Efficacy switching SAR of mGluR5 allosteric modulators: Highly potent positive and negative modulators from one chemotype

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 11, 2011, Pages 3407-3410

  Sams, Anette Graven ^a   Mikkelsen, Gitte Kobberøe ^a   Brodbeck, Robbin M ^b   Pu, Xiaosui ^b   Ritzén, Andreas ^a  

^a H LUNDBECK A S   (Denmark)

^b LUNDBECK RESEARCH USA   (United States)

Author keywords

Allosteric modulator; Efficacy switching; Glutamate; mGluR5; NAM; PAM

Indexed keywords

FENOBAM; METABOTROPIC RECEPTOR 5; METABOTROPIC RECEPTOR 5 NEGATIVE ALLOSTERIC MODULATOR; METABOTROPIC RECEPTOR 5 POSITIVE ALLOSTERIC MODULATOR; METABOTROPIC RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ALLOSTERISM; ARTICLE; DRUG EFFICACY; DRUG POTENCY; STRUCTURE ACTIVITY RELATION;

ALLOSTERIC REGULATION; DRUG DESIGN; INHIBITORY CONCENTRATION 50; LIGANDS; MOLECULAR STRUCTURE; PROTEIN BINDING; RECEPTORS, METABOTROPIC GLUTAMATE; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79956119128     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.03.103     Document Type: Article

References (30)

1. D.D. Schoepp, D.E. Jane, and J.A. Monn Neuropharmacology 38 1999 1431
2. J.P. Pin, T. Galvez, and L. Prezeau Pharmacol. Ther. 98 2003 325
3. R.H.P. Porter, G. Jaeschke, W. Spooren, T.M. Ballard, B. Buttelmann, S. Kolczewski, J.U. Peters, E. Prinseen, J. Wichmann, E. Vieira, A. Muhlemann, S. Gatti, V. Mutel, and P. Malherbe J. Pharmacol. Exp. Ther. 315 2005 711
4. M.F. Bear, K.M. Huber, and S.T. Warren Trends Neurosci. 27 2004 370
5. Q.J. Yan, M. Rammal, M. Tranfaglia, and R.P. Bauchwitz Neuropharmacology 49 2005 1053
6. G. Doelen, R.L. Carpenter, T.D. Ocain, and M.F. Bear Pharmacol. Ther. 127 2010 78
7. K.A. Johnson, P.J. Conn, and C.M. Niswender CNS Neurol. Disord.: Drug Targets 8 2009 475
8. N. Morin, L. Gregoire, B. Gomez-Mancilla, F. Gasparini, and T. Di Paolo Neuropharmacology 58 2010 981
9. D. Rylander, H. Iderberg, Q. Li, A. Dekundy, J. Zhang, H. Li, R. Baishen, W. Danysz, E. Bezard, and M.A. Cenci Neurobiol. Dis. 39 2010 352
10. J. Jensen, A. Lehmann, A. Uvebrant, A. Carlsson, G. Jerndal, K. Nilsson, C. Frisby, L.A. Blackshaw, and J.P. Mattsson Eur. J. Pharmacol. 519 2005 154
11. F. Gasparini, G. Bilbe, B. Gomez-Mancilla, and W. Spooren Curr. Opin. Drug Disc. 11 2008 655
12. G.G. Kinney, M. Burno, U.C. Campbell, L.M. Hernandez, D. Rodriguez, L.J. Bristow, and P.J. Conn J. Pharmacol. Exp. Ther. 306 2003 116
13. H. Homayoun, M.R. Stefani, B.W. Adams, G.D. Tamagan, and B. Moghaddam Neuropsychopharmacology 29 2004 1259
14. L.E. Chavez-Noriega, M.J. Marino, H. Schaffhauser, U.C. Campbell, and P.J. Conn Curr. Neuropharmacol. 3 2005 9
15. G.G. Kinney, J.A. O'Brien, W. Lemaire, M. Burno, D.J. Bickel, M.K. Clements, T.B. Chen, D.D. Wisnoski, C.W. Lindsley, P.R. Tiller, S. Smith, M.A. Jacobson, C. Sur, M.E. Duggan, D.J. Pettibone, P.J. Conn, and D.L. Williams Jr. J. Pharmacol. Exp. Ther. 313 2005 199
16. L. Lecourtier, H. Homayoun, G. Tamagnan, and B. Moghaddam Biol. Psychiatry 62 2007 739
17. J.M. Darrah, M.R. Stefani, and B. Moghaddam Behav. Pharmacol. 19 2008 225
18. F. Liu, S. Grauer, C. Kelley, R. Navarra, R. Graf, G. Zhang, P.J. Atkinson, M. Popiolek, C. Wantuch, X. Khawaja, D. Smith, M. Olsen, E. Kouranova, M. Lai, F. Pruthi, C. Pulicicchio, M. Day, A. Gilbert, M.H. Pausch, N.J. Brandon, C.E. Beyer, T.A. Comery, S. Logue, S. Rosenzweig-Lipson, and K.L. Marquis J. Pharmacol. Exp. Ther. 327 2008 827
19. A. Ritzén, R. Sindet, M. Hentzer, N. Svendsen, R.M. Brodbeck, and C. Bundgaard Bioorg. Med. Chem. Lett. 19 2009 3275
20. A.L. Rodriguez, Y. Nong, N.K. Sekaran, D. Alagille, G.D. Tamagnan, and P.J. Conn Mol. Pharmacol. 68 2005 1793
21. S. Sharma, A.L. Rodriguez, P.J. Conn, and C.W. Lindsley Bioorg. Med. Chem. Lett. 18 2008 4098
22. A.L. Rodriguez, R. Williams, Y. Zhou, S.R. Lindsley, U. Le, M.D. Grier, C. vid Weaver, P. Jeffrey Conn, and C.W. Lindsley Bioorg. Med. Chem. Lett. 19 2009 3209
23. Y. Zhou, A.L. Rodriguez, R. Williams, C.D. Weaver, P.J. Conn, and C.W. Lindsley Bioorg. Med. Chem. Lett. 19 2009 6502
24. A.S. Felts, S.A. Saleh, U. Le, A.L. Rodriguez, C.D. Weaver, P.J. Conn, C.W. Lindsley, and K.A. Emmitte Bioorg. Med. Chem. Lett. 19 2009 6623
25. S. Sharma, J. Kedrowski, J.M. Rook, R.L. Smith, C.K. Jones, A.L. Rodriguez, P.J. Conn, and C.W. Lindsley J. Med. Chem. 52 2009 4103
26. Y. Zhou, J.T. Manka, A.L. Rodriguez, C.D. Weaver, E.L. Days, P.N. Vinson, S. Jadhav, E.J. Hermann, C.K. Jones, P.J. Conn, C.W. Lindsley, and S.R. Stauffer ACS Med. Chem. Lett. 1 2010 433
27. H.D.H. Showalter J. Heterocycl. Chem. 43 2006 1311
28. Y. Chen, Y. Nong, C. Goudet, K. Hemstapat, T. de Paulis, J.P. Pin, and P.J. Conn Mol. Pharmacol. 71 2007 1389
29. For another example of highly potent mGluR5 PAMs, see: A.L. Rodriguez, M.D. Grier, C.K. Jones, E.J. Herman, A.S. Kane, R.L. Smith, R. Williams, Y. Zhou, J.E. Marlo, E.L. Days, T.N. Blatt, S. Jadhav, U.N. Menon, P.N. Vinson, J.M. Rook, S.R. Stauffer, C.M. Niswender, C.W. Lindsley, C.D. Weaver, and P.J. Conn Mol. Pharmacol. 78 2010 1105
30. During the preparation of this manuscript, a paper describing a very similar series of mGluR5 allosteric modulators was published, see: R. Williams, J.T. Mankaa, A.L. Rodriguez, P.N. Vinson, C.M. Niswender, C.D. Weaver, C.K. Jones, P.J. Conn, C.W. Lindsley, and S.R. Stauffer Bioorg. Med. Chem. Lett. 21 2011 1350