ACS Medicinal Chemistry Letters
Letter
receptor GPR17 is a cell-intrinsic timer of myelination. Nat. Neurosci.
2009, 12, 1398−406.
(16) Salituro, F. G.; Harrison, B. L.; Baron, B. M.; Nyce, P. L.;
Stewart, K. T.; Kehne, J. H.; White, H. S.; McDonald, I. A. 3-(2-
Carboxyindol-3-yl)propionic acid-based antagonists of the N-methyl-
D-aspartic acid receptor associated glycine binding site. J. Med. Chem.
1992, 35, 1791−1799.
(17) Baron, B. M.; Cregge, R. J.; Farr, R. A.; Friedrich, D.; Gross, R.
S.; Harrison, B. L.; Janowick, D. A.; Matthews, D.; McCloskey, T. C.;
Meikrantz, S.; Nyce, P. L.; Vaz, R.; Metz, W. A. CoMFA, synthesis, and
pharmacological evaluation of (E)-3-(2-carboxy-2-arylvinyl)-4,6-di-
chloro-1H-indole-2-carboxylic acids: 3-[2-(3-aminophenyl)-2-carbox-
yvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, a potent selective
glycine-site NMDA receptor antagonist. J. Med. Chem. 2005, 48, 995−
1018.
(18) Bigge, C. F.; Graham, J.; Po-Wai, Y. Derivatives of 2-
carboxyindoles having pharmaceutical activity. Warner Lambert
Company, Ann Arbor, Michigan, USA, US Patent 5,284,862, 1994.
(19) Ward, R. J.; Alvarez-Curto, E.; Milligan, G. Using the Flp-In T-
Rex system to regulate GPCR expression. Methods Mol. Biol. 2011,
746, 21−37.
(3) Lecca, D.; Trincavelli, M. L.; Gelosa, P.; Sironi, L.; Ciana, P.;
Fumagalli, M.; Villa, G.; Verderio, C.; Grumelli, C.; Guerrini, U.;
Tremoli, E.; Rosa, P.; Cuboni, S.; Martini, C.; Buffo, A.; Cimino, M.;
Abbracchio, M. P. The recently identified P2Y-like receptor GPR17 is
a sensor of brain damage and a new target for brain repair. PLoS One
2008, 3, e3579.
(4) Fumagalli, M.; Daniele, S.; Lecca, D.; Lee, P. R.; Parravicini, C.;
Fields, R. D.; Rosa, P.; Antonucci, F.; Verderio, C.; Trincavelli, M. L.;
Bramanti, P.; Martini, C.; Abbracchio, M. P. Phenotypic changes,
signaling pathway, and functional correlates of GPR17-expressing
neural precursor cells during oligodendrocyte differentiation. J. Biol.
Chem. 2011, 286, 10593−10604.
(5) Hennen, S.; Peters, L.; Wang, H.; Spinrath, A.; Merten, N.;
Blattermann, S.; Akkari, R.; Schrage, R.; Simon, K.; Schroder, R.;
̈
̈
Schulz, D.; Vermeiren, C.; Zimmermann, K.; Kehraus, S.; Drewke, C.;
Pfeifer, A.; Konig, G. M.; Mohr, K.; Gillard, M.; Muller, C. E.; Lu, Q.
̈
̈
R.; Gomeza, J.; Kostenis, E. Decoding signaling and function of the
orphan G protein-coupled receptor GPR17 with a small molecule
agonist. Sci. Signaling 2013, 6, ra93.
(20) Liu, W.; Chun, E.; Thompson, A. A.; Chubukov, P.; Xu, F.;
Katritch, V.; Han, G. W.; Roth, C. B.; Heitman, L. H.; IJzerman, A. P.;
Cherzov, V.; Stevens, R. C. Structural basis for allosteric regulation of
GPCRs by sodium ions. Science 2012, 337, 232−236.
(6) Parravicini, C.; Abbracchio, M. P.; Fantucci, P.; Ranghino, G.
Forced unbinding of GPR17 ligands from wild type and R255I mutant
receptor models through a computational approach. BMC Struct. Biol.
2010, 10, 8.
(7) Pugliese, A. M.; Trincavelli, M. L.; Lecca, D.; Coppi, E.;
Fumagalli, M.; Ferrario, S.; Failli, P.; Daniele, S.; Martini, C.; Pedata,
F.; Abbracchio, M. P. Functional characterization of two isoforms of
the P2Y-like receptor GPR17: [35S]GTPgammaS binding and
electrophysiological studies in 1321N1 cells. Am. J. Physiol., Cell
Physiol. 2009, 297, C1028−1040.
(8) Buccioni, M.; Marucci, G.; Dal, B. D.; Giacobbe, D.; Lambertucci,
C.; Soverchia, L.; Thomas, A.; Volpini, R.; Cristalli, G. Innovative
functional cAMP assay for studying G protein-coupled receptors:
application to the pharmacological characterization of GPR17.
Purinergic Signalling 2011, 7, 463−468.
(9) Daniele, S.; Trincavelli, M. L.; Gabelloni, P.; Lecca, D.; Rosa, P.;
Abbracchio, M. P.; Martini, C. Agonist-induced desensitization/
resensitization of human G protein-coupled receptor 17: a functional
cross-talk between purinergic and cysteinyl-leukotriene ligands. J.
Pharmacol. Exp. Ther. 2011, 338, 559−567.
(10) Coppi, E.; Maraula, G.; Fumagalli, M.; Failli, P.; Cellai, L.;
Bonfanti, E.; Mazzoni, L.; Coppini, R.; Abbracchio, M. P.; Pedata, F.;
Pugliese, A. M. UDP-glucose enhances outward K(+) currents
necessary for cell differentiation and stimulates cell migration by
activating the GPR17 receptor in oligodendrocyte precursors. Glia
2013, 61, 1155−1171.
(11) Benned-Jensen, T.; Rosenkilde, M. M. Distinct expression and
ligand-binding profiles of two constitutively active GPR17 splice
variants. Br. J. Pharmacol. 2010, 159, 1092−1105.
(12) Maekawa, A.; Balestrieri, B.; Austen, K. F.; Kanaoka, Y. GPR17
is a negative regulator of the cysteinyl leukotriene 1 receptor response
to leukotriene D4. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 11685−
11690.
(21) Thimm, D.; Funke, M.; Meyer, A.; Muller, C E. 6-Bromo-8-(4-
̈
[3H]methoxy-benzamido)-4-oxo-4H-chromene-2-carboxylic acid
([3H]PSB-13253): a powerful tool for studying orphan G protein-
coupled receptor GPR35. J. Med. Chem. 2013, 56, 7084−7099.
(22) Hulme, E. C.; Trevethick, M. A. Ligand binding assays at
equilibrium: validation and interpretation. Br. J. Pharmacol. 2010, 161,
1219−1237.
(23) Borrmann, T.; Hinz, S.; Bertarelli, D. C.; Li, W.; Florin, N. C.;
Scheiff, A. B.; Muller, C. E. 1-Alkyl-8-(piperazine-1-sulfonyl) phenyl-
̈
xanthines: development and characterization of adenosine A2B
receptor antagonists and a new radioligand with subnanomolar affinity
and subtype specificity. J. Med. Chem. 2009, 52, 3994−4006.
(24) Bertarelli, D. C.; Diekmann, M.; Hayallah, A. M.; Rusing, D.;
̈
Iqbal, J.; Preiss, B.; Verspohl, E. J.; Muller, C. E. Characterization of
̈
human and rodent native and recombinant adenosine A2B receptors by
radioligand binding studies. Purinergic Signalling 2006, 2, 559−571.
(25) Muller, C. E.; Maurinsh, J.; Sauer, R. Binding of [3H]MSX-2 (3-
̈
(3-hydroxypropyl)-7-methyl-8-(m-methoxystyryl)-1-propargylxan-
thine) to rat striatal membranes: a new, selective antagonist
radioligand for A2A adenosine receptors. Eur. J. Pharm. Sci. 2000, 10,
259−265.
(26) Schiedel, A. C.; Meyer, H.; Alsdorf, B. B.; Gorzalka, S.; Brussel,
̈
H.; Muller, C. E. [3H]Adenine is a suitable radioligand for the labeling
̈
of G protein-coupled adenine receptors but shows high affinity to
bacterial contaminations in buffer solutions. Purinergic Signalling 2007,
3, 347−358.
(27) Christopoulos, A.; Kenakin, T. G protein-coupled receptor
allosterism and complexing. Pharmacol. Rev. 2002, 54, 323−373.
(28) Muller, C. E.; Schiedel, A. C.; Baqi, Y. Allosteric modulators of
̈
rhodopsin-like G protein-coupled receptors: opportunities in drug
development. Pharmacol. Ther. 2012, 135, 292−315.
(13) Qi, A.-D.; Harden, T. K.; Nicholas, R. A. Is GPR17 a P2Y/
leukotriene receptor? Examination of uracil nucleotides, nucleotide
sugars, and cysteinyl-leukotrienes as agonists of GPR17. J. Pharmacol.
Exp. Ther. 2013, 347, 38−46.
(14) Baqi, Y.; Alshaibani, S.; Ritter, K.; Abdelrahman, A.; Spinrath,
A.; Kostenis, E.; Muller, C. E. Improved synthesis of 4-/6-substituted
̈
2-carboxy-1H-indole-3-propionic acid derivatives and structure−
activity relationships as GPR17 agonists. MedChemComm 2014, 5,
86−92.
(15) Di Fabio, R.; Capelli, A. M.; Conti, N.; Cugola, A.; Donati, D.;
Feriani, A.; Gastaldi, P.; Gaviraghi, G.; Hewkin, C. T.; Micheli, F.;
Missio, A.; Mugnaini, M.; Pecunioso, A.; Quaglia, A. M.; Ratti, E.;
Rossi, L.; Tedesco, G.; Trist, D. G.; Reggiani, A. Substituted indole-2-
carboxylates as in vivo potent antagonists acting as the strychnine-
insensitive glycine binding site. J. Med. Chem. 1997, 40, 841−50.
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