
Kargman S, Levesque JF, and Mamane Y et al. (2011) Applying the pro-drug
approach to afford highly bioavailable antagonists of P2Y14. Bioorg Med Chem Lett
21:4366–4368.
Salomon Y, Londos C, and Rodbell M (1974) A highly sensitive adenylate cyclase
assay. Anal Biochem 58:541–548.
Schachter JB, Li Q, Boyer JL, Nicholas RA, and Harden TK (1996) Second messenger
cascade specificity and pharmacological selectivity of the human P2Y1-purino-
ceptor. Br J Pharmacol 118:167–173.
References
Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C,
Knight GE, Fumagalli M, Gachet C, and Jacobson KA et al. (2006) International
Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide
receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol
Rev 58:281–341.
Arase T, Uchida H, Kajitani T, Ono M, Tamaki K, Oda H, Nishikawa S, Kagami M,
Nagashima T, and Masuda H, et al. (2009) The UDP-glucose receptor P2RY14
triggers innate mucosal immunity in the female reproductive tract by inducing
IL-8. J Immunol 182:7074–7084.
Belly M, Deschenes D, Fortin R, Fournier JF, Gagne S, Gareau Y, Gautheir JY, Li L,
Robichaud J, Therien M, Tranmer GK, and Wang Z (2009) inventors, Merck Frosst
Canada LTD, assignee. Substituted 2-naphthoic acids as antagonists of GPR105
activity. WO 2009/070873A1. 2010 Nov 25.
Boger DL, Han N, Tarby CM, Boyce CW, Cai H, Jin Q, and Kitos PA (1996) Syn-
thesis, chemical properties, and preliminary evaluation of substituted CBI analogs
of CC-1065 and the duocarmycins incorporating the 7-cyano-1,2,9,9a-tetrahydrocyclopropa
[c]benz[e]indol-4-one alkylation subunit: Hammett quantitation of the magnitude
of electronic effects on functional reactivity. J Org Chem 61:4894–4912.
Brown HA, Lazarowski ER, Boucher RC, and Harden TK (1991) Evidence that UTP
and ATP regulate phospholipase C through a common extracellular 59-nucleotide
receptor in human airway epithelial cells. Mol Pharmacol 40:648–655.
Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission.
Physiol Rev 87:659–797.
Carter RL, Fricks IP, Barrett MO, Burianek LE, Zhou Y, Ko H, Das A, Jacobson KA,
Lazarowski ER, and Harden TK (2009) Quantification of Gi-mediated inhibition of
adenylyl cyclase activity reveals that UDP is a potent agonist of the human P2Y14
receptor. Mol Pharmacol 76:1341–1348.
Chambers JK, Macdonald LE, Sarau HM, Ames RS, Freeman K, Foley JJ, Zhu Y,
McLaughlin MM, Murdock P, and McMillan L et al. (2000) A G protein-coupled
receptor for UDP-glucose. J Biol Chem 275:10767–10771.
Coward P, Chan SD, Wada HG, Humphries GM, and Conklin BR (1999) Chimeric G
proteins allow a high-throughput signaling assay of Gi-coupled receptors. Anal
Biochem 270:242–248.
Das A, Ko H, Burianek LE, Barrett MO, Harden TK, and Jacobson KA (2010) Human
P2Y14 receptor agonists: truncation of the hexose moiety of uridine-59-diphos-
phoglucose and its replacement with alkyl and aryl groups. J Med Chem 53:
471–480.
Scrivens M and Dickenson JM (2006) Functional expression of the P2Y14 receptor in
human neutrophils. Eur J Pharmacol 543:166–173.
Sesma JI, Esther CR, Jr, Kreda SM, Jones L, O’Neal W, Nishihara S, Nicholas RA,
and Lazarowski ER (2009) Endoplasmic reticulum/golgi nucleotide sugar trans-
porters contribute to the cellular release of UDP-sugar signaling molecules. J Biol
Chem 284:12572–12583.
Sesma JI, Kreda SM, Steinckwich-Besancon N, Dang H, García-Mata R, Harden TK,
and Lazarowski ER (2012) The UDP-sugar-sensing P2Y14 receptor promotes Rho-
mediated signaling and chemotaxis in human neutrophils. Am J Physiol Cell
Physiol 303:C490–C498.
Freeman K, Tsui P, Moore D, Emson PC, Vawter L, Naheed S, Lane P, Bawagan H,
Herrity N, and Murphy K et al. (2001) Cloning, pharmacology, and tissue distri-
bution of G-protein-coupled receptor GPR105 (KIAA0001) rodent orthologs.
Genomics 78:124–128.
Fricks IP, Maddileti S, Carter RL, Lazarowski ER, Nicholas RA, Jacobson KA,
and Harden TK (2008) UDP is a competitive antagonist at the human P2Y14 re-
ceptor. J Pharmacol Exp Ther 325:588–594.
Fricks IP, Carter RL, Lazarowski ER, and Harden TK (2009) Gi-dependent cell
signaling responses of the human P2Y14 receptor in model cell systems. J Phar-
macol Exp Ther 330:162–168.
Gao ZG, Wei Q, Jayasekara MP, and Jacobson KA (2013) The role of P2Y14 and other
P2Y receptors in degranulation of human LAD2 mast cells. Purinergic Signal 9:
31–40.
Skelton L, Cooper M, Murphy M, and Platt A (2003) Human immature monocyte-
derived dendritic cells express the G protein-coupled receptor GPR105 (KIAA0001,
P2Y14) and increase intracellular calcium in response to its agonist, uridine
diphosphoglucose. J Immunol 171:1941–1949.
Vaughan KR, Stokes L, Prince LR, Marriott HM, Meis S, Kassack MU, Bingle CD,
Sabroe I, Surprenant A, and Whyte MK (2007) Inhibition of neutrophil apoptosis
by ATP is mediated by the P2Y11 receptor. J Immunol 179:8544–8553.
Verghese MW, Kneisler TB, and Boucheron JA (1996) P2U agonists induce chemo-
taxis and actin polymerization in human neutrophils and differentiated HL60 cells.
J Biol Chem 271:15597–15601.
Gauthier JY, Belley M, Deschênes D, Fournier JF, Gagné S, Gareau Y, Hamel M,
Hénault M, Hyjazie H, and Kargman S et al. (2011) The identification of 4,7-
disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14
.
Xu J, Morinaga H, Oh D, Li P, Chen A, Talukdar S, Mamane Y, Mancini JA,
Nawrocki AR, and Lazarowski E et al. (2012) GPR105 ablation prevents in-
flammation and improves insulin sensitivity in mice with diet-induced obesity.
J Immunol 189:1992–1999.
von Küglegen V and Harden TK (2012) Molecular pharmacology, physiology, and
structure of the P2Y receptors. Adv Pharmacol 61:373–451.
Bioorg Med Chem Lett 21:2836–2839.
Guay D, Beaulieu C, Belley M, Crane SN, DeLuca JC, Gareau Y, Hamel M, Henault
M, Hyjazie H, and Kargman S et al. (2011) Synthesis and SAR of pyrimidine-based,
non-nucleotide P2Y14 receptor antagonists. Bioorg Med Chem Lett 21:2832–2835.
Hamel M, Henault M, Hyjazie H, Morin N, Bayly C, Skorey K, Therien AG, Mancini
J, Brideau C, and Kargman S (2011) Discovery of novel P2Y14 agonist and an-
tagonist using conventional and nonconventional methods. J Biomol Screen 16:
1098–1105.
Zimmermann H (2000) Extracellular metabolism of ATP and other nucleotides.
Naunyn Schmiedebergs Arch Pharmacol 362:299–309.
Harden TK, Scheer AG, and Smith MM (1982) Differential modification of the in-
teraction of cardiac muscarinic cholinergic and beta-adrenergic receptors with
a guanine nucleotide binding component(s). Mol Pharmacol 21:570–580.
Harden TK, Sesma JI, Fricks IP, and Lazarowski ER (2010) Signalling and phar-
macological properties of the P2Y14 receptor. Acta Physiol (Oxf) 199:149–160.
Address correspondence to: Dr. T. Kendall Harden, Department of
Pharmacology, University of North Carolina School of Medicine, Chapel Hill,