4896
J. W. Coe et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4889–4897
Leonardon, J.; Avenet, P.; Sgard, F.; Besnard, F.;
Graham, D.; Coste, A.; Oblin, A.; Curet, O.; Voltz, C.;
Gardes, A.; Caille, D.; Perrault, G.; George, P.; Soubrie,
P.; Scatton, B. J. Pharmacol. Exp. Ther. 2003, 306(1),
407.
the same alone and in the presence of nicotine. These
data demonstrate that all of these compounds are partial
agonists and that more potent in vivo activity is ob-
served with 1h, 1l, and 9a than with (ꢀ)-cytisine.51
6. Tapper, A. R.; McKinney, S. L.; Nashmi, R.; Schwarz, J.;
Deshpande, P.; Labarca, C.; Whiteaker, P.; Marks, M. J.;
Collins, A. C.; Lester, H. A. Science 2004, 5, 1029.
7. Maskos, U.; Molles, B. E.; Pons, S.; Besson, M.; Guiard,
B. P.; Guilloux, J.-P.; Evrard, A.; Cazala, P.; Cormier, A.;
Mameli-Engvall, M.; Dufour, N.; Cloe¨z-Tayarani, I.;
Bemelmans, A.-P.; Mallet, J.; Gardier, A. M.; David, V.;
Faure, P.; Granon, S.; Changeux, J.-P. Nature 2005, 436,
103.
8. Mansbach, R. S.; Chambers, L. K.; Rovetti, C. C.
Psychopharmacology 2000, 148, 234.
9. (a) Di Chiara, G. Eur. J. Pharmacol. 2000, 393, 295; (b)
Dani, J. A.; De Biasi, M. Pharmacol. Biochem. Behav.
2001, 70, 439.
10. Fagerstrom, K. J. Clin. Psychiatry. Monograph. 2003, 18,
35.
11. (a) Hughes, J. R.; Higgins, S. T.; Bickel, W. K. Addiction
1994, 89, 1461; (b) Malin, D. H. Pharmacol. Biochem.
Behav. 2001, 70, 551.
12. DiFranza, J. R.; Wellman, R. J. Nic. Tobacco Res. 2005, 7,
9; Quick, M. W.; Lester, R. A. M. J. Neurobiol. 2002, 53,
457; Littleton, J. Addiction 2001, 96, 87.
13. Fiore, M. C.; Bailey, W. C.; Cohen, S. J., et al. Treating
tobacco use and dependence: Clinical practice guideline;
Department of Health and Human Services: Washington,
DC, USA, 2000.
More effective therapeutic approaches for smoking ces-
sation are needed than are currently available, as half
of todayÕs smokers will die of smoking-related illness.
We have pursued selective nicotinic receptor partial ago-
nists for this indication that are expected to provide suf-
ficient dopaminergic tone to overcome the craving and
withdrawal syndrome experienced upon quitting, while
simultaneously attenuating the reinforcing actions of
nicotine. The discovery that benzazapine 1 is a nicotinic
agent has led to the study of a series of bicyclic aryl pip-
eridines, or modified benzazapine derivatives, that
exhibit significant affinity at the a4b2 nAChR. In vitro
activity of the analogs is sensitive to structural modifica-
tion, showing a striking dependence on both the steric
and the electronic nature of appended residues. Further-
more, the series exhibits a range of partial agonist activ-
ity and potency in vivo. The methods reported here have
identified agents with desirable in vivo partial agonist
profiles, such as 1h, 1l, and 9a, which are partial agonists
alone and fully block nicotineÕs effect in vivo. From this
series of compounds, varenicline (9a) has been pro-
gressed to human clinical trials as a smoking cessation
treatment.21
14. Rose, J. E. Annu. Rev. Med. 1996, 47, 493.
15. Hays, J. T.; Ebbert, J. O. Mayo Clin. Proc. 2003, 78, 1020.
16. Holm, K. J.; Spencer, C. M. Drugs 2000, 59, 1007.
17. de Villiers, S. H.; Lindblom, N.; Kalayanov, G.; Gordon,
S.; Malmerfelt, A.; Johansson, A. M.; Svensson, T. H.
Respiration 2002, 69, 247; Lindblom, N.; de Villiers, S. H.;
Kalayanov, G.; Gordon, S.; Johansson, A. M.; Svensson,
T. H. Respiration 2002, 69, 254.
Supplementary data
Supplementary data associated with this article can be
18. Cryan, J. F.; Gasparini, F.; van Heeke, G.; Markou, A.
Drug Disc. Today 2003, 8, 1025.
19. Lieberman, J. A. CNS Drugs 2004, 8, 251; Zhu, B. T.
J. Theor. Biol. 1996, 181, 273.
References and notes
20. Coe, J. W.; Vetelino, M. G.; Bashore, C. G.; Wirtz, M. C.;
Brooks, P. R.; Arnold, E. P.; Lebel, L. A.; Fox, C. B.;
Sands, S. B.; Davis, T. I.; Rollema, H.; Schaeffer, E.;
Schulz, D. W.; Tingley, F. D., III; OÕNeill, B. T. Bioorg.
Med. Chem. Lett. 2005, 15, 2974.
21. Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.;
Arnold, E. P.; Sands, S. B.; Davis, T. I.; Lebel, L. A.; Fox,
C. B.; Shrikhande, A.; Schaeffer, E.; Rollema, H.; Lu, Y.;
Mansbach, R. S.; Chambers, L. K.; Rovetti, C. C.; Schulz,
D. W.; Tingley, F. D., III; OÕNeill, B. T. J. Med. Chem.
2005, 48, 3474.
22. For leading reviews in this area see (a) Bunnelle, W. H.;
Dart, M. J.; Schrimpf, M. R. Curr. Med. Chem. 2004, 4,
299; (b) Holladay, M. W.; Dart, M. J.; Lynch, J. K. J.
Med. Chem. 1997, 40, 4169; (c) Glennon, R. A.; Dukat, M.
Med. Chem. Res. 1996, 6, 465; (d) Jensen, A. A.; Frlund,
B.; Liljefors, T.; Krogsgaard-Larsen, P. J. Med. Chem.
2005, 48, 4705.
1. (a) World Health Organization. Geneva, 1997(b) Doll, R.;
Peto, R.; Boreham, J.; Sutherland, I. BMJ 2004, 328,
1519.
2. Dani, J. A.; De Biasi, M. Pharmacol. Biochem. Behav.
2001, 70, 439.
3. Nicotine, a powerful agonist at the a4b2 nAChR, is more
potent than the endogenous ligand acetylcholine (EC50 is
3.5 vs. 100 lM) but is less efficacious (ꢁ67% maximal
efficacy vs. ACh) which defines it as a partial agonist
relative to ACh. For upper and lower limits for these
values see (a) Chavez-Noriega, L. E.; Gillespie, A.;
Stauderman, K. A.; Crona, J. H.; Claeps, B. O.; Elliott,
K. J.; Reid, R. T.; Rao, T. S.; Velicelebi, G.; Harpold, M.
M.; Johnson, E. C.; Corey-Naeve, J. Neuropharmacology
2000, 39, 2543; (b) Nelson, M. E.; Kuryatov, A.; Choi, C.
H.; Zhou, Y.; Lindstrom, J. M. Mol. Pharmacol. 2003, 63,
332.F.
4. Hogg, R. C.; Bertrand, D. Curr. Drug. Targets CNS
Neuro. Disord. 2004, 3, 123.
23. (a) Coe, J. W. Org. Lett. 2000, 2, 4205; (b) OÕNeill, B. T.;
Yohannes, D.; Bundesmann, M. W.; Arnold, E. P. Org.
Lett. 2000, 2, 4201.
24. (a) OÕNeill, B. T. PCT Int. Appl. WO98 1998, 18, 798; (b)
Marriere, E.; Rouden, J.; Tadino, V.; Lasne, M.-C. Org.
Lett. 2000, 2, 1121; (c) Nicolotti, O.; Canu Boido, C.;
Sparatore, F.; Carotti, A. Farmaco 2002, 57, 469; (d)
CanuBoido, C.; Carotti, A.; Sparatore, F. Farmaco 2003,
5. (a) Picciotto, M. R.; Zoli, M.; Rimondini, R.; Lena, C.;
Marubio, L. M.; Pich, E. M.; Fuxe, K.; Changeux, J. P.
Nature 1998, 391, 173; (b) Watkins, S. S.; Epping-
Jordan, M. P.; Koob, G. F.; Markou, A. Pharmacol.
Biochem. Behav. 1999, 62, 743; (c) Cohen, C.; Bergis, O.
E.; Galli, F.; Lochead, A. W.; Jegham, S.; Biton, B.;