Non-competitive inhibitors of metabotropic glutamate receptor 5 (mGluR5)

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 11, 2005, Pages 2876-2880

  Tasler, Stefan ^a   Kraus, Jürgen ^a   Pegoraro, Stefano ^a   Aschenbrenner, Andrea ^a   Poggesi, Elena ^b   Testa, Rodolfo ^b   Motta, Gianni ^b   Leonardi, Amedeo ^b  

^a 4SC AG   (Germany)

^b Recordati SpA   (Italy)

Author keywords

Metabotropic glutamate receptor; Molecular modeling; Neuroplasticity; Non competitive antagonist

Indexed keywords

METABOTROPIC RECEPTOR ANTAGONIST;

ANALYTIC METHOD; ARTICLE; DRUG STRUCTURE; ENZYME ASSAY; ENZYME BINDING; IC 50; PHARMACOPHORE; STRUCTURE ANALYSIS;

EXCITATORY AMINO ACID ANTAGONISTS; RECEPTORS, METABOTROPIC GLUTAMATE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 19544393376     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.03.089     Document Type: Article

References (19)

1. V. Neugebauer Expert Rev. Neurother. 1 2001 89
2. J.C. Watkins Biochem. Soc. Trans. 28 2000 297
3. H. Bräuner-Osborne, J. Egebjerg, E.O. Nielsen, U. Madsen, and P. Krogsgaard-Larsen J. Med. Chem. 43 2000 2609
4. R. Pellicciari, and G. Costantino Curr. Opin. Chem. Biol. 3 1999 433
5. D.D. Schoepp, D.E. Jane, and J.A. Monn Neuropharmacology 38 1999 1431
6. P.J. Conn, and J.P. Pin Annu. Rev. Pharmacol. Toxicol. 37 1997 205
7. E. Hermans, and R.A.J. Challiss Biochem. J. 359 2001 465
8. N. Kunishima, Y. Shimada, Y. Tsuji, T. Sato, M. Yamamoto, T. Kumasaka, S. Nakanishi, H. Jingami, and K. Morikawa Nature 407 2000 971
9. M.-L. Parmentier, L. Prezeau, J. Bockaert, and J.P. Pin Trends Pharmacol. Sci. 23 2002 268
10. J.P. Pin, C. De Colle, A.-S. Bessis, and F. Acher Eur. J. Pharmacol. 375 1999 277
11. F. Gasparini, H. Andres, P.J. Flor, M. Heinrich, W. Inderbitzin, K. Lingenhöhl, H. Müller, V.C. Munk, K. Omilusik, C. Stierlin, N. Stoehr, I. Vranesic, and R. Kuhn Bioorg. Med. Chem. Lett. 12 2002 407
12. Van Wagenen, B. C.; Stormann, T. M.; Moe, S. T.; Sheehan, S. M.; McLeod, D. A.; Smith, D. L.; Isaac, M. B.; Slassi, A. WO Patent 01/12627 A1, 2001
13. For a pharmacophore alignment, compounds of a virtual library are partitioned into fragments, an anchor fragment is selected and aligned on the parent structure, for example, MMPEP (1), and adjusted in a way that similar electrostatic and hydrophobic interaction possibilities become superimposed (unlike a structural alignment, in which similar parts of the molecules are superimposed). Next fragment is then connected to the first one and again adjusted for maximal interaction identities based on the position chosen for the first fragment. Several permutations of starting fragments are evaluated, resulting in a pharmacophore alignment of maximal similarities in interaction possibilities. For details, see: M.H.J. Seifert, K. Wolf, and D. Vitt Biosilico 1 2003 143
14. 3H]MMPEP according to: V. Mutel, G.J. Ellis, G. Adam, S. Chaboz, A. Nilly, J. Messer, Z. Blueuel, V. Metzler, P. Malherbe, E.-J. Schlaeger, B.S. Roughley, R.L.M. Faull, and G. Richards J. Neurochem. 75 2000 2590
15. If not commercially available, synthesized according to: K. Schwetlick Organikum 21st ed. 2001 Wiley-VCH Weilheim 613 614
16. J.H. Clark, and J.M. Miller Tetrahedron Lett. 1977 599
17. Products showed >95% purity as determined by LC-MS and NMR spectroscopy
18. Functional effects of the compounds were evaluated in a FLIPR assay on CHO cells transfected with mGlu5 receptors
19. All compounds tested were completely stable in physiological buffer (PBS) for at least 24 h