A. B. Pinkerton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1565–1571
1571
11. Grillon, C.; Cordova, J.; Levine, L. R.; Morgan, C. A.,
III. Psychopharmacology 2003, 168, 446; Schoepp, D. D.;
Wright, R. A.; Levine, L. R.; Gaydos, B.; Potter, W. Z.
Stress 2003, 6, 189.
12. Knoflach, F.; Mutel, V.; Jolidon, S.; Kew, J. N. C.;
Malherbe, P.; Viera, E.; Wichmann, J.; Kemp, J. A. Proc.
Natl. Acad. Sci. U.S.A. 2001, 98, 13402.
5. Conclusion
In conclusion, a new class of indanone mGlu2 receptor
potentiators has been described. Optimization of the ser-
ies has led to compounds such as 28, which shows activ-
ity after systemic dosing in rodent models with relevance
to schizophrenia. This result helps validate the potential
application of mGlu2 receptor potentiators in a variety
of CNS disorders. Further optimization and application
of this series of compounds will be reported in due
course.
13. (a) Johnson, M. P.; Baez, M.; Jagdmann, G. E., Jr.;
Britton, T. C.; Large, T. H.; Callagaro, D. O.; Tizzano, J.
P.; Monn, J. A.; Schoepp, D. D. J. Med. Chem. 2003, 46,
3189; (b) Barda, D. A.; Wang, Z.; Britton, T. C.; Henry, S.
S.; Jagdmann, G. E.; Coleman, D. S.; Johnson, M. P.;
Andis, S. L.; Schoepp, D. D. Bioorg. Med. Chem. Lett.
2004, 14, 3099; (c) Hu, E.; Chua, P. C.; Tehrani, L.;
Nagasawa, J. Y.; Pinkerton, A. B.; Rowe, B. A.; Vernier,
J.-M.; Hutchinson, J. H.; Cosford, N. D. P. Bioorg. Med.
Chem. Lett. 2004, 14, 5071.
14. Schaffhauser, H.; Rowe, B. A.; Morales, S.; Chavez-
Noriega, L. E.; Yin, R.; Jachec, C.; Rao, S. P.; Bain, G.;
Pinkerton, A. B.; Vernier, J.-M.; Bristow, L. J.; Varney,
M. A.; Daggett, L. P. Mol. Pharmacol. 2003, 64, 798.
15. The effect of these compounds was characterized in the
[35S]-GTPcS binding assay using a cell line expressing
human mGlu2 receptor. See Ref. 14 for a detailed
description of this assay. First, an EC10 (1 lM) of
glutamate was added to the cell line followed immediately
by the test compound at varying concentrations. The
response was then compared to a response using a
saturating amount of glutamate (1 mM) to give both an
EC50 and a percent potentiation (the response normalized
to the maximum response of glutamate alone). The same
experiment was carried out in the absence of glutamate to
test if the compound was truly a positive allosteric
modulator. Nonspecific binding was determined by addi-
tion of 10 lM unlabeled GTPcS.
16. Pinkerton, A. B.; Vernier, J.-M.; Schaffahuser, H.; Rowe,
B. A.; Campbell, U. C.; Rodriguez, D. E.; Lorrain, D. S.;
Baccei, C. S.; Daggett, L. P.; Bristow, L. J. J. Med. Chem.
2004, 47, 4595.
17. Pinkerton, A. B.; Cube, R. V.; Hutchinson, J. H.; Rowe,
B. A.; Schaffhauser, H.; Zhao, X.; Daggett, L. P.; Vernier,
J.-M. Bioorg. Med. Chem. Lett. 2004, 14, 5329.
18. Pinkerton, A. B.; Cube, R. V.; Hutchinson, J. H.; James,
J. K.; Gardner, M. F.; Rowe, B. A.; Schaffhauser, H.;
Daggett, L. P.; Vernier, J.-M. Bioorg. Med. Chem. Lett.
2004, 14, 5867.
19. Lorrain, D. S.; Schaffhauser, H.; Campbell, U. C.; Baccei,
C. S.; Correa, L. D.; Rowe, B.; Rodriguez, D. E.;
Anderson, J. J.; Varney, M. A.; Pinkerton, A. B.; Vernier,
J.-M.; Bristow, L. J. Neuropsychopharmacology 2003, 28,
1622.
Acknowledgments
We thank Merryl Cramer for assistance in measuring
the PK parameters for 1, 9, 12, and 28.
References and notes
1. Pin, J.-P.; Acher, F. Curr. Drug Targets: CNS Neurol.
Disord. 2002, 1, 297; Conn, P. J.; Pin, J. P. Ann. Rev.
Pharmacol. Toxicol. 1997, 37, 205.
2. Schoepp, D. D.; Jane, D. E.; Monn, J. A. Neuropharma-
cology 1999, 38, 1431.
3. Lam, A. G.; Soriano, M. A.; Monn, J. A.; Schoepp, D. D.;
Lodge, D.; McCulloch, J. Neurosci. Lett. 1998, 254, 121.
4. Kingston, A. E.; OÕNeill, M. J.; Lam, A.; Bales, K. R.;
Monn, J. A.; Schoepp, D. D. Eur. J. Pharmacol. 1999, 377,
155.
5. Helton, D. R.; Tizzano, J. P.; Monn, J. A.; Schoepp, D.
D.; Kallman, M. J. J. Pharmacol. Exp. Ther. 1998, 284,
651.
6. Chavez-Noriega, L. E.; Schaffhauser, H.; Campbell, U. C.
Curr. Drug Targets: CNS Neurol. Disord. 2002, 1, 261.
7. Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R. A.;
Salhoff, C. R.; Johnson, B. G.; Howe, T.; Alt, C. A.;
Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J.
P.; Kallman, M. J.; Helton, D. R.; Schoepp, D. D. J. Med.
Chem. 1997, 40, 528.
8. Monn, J. A.; Valli, M. J.; Massey, S. M.; Hansen, M. M.;
Kress, T. J.; Wepsiec, J. P.; Harkness, A. R.; Grutsch, J.
L., Jr.; Wright, R. A.; Johnson, B. G.; Andis, S. L.;
Kingston, A.; Tomlinson, R.; Lewis, R.; Griffey, K. R.;
Tizzano, J. P.; Schoepp, D. D. J. Med. Chem. 1999, 42,
1027.
9. Nakazato, A.; Kumagai, T.; Sakagami, K.; Yoshikawa,
R.; Suzuki, Y.; Chaki, S.; Ito, H.; Taguchi, T.; Nakanishi,
S.; Okuyama, S. J. Med. Chem. 2000, 43, 4893.
10. Levine, L.; Gaydos, B.; Sheehan, D.; Goddarg, A. W.;
Feighner, J.; Potter, W. Z.; Schoepp, D. D. Neurophar-
macology 2002, 43, 294.
20. All final compounds displayed spectral data (NMR, MS)
that was consistent with the assigned structure.
21. Woltersdorf, O. W., Jr.; deSolms, S. J.; Schultz, E. M.;
Cragoe, E. J., Jr. J. Med. Chem. 1977, 20, 1400.