1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and selective iGluR5 modulators

Journal of Medicinal Chemistry

Volumn 51, Issue 20, 2008, Pages 6614-6618

  Butini, Stefania ^a,b   Pickering, Darryl S ^c   Morelli, Elena ^b,d   Coccone, Salvatore Sanna ^a,b   Trotta, Francesco ^a,b   De Angelis, Meri ^a,b   Guarino, Egeria ^a,b   Fiorini, Isabella ^a,b   Campiani, Giuseppe ^a,b   Novellino, Ettore ^b,e   Schousboe, Arne ^c   Christensen, Jeppe K ^e   Gemma, Sandra ^a,b  

^a European Research Centre for Drug Discovery and Development   (Italy)

^b UNIVERSITY OF SIENA   (Italy)

^c UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^d UNIVERSITY OF COPENHAGEN   (Denmark)

^e NEUROSEARCH A S   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2 AMINO 2 CARBOXYETHYL) 6,7 DIHYDRO 1H CYCLOPENTA[D]PYRIMIDIN 2,4(1H,3H) DIONE; 1 (2' AMINO 2' CARBOXYETHYL) 3 BENZYLFURO[3,4 D]PYRIMIDIN 2,4 DIONE; 1 (2' AMINO 2' CARBOXYETHYL) 3 BENZYLQUINAZOLINE 2,4(1H,3H) DIONE; 1 (2' AMINO 2' CARBOXYETHYL) 5,7 DIHYDROTHIENO[3,4 D]PYRIMIDIN 2,4(1H,3H) DIONE; 1 (2' AMINO 2' CARBOXYETHYL) 6,6 DIMETHYL 2,3,4,5,6,7 HEXAHYDROCYCLOPENTAPYRIMIDIN 2,4 DIONE; 1 (2' AMINO 2' CARBOXYETHYL)FURO[3,4 D]PYRIMIDIN 2,4 DIONE; 1 (2' AMINO 2' CARBOXYETHYL)QUINAZOLINE 2,4(1H,3H) DIONE; 1 (2' AMINO 2' CARBOXYETHYL)THIENO[3,2 D]PYRIMIDIN 2,4 DIONE; 1 (3' AMINO 3' CARBOXYPROPYL) 6,7 DIHYDRO 1H CYCLOPENTA[D]PYRIMIDIN 2,4(3H,5H) DIONE; 1,3 DI(3' AMINO 3' CARBOXYPROPYL) 6,7 DIHYDRO 1H CYCLOPENTA[D]PYRIMIDIN 2,4(3H,5H) DIONE; 1H CYCLOPENTAPYRIMIDINE 2,4(1H,3H) DIONE DERIVATIVE; AMPA RECEPTOR AGONIST; CPW 399; CYCLOPENTANE DERIVATIVE; GLUTAMATE RECEPTOR 5; IONOTROPIC RECEPTOR ANTAGONIST; KAINIC ACID RECEPTOR ANTAGONIST; RECEPTOR SUBTYPE; UNCLASSIFIED DRUG;

ARTICLE; BINDING ASSAY; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; EXCITOTOXICITY; HUMAN; IC 50; LIGAND BINDING; NONHUMAN; RAT; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION;

ANIMALS; CELL LINE; ELECTROPHYSIOLOGY; EXCITATORY AMINO ACID ANTAGONISTS; FEMALE; HUMANS; LIGANDS; MOLECULAR STRUCTURE; OOCYTES; PYRIMIDINONES; RATS; RECEPTORS, GLUTAMATE; SPODOPTERA; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES; XENOPUS LAEVIS;

EID: 54549112164     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800865a     Document Type: Article

References (13)

1. Bräuner-Osborne, H.; Egebjerg, J.; Nielsen, E.; Madsen, U.; Krogsgaard-Larsen, P. Ligands for glutamate receptors: design and therapeutic prospects. J. Med. Chem. 2000, 43, 2609-2645.
2. (a) Rosenmund, C.; Stern-Bach, Y.; Stevens, C. F. The tetrameric structure of a glutamate receptor channel. Science 1998, 280, 1596-1599.
3. (b) Sun, Y.; Olson, R.; Horning, M.; Armstrong, N.; Mayer, M.; Gouaux, E. Mechanism of glutamate receptor desensitization. Nature 2002, 417, 245-253.
4. (c) Laube, B.; Kuhse, J.; Betz, H. J. Evidence for a tetrameric structure of recombinant NMDA receptors. Neuroscience 1998, 18, 2954-2961.
5. Frandsen, A.; Schousboe, A. Excitatory amino acid-mediated cytotoxicity and calcium homeostasis in cultured neurons. J. Neurochem. 1993, 60, 1202-1211.
6. Campiani, G.; Morelli, E.; Nacci, V.; Fattorusso, C.; Ramunno, A.; Novellino, E.; Greenwood, J.; Liljefors, T.; Griffiths, R.; Sinclair, C.; Reavy, H.; Kristensen, A. S.; Pickering, D. S.; Schousboe, A.; Cagnotto, A.; Fumagalli, E.; Mennini, T. Characterization of the 1H-cyclopentapyrimidine-2,4(1H,3H)-dione derivative (S)-CPW399 as a novel, potent, and subtype-selective AMPA receptor full agonist with partial desensitization properties. J. Med. Chem. 2001, 44, 4501-4504.
7. Dolman, N. P.; Troop, H. M.; More, J. C. A.; Alt, A.; Knauss, J. L.; Nistico, R.; Jack, S.; Morley, R. M.; Bortolotto, Z. A.; Roberts, P. J.; Bleakman, D.; Collingridge, G. L.; Jane, D. E. Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors. J. Med. Chem. 2005, 48, 7867-7881.
8. Hogner, A.; Kastrup, J. S.; Jin, R.; Liljefors, T.; Mayer, M. L.; Egebjerg, J.; Larsen, I. K.; Gouaux, E. Structural basis for AMPA receptor activation and ligand selectivity: crystal structures of five agonist complexes with the GluR2 ligand-binding core. J. Mol. Biol. 2002, 322, 93-109.
9. Mayer, M. L. Crystal structures of the GluR5 and GluR6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity. Neuron 2005, 45, 539-552.
10. Frandsen, A.; Pickering, D. S.; Vestergaard, B.; Kasper, C.; Bryde Nielsen, B.; Greenwood, J. R.; Campiani, G.; Fattorusso, C.; Gajhede, M.; Schousboe, A.; Kastrup, J. S. Tyr702 is an important determinant of agonist binding and domain closure of the ligand-binding core of GluR2. Mol. Pharmacol. 2005, 67, 1-11.
11. K5 kainate receptor antagonists. J. Med. Chem. 2007, 50, 1558-1570.
12. Kizelsztein, P.; Eisenstein, M.; Strutz, N.; Hollmann, M.; Teichberg, V. I. Mutant cycle analysis of the active and desensitized states of an AMPA receptor induced by willardiines. Biochemistry 2000, 39, 12819-12827.
13. Greenwood, J. R.; Mewett, K. N.; Allan, R. D.; Martín, B. O.; Pickering, D. S. 3-Hydroxypyridazine 1-oxides as carboxylate bioisosteres: a new series of subtype-selective AMPA receptor agonists. Neuropharmacology 2006, 51, 52-59.