T. J. Woltering et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1091–1095
1095
Swanson, C. J.; Bures, M.; Johnson, M. P.; Linden, A.-
M.; Monn, J. A.; Schoepp, D. D. Nat. Rev. Drug Discov.
2005, 4, 131; (c) Higgins, G. A.; Miczek, K. A. Psycho-
pharmacology 2005, 179, 1; (d) Mutel, V. Expert Opin.
Ther. Patents 2002, 12, 1845; (e) Schoepp, D. D. J.
Pharmacol. Exp. Ther. 2001, 299, 12.
We assessed the selectivity of 15o and 15q and these
compounds neither activated nor inhibited glutamate-
stimulated rat mGluR1a and mGluR5a (using a Ca2+
mobilization functional assay, when tested at 30 lM fi-
nal concentration). Compound 15o was also inactive in
the binding of [3H]-L-AP4 to rat mGluR8a, while 15q
showed an IC50 of 5 lM. In addition both compounds
were devoid of any affinity at NMDA and GABAA
receptors (data not shown).
3. Spinelli, S.; Ballard, T.; Gatti-McArthur, S.; Richards, G.
J.; Kapps, M.; Woltering, T.; Wichmann, J.; Stadler, H.;
Feldon, J.; Pryce, C. R. Psychopharmacology 2005, 179, 292.
4. Higgins, G. A.; Ballard, T. M.; Kew, J. N. C.;
Richards, J. G.; Kemp, J. A.; Adam, G.; Woltering,
T.; Nakanishi, S.; Mutel, V. Neuropharmacology 2004,
46, 907.
5. (a) Schweizer, C.; Kratzeisen, C.; Adam, G.; Lundstrom,
K.; Malherbe, P.; Ohresser, S.; Stadler, H.; Wichmann, J.;
Woltering, T.; Mutel, V. Neuropharmacology 2000, 39,
1700; (b) Schaffhauser, H.; Richards, J. G.; Cartmell, J.;
Chaboz, S.; Kemp, J. A.; Klingelschmidt, A.; Messer, J.;
Stadler, H.; Woltering, T.; Mutel, V. Mol. Pharmacol.
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6. Woltering, T. J.; Adam, G.; Alanine, A.; Wichmann, J.;
Knoflach, F.; Mutel, V.; Gatti, S. Bioorg. Med. Chem.
Lett. 2007, 17, 6811.
7. Hemstapat, K.; Da Costa, H.; Nong, Y.; Brady, A. E.;
Luo, Q.; Niswender, C. M.; Tamagnan, G. D.; Conn, P. J.
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Using compound 15o we could also demonstrate antag-
onism at native group II metabotropic glutamate recep-
tors by reversal of LY354740-mediated inhibition of
fEPSPs in the dentate gyrus (Fig. 4).14
In summary, by replacement of a nitrile with a five-mem-
bered heterocycle we were able to develop a series of 1,3-
dihydro-benzo[b][1,4]diazepin-2-one derivatives which
are selective and potent non-competitive antagonists at
recombinant group II metabotropic glutamate receptors.
Further optimization of physicochemical properties is re-
quired before approaching in vivo studies.
8. (a) Adam, G.; Alanine, A.; Goetschi, E.; Mutel, V.;
Woltering, T. J. World Patent WO01/029011, 2001;
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schi, E.; Mutel, V.; Wichmann, J.; Woltering, T. J.
World Patent WO02/083652, 2002; Chem. Abstr. 2002,
137, 325447.
9. Hagedorn, A. A., III; Erhardt, P. W.; Lumma, W. C., Jr.;
Wohl, R. A.; Cantor, E.; Chou, Y. L.; Ingebretsen, W. R.;
Lampe, J. W.; Pang, D.; Pease, C. A.; Wiggins, J. J. Med.
Chem. 1987, 30, 1342.
Acknowledgments
We cordially thank N. Benedetti, D. Buchy, M. Burn, S.
Chaboz, M. Dellenbach, A. Maier, A. Nilly, H. Scha¨r,
M.-C. Pflimlin, R. Haab, and M. Weber for their skilful
technical assistance.
References and notes
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13. Gatti, S.; Knoflach, F.; Kew. J.; Adam, G.; Goetschi,
E.; Wichmann, J.; Woltering, T.; Kemp, J.; Mutel, V.
Abstract of Papers, 31st Annual Meeting of the
Society for Neuroscience, San Diego, CA; Society
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