Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: Unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 14, 2008, Pages 4098-4101

  Sharma, Sameer ^a,b   Rodriguez, Alice L ^a,b   Conn, P Jeffrey ^a,b   Lindsley, Craig W ^a,b  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

Allosteric; Antagonist; mGluR5; Partial antagonism; Positive allosteric modulation

Indexed keywords

5 (PHENYLETHYNYL)PYRIMIDINE DERIVATIVE; GLUTAMATE RECEPTOR 5; GLUTAMATE RECEPTOR ANTAGONIST; PYRIMIDINE DERIVATIVE;

ARTICLE; DRUG ACTIVATION; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

ALLOSTERIC REGULATION; ALLOSTERIC SITE; ANIMALS; BINDING, COMPETITIVE; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; HUMANS; INHIBITORY CONCENTRATION 50; LIGANDS; MODELS, CHEMICAL; PYRIMIDINES; RATS; RECEPTORS, METABOTROPIC GLUTAMATE; STRUCTURE-ACTIVITY RELATIONSHIP; TIME FACTORS;

EID: 47149106805     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.05.091     Document Type: Article

References (17)

1. Schoepp D.D., Jane D.E., and Monn J.A. Neuropharmacology 38 (1999) 1431
2. Conn P.J., and Pin J.-P. Annu. Rev. Pharmacol. Toxicol. 37 (1997) 205
3. Gasparini F., Lingenhohl K., Stoehr N., Flor P.J., Heinrich M., and Vranesic I. Neuropharmacology 38 (1999) 1493
4. Roppe J.R., Wang B., Huang D., Tehrani L., Kamenecka T., Schweiger E.J., Anderson J.J., Brodkin J., Jiang X., Cramer M., Chung J., Reyes-Manalo G., Munoz B., and Cosford N.D.P. Bioorg. Med. Chem. Lett. 14 (2004) 3993
5. Lea, P. M., IV; Faden, A. I. CNS Drug Rev. 2006, 12, 149-166.
6. Porter R.H.P., Jaeschke G., Spooren W., Ballard T.M., Buttelmann B., Kolczewski S., Peters J.-U., Prinseen E., Wichmann J., Vieira E., Muhlemann A., Gatti S., Mutel V., and Malherbe P. J. Pharm. Exp. Ther. 315 (2005) 711
7. Rodriguez A.L., Nong Yi., Sekaran N.K., Alagille D., Tamagnan G.D., and Conn P.J. Mol. Pharm. 68 (2005) 793
8. Williams Jr. D.L., and Lindsley C.W. Curr. Topics Med. Chem. 5 (2005) 825
9. O'Brien, J. A.; Lemaire, W.; Chen, T.-B.; Chang, R. S. L.; Jacobson, M. A.; Ha, S. N.; Lindsley, C. W.; Sur, C.; Pettibone, D. J.; Conn, J.; Wiliams, D. L. Mol. Pharmacol. 2003, 64, 731-740.
10. O'Brien, J. A.; Lemaire, W.; Wittmann, M.; Jacobson, M. A.; Ha, S. N.; Wisnoski, D. D.; Lindsley, C. W.; Schaffhauser, H. J.; Sur, C.; Duggan, M. E.; Pettibone, D. J.; Conn, J.; Williams, D. L. J. Pharmacol. Exp. Ther. 2004, 309, 568-577.
11. Zhao Z., Wisnoski D.D., O'Brien J.A., Lemiare W., Williams Jr. D.L., Jacobson M.A., Wittman M., Ha S., Schaffhauser H., Sur C., Pettibone D.J., Duggan M.E., Conn P.J., Hartman G.D., and Lindsley C.W. Bioorg. Med. Chem. Lett. 17 (2007) 1386
12. Lindsley C.W., Wisnoski D.D., Leister W.H., O'Brien J.A., Lemiare W., Williams Jr. D.L., Burno M., Sur C., Kinney G.G., Pettibone D.J., iller P.R., Smith S., Duggan M.E., Hartman G.D., Conn P.J., and Huff J.R. J. Med. Chem. 47 (2004) 5825
13. Kinney, G. G.; O'Brien; Lemaire, W.; Burno, M.; Bickel, D. J.; Clements, M. K.; Wisnoski, D. D.; Lindsley, C. W.; Tiller, P. R.; Smith, S.; Jacobson, M. A.; Sur, C.; Duggan, M. E.; Pettibone, D. J.; Williams, D. W., Jr. J. Pharmacol. Exp. Ther. 2005, 313, 199-206.
14. de Paulis, T.; Hemstapat, K.; Chen, Y.; Zhang, Y.; Saleh, S.; Alagille, D.; Baldwin, R. M.; Tamagnan, G. D.; Conn, P. J. J. Med. Chem. 2006, 49, 3332-3344.
15. 2.
16. 3H]methoxy-PEPy (100 μL) (2 nM final concentration in assay buffer) was added, and the reaction mixture was incubated at room temperature for 60 min with shaking. After the incubation period, the membrane-bound ligand was separated from free ligand by filtration through glass fiber 96-well filter plates (Unifilter-96, GF/B). The contents of each well were transferred simultaneously to the filter plate and washed four times with assay buffer (Brandel cell harvester). Scintillation fluid (40 μL) was added to each well, and the membrane-bound radioactivity was determined by scintillation counting (TopCount). Non-specific binding was estimated using 5 μM MPEP. Assays were performed in triplicate on three different days. Concentration response curves were generated using GraphPad Prism 4.0.
17. Kennedy J.P., Williams L., Bridges T.M., Daniels R.N., Weaver D., and Lindsley C.W. J. Comb. Chem. 10 (2008) 345-354