P. Carato et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1565–1569
1569
14. Rubinstein, M.; Cepeda, C.; Hurst, R. S.; Flores-Hernan-
dez, J.; Ariano, M. A.; Falzone, T. L.; Kozell, L. B.;
Meshul, C. K.; Bunzow, J. R.; Low, M. J.; Levine, M. S.;
Grandy, D. K. J. Neurosci. 2001, 21, 3756.
15. Truffinet, P.; Tamminga, C. A.; Fabre, L. F.; Meltzer, H.
Y.; Riviere, M. E.; Papillon-Downey, C. Am. J. Psychiatry
1999, 156, 419.
The compounds were antagonists at both sites. Their
affinities are in a similar range compared to clozapine,
however, D2L affinity is strongly reduced. Compound
2 appears to be promising for further biological
evaluation.
16. Tarazi, F. I.; Zhang, K.; Baldessarini, R. J. J. Pharmacol.
Exp. Ther. 2001, 297, 711.
Acknowledgments
17. Tarazi, F. I.; Zhang, K.; Baldessarini, R. J. Psychophar-
macology 2002, 161, 263.
18. Petcher, T. J.; Weber, H.-P. J. Chem. Soc., Perkin Trans.
II 1976, 1415.
The technical assistance of Y. Abrassart, S. Counerotte
is gratefully acknowledged. A.G. is a Research Fellow of
`
the ‘Fonds pour la formation a la Recherche Industrielle
´
19. Liegeois, J.-F.; Eyrolles, L.; Ellenbroek, B. A.; Lejeune,
C.; Carato, P.; Bruhwyler, J.; Geczy, J.; Damas, J.;
Delarge, J. J. Med. Chem. 2002, 45, 5136.
20. Cheng, Y.-C.; Prusoff, W. H. Biochem. Pharmacol. 1973,
22, 3099.
et Agricole (F.R.I.A.)’. J.F.L. is a Senior Research
Associate of the ‘Fonds National de la Recherche Scien-
tifique de Belgique (F.N.R.S.)’. P.C. was supported by a
´
`
post-doctoral fellowship of the University of Liege.
Functional data were generously provided in the context
of the National Institute of Mental Health’s Psychoac-
tive Drug Screening Program (NIMH PDSP) Contract
NO1MH32004.
21. Jaen, J. C.; Caprathe, B. W.; Pugsley, T. A.; Wise, L. D.;
Hyacinth Akunne, H. J. Med. Chem. 1993, 36, 3929.
22. GTP-c32S functional assay using membranes of cells stably
expressing the human D4 receptor. Membrane prepara-
tions were preincubated in a total volume of 300 ll for
25 min at 30 °C in assay buffer (50 mM HEPES, 100 mM
NaCl, 4 mM MgCl2, 1 mM EDTA, 100 mg/l BSA, 100 mg/
l ascorbic acid, pH 7.4 (adjusted with NaOH), and 20 lM
GDP) in the presence 5 lM of the test compounds and
500 nM dopamine for coapplications. GTP-c35S was
added for a final concentration of 300 pM and the
incubation was continued for 60 min. The membranes
were harvested on type-B glass fiber filters and washed with
ice-cold wash buffer (50 mM HEPES, 4 mM MgCl2, pH
7.4, adjusted with KOH). The experiments were run twice
with each data point measured in triplicate.
References and notes
1. Wong, A. H. C.; Van Tol, H. H. M. Neurosci. Biobehav.
Rev. 2003, 27, 269.
´
2. Ellenbroek, B. A.; Liegeois, J.-F. CNS Drug Rev. 2003,
9, 41.
´
3. Liegeois, J.-F.; Bruhwyler, J.; Damas, J.; Nguyen, T. P.;
Chleide, E.; Mercier, M.; Rogister, F.; Delarge, J. J. Med.
Chem. 1993, 36, 2107.
´
4. Liegeois, J.-F.; Rogister, F.; Bruhwyler, J.; Damas, J.;
Nguyen, T. P.; Inarejos, M.-O.; Chleide, E.; Mercier, M.;
Delarge, J. J. Med. Chem. 1994, 37, 519.
5. Roth, B. L.; Sheffler, D. L.; Kroeze, W. K. Nature Rev.
Drug Discov. 2004, 3, 353.
6. Van Tol, H. H. M.; Bunzow, J. R.; Guan, H. C.;
Sunahara, R. K.; Seeman, P.; Niznik, H. B.; Civelli, O.
Nature 1991, 350, 610.
7. Seeman, P.; Corbett, R.; Van Tol, H. H. M. Neuropsy-
chopharmacology 1997, 16, 93.
23. Davies, M. A.; Setola, V.; Strachan, R. T.; Sheffler, D. J.;
Salay, E.; Hufeisen, S. J.; Roth, B. L. Pharmacogenomics
J. 2005, eFirst.
24. Boyfield, I.; Brown, T. H.; Coldwell, M. C.; Cooper, D.
G.; Hadley, M. S.; Hagan, J. J.; Healy, M. A.; Johns, A.;
King, R. J.; Middlemiss, D. N.; Nash, D. J.; Riley, G. J.;
Scott, E. E.; Smith, S. A.; Stemp, G. J. Med. Chem. 1996,
39, 1946.
25. Ho¨gberg, T. Drugs Future 1991, 16, 333.
8. Roth, B. L.; Tandra, S.; Burgess, L. H.; Sibley, D. R.;
Meltzer, H. Y. Psychopharmacology 1995, 120, 365.
9. Meltzer, H. Y.; Matsubara, S.; Lee, J.-C. J. Pharmacol.
Exp. Ther. 1989, 251, 238.
10. Saller, C. F.; Czupryna, M. J.; Salama, A. I. J. Pharmacol.
Exp. Ther. 1990, 253, 1162.
11. Corrigan, M. H.; Gallen, C. C.; Bonura, M. L.; Merchant,
K. M., et al. Biol. Psychiatry 2004, 55, 445.
12. Hrib, N. J. Drugs Future 2000, 25, 587.
13. Kotecha, S. A.; Oak, J. N.; Jackson, M. F.; Perez, Y.;
Orser, B. A.; Van Tol, H. H. M.; MacDonald, J. F.
Neuron 2002, 35, 1111.
26. Arora, J.; Bordeleau, M.; Dube, L.; Jarvie, K.; Mazzocco,
L.; Peragine, J.; Tehim, A.; Egle, I. Biorg. Med. Chem.
Lett. 2005, 15, 5253.
27. Kapur, S.; Seeman, P. J. Psychiatry Neurosci. 2000, 25,
161.
28. Kapur, S.; Zipursky, R.; Jones, C.; Shammi, C. S.;
Remington, G.; Seeman, P. Arch. Gen. Psychiatry 2000,
57, 553.
´
29. Scuvee-Moreau, J.; Boland, A.; Graulich, A.; Van Over-
meire, L.; D’hoedt, D.; Graulich-Lorge, F.; Thomas, E.;
´
Abras, A.; Stocker, M.; Liegeois, J.-F.; Seutin, V. Br. J.
Pharmacol. 2004, 143, 753.