3986
T. Troxler et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3983–3987
18. Vasilaki, A.; Papasava, D.; Kocharyan, A.; Schulz, S.;
Hoyer, D.; Meyerhof, D.; Thermos, K. Neuropharmacol-
ogy 2004, 47, 612.
19. Thermos, K.; Bagnoli, P.; Epelbaum, J.; Hoyer, D.
Pharmacol. Ther. 2006, 110, 455.
20. Hannon, J. P.; Nunn, C.; Stolz, B.; Bruns, C.; Weckbec-
ker, G.; Lewis, I.; Troxler, T.; Hurth, K.; Hoyer, D. J.
Mol. Neurosci. 2002, 18, 15.
highly selective for sst1 over the other four subtypes. In
extensive radioligand binding studies, 3a showed low
affinities for a panel of 40 neurotransmitter and mono-
amine receptors, with the exception of the human dopa-
mine D4 receptor (pKd = 8.30), 5-HT1D (pKd = 6.95)
and b1-adrenoceptors (pKd = 6.65).39
In a functional assay, 3a acted as an antagonist at hu-
man recombinant sst1 receptors. It blocked SRIF-14 in-
duced inhibition of forskolin-stimulated adenylate
cyclase activity with a pKb of 7.50. The compound was
devoid of intrinsic activity. Compound 3a also acted
as an antagonist in other sst1 receptor assays, e.g. inhi-
bition of somatostatin stimulated GTPcS binding or in
reporter gene assays (somatostatin induced luciferase
gene expression) with similar potency.39
21. Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy,
E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors, P.
G.; Shakespeare, W. C. J. Am. Chem. Soc. 1993, 115,
12550.
22. Papageorgiou, C.; Haltiner, R.; Bruns, C.; Petcher, T. J.
Bioorg. Med. Chem. Lett. 1992, 2, 135.
23. Damour, D.; Barreau, M.; Blanchard, J.-C.; Burgevin,
M.-C.; Doble, A.; Herman, F.; Pantel, G.; James-Surcouf,
E.; Vuilhorgne, M. Bioorg. Med. Chem. Lett. 1996, 6,
1667.
24. Papageorgiou, C.; Borer, X. Bioorg. Med. Chem. Lett.
1996, 6, 267.
25. Liu, S.; Tang, C.; Ho, B.; Ankersen, M.; Stidsen, C. E.;
Crider, A. M. J. Med. Chem. 1998, 41, 4693.
In conclusion, we identified novel octahydrobenzo[g]-
quinoline derivatives that are highly potent and selective
antagonists at the somatostatin sst1 receptor. Further
studies concerning PK properties of these compounds
and their evaluation in different in vivo animal models
will be published elsewhere in due course.
26. Rohrer, S. P.; Birzin, E. T.; Mosley, R. T.; Berk, S. C.;
Hutchins, S. M.; Shen, D.-M.; Xiong, Y.; Hayes, E. C.;
Parmar, R. M.; Foor, F.; Mitra, S. W.; Degrado, S. J.;
Shu, M.; Klopp, J. M.; Cai, S.-J.; Blake, A.; Chan, W. W.
S.; Pasternak, A.; Yang, L.; Patchett, A. A.; Smith, R. G.;
Chapman, K. T.; Schaeffer, J. M. Science 1998, 282, 737.
27. Berk, S. C.; Rohrer, S. P.; Degrado, S. J.; Birzin, E. T.;
Mosley, R. T.; Hutchins, S. M.; Pasternak, A.; Schaeffer,
J. M.; Underwood, D. J.; Chapman, K. T. J. Comb. Chem.
1999, 1, 388.
Supplementary data
Supplementary data associated with this article can be
28. Yang, L.; Guo, L.; Pasternak, A.; Mosley, R.; Rohrer, S.;
Birzin, E.; Foor, F.; Cheng, K.; Schaeffer, J.; Patchett, A.
A. J. Med. Chem. 1998, 41, 2175.
References and notes
29. Yang, L.; Berk, S. C.; Rohrer, S. P.; Mosley, R. T.; Guo,
L.; Underwood, D. J.; Arison, B. H.; Birzin, E. T.; Hayes,
E. C.; Mitra, S. W.; Parmar, R. M.; Cheng, K.; Wu, T. J.;
Butler, B. S.; Foor, F.; Pasternak, A.; Pan, Y.; Silva, M.;
Freidinger, R. M.; Smith, R. G.; Chapman, K.; Schaeffer,
J. M.; Patchett, A. A. Proc. Natl. Acad. Sci. USA 1998, 95,
10836.
30. Nunn, C.; Rueping, M.; Langenegger, D.; Schuepbach, E.;
Kimmerlin, T.; Micuch, P.; Hurth, K.; Seebach, D.;
Hoyer, D. Naunyn-Schmiedeberg’s Arch. Pharmacol.
2003, 367, 95.
1. Brazeau, P.; Vale, W.; Burgus, R.; Ling, N.; Butcher, M.;
Rivier, J.; Guillemin, R. Science 1973, 179, 77.
2. Gerich, J. E.; Lovinger, R.; Grodsky, G. M. Endocrinology
1975, 96, 749.
3. Johansson, C.; Wisen, O.; Efendic, S.; Uvnas-Wallensten,
K. Digestion 1981, 22, 126.
4. Lamberts, S. W.; Krenning, E. P.; Reubi, J. C. Endocr.
Rev. 1991, 12, 450.
5. Schettini, G. Pharmacol. Res. 1991, 23, 203.
6. Havlicek, V.; Rezek, M.; Friesen, H. Biochem. Behav.
1976, 4, 455.
31. Hay, B. A.; Cole, B. M.; DiCapua, F. M.; Kirk, G. W.;
Murray, M. C.; Nardone, R. A.; Pelletier, D. J.; Ricketts,
A. P.; Robertson, A. S.; Siegel, T. W. Bioorg. Med. Chem.
Lett. 2001, 11, 2731.
7. Chesselet, M. F.; Reisine, T. D. J. Neurosci. 1983, 3, 232.
8. Gothert, M. Nature 1980, 288, 86.
32. Moinet, C.; Contour-Galcera, M.-O.; Poitout, L.; Mor-
gan, B.; Gordon, T.; Roubert, P.; Thurieau, C. Bioorg.
Med. Chem. Lett. 2001, 11, 991.
33. Poitout, L.; Roubert, P.; Contour-Galcera, M.-O.; Moi-
net, C.; Lannoy, J.; Pommier, J.; Plas, P.; Bigg, D.;
Thurieau, C. J. Med. Chem. 2001, 44, 2990.
34. Hurth, K.; Floersheim, P.; Hoyer, D.; Langenegger, D.;
Neumann, P.; Pfa¨ffli, P.; Sorg, D.; Swoboda, R.; Troxler,
T. Bioorg. Med. Chem. Lett. 2007, 17, 3988–3991.
9. Gillies, G. Trends Parmacol. Sci. 1997, 18, 87.
10. Dournaud, P.; Jazat-Poindessous, F.; Slama, A.; Lamour,
Y.; Epelbaum, J. Eur. J. Neurosci. 1996, 8, 476.
11. Patel, Y. C. Front. Neuroendocrinol. 1999, 20, 157.
12. Hoyer, D.; Bell, G. I.; Berelowitz, M.; Epelbaum, J.; Feniuk,
W.; Humphrey, P. P. A.; O’Carroll, A.-M.; Patel, Y. C.;
Schonbrunn, A. Trends Pharmacol. Sci. 1995, 16, 86.
13. Bell, G. I.; Reisine, T. Trends Neurosci. 1993, 16, 34.
14. Lloyd, K. C.; Amirmoazzami, S.; Friedik, F.; Chew, P.;
Walsh, J. H. Am. J. Physiol. 1997, 272, G1481.
15. Rossowski, W. J.; Coy, D. H. Biochem. Biophys. Res.
Commun. 1994, 205, 341.
16. Lanneau, C.; Bluet-Pajot, M. T.; Zizzari, P.; Csaba, Z.;
Dournaud, P.; Helboe, L.; Hoyer, D.; Pellegrini, E.;
Tannenbaum, G. S.; Epelbaum, J.; Gardette, R. Endocri-
nology 2000, 14, 967.
17. DalMonte, M.; Petrucci, C.; Cervia, D.; Vasilaki, A.;
Drouselle, D.; Epelbaum, J.; Richter, D.; Hoyer, D.;
Bagnoli, P. Neuropharmacology 2003, 45, 1080.
35. Pfaeffli, P.; Neumann, P.; Swoboda, R.; Stutz, P. PCT
¨
Int. Appl. WO 9854183, 1998; Chem. Abstr. 1998, 130,
25220.
36. Hoyer, D.; Perez, J.; Schoeffter, P.; Langenegger, D.;
Schupbach, E.; Kaupmann, K.; Lubbert, H.; Bruns, C.;
¨
¨
Reubi, J. C. Eur. J. Pharmacol. 1995, 289, 151.
37. Nordmann, R.; Petcher, T. J. J. Med. Chem. 1985, 28,
367.
38. All compounds listed in Tables 1–3 were prepared
according to procedures given as Supporting information.