1992
M. Lee et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1989–1992
entirely different manner. These factors need to be taken
into account in future molecular modeling studies and
proposals of possible pharmacophore models.
References and Notes
1. Arneric, S. P.; Brioni, J. D., Eds. Neuronal Nicotinic
Receptors. John Wiley and Sons: New York, 1999.
2. Beers, W. H.; Reich, E. Nature 1970, 225, 917.
3. Sheridan, R. P.; Nilakantan, R.; Dixon, J. S.; Venkatar-
aghavan, R. J. Med. Chem. 1986, 29, 899.
Methods
4. Glennon, R. A.; Dukat, M. In Neuronal Nicotinic Recep-
tors; Arneric, S. P., Brioni, J. D., Eds.; John Wiley and Sons:
New York, 1999; p 271.
5. Glennon, R. A.; Dukat, M. Pharm. Helv. Acta 2000, 74,
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Kimes, A. S.; Dannals, R. F.; London, E. D. J. Med. Chem.
1998, 41, 3690.
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Rimvall, K.; Christensen, B.; Ehrbar, U.; Olesen, P. H. J.
Med. Chem. 1999, 42, 4970.
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10. Carroll, F. I.; Liang, F.; Navarro, H. A.; Brieaddy, L. E.;
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E. L.; Martin, B. R.; Glennon, R. A. Med. Chem. Res. 1993, 3,
131.
The benz-fused analogue of nicotine 1 was prepared
according to a literature procedure by Ide and co-
workers17 except that N-vinylpyrrolidin-2-one and NaH
were used in the first step of the preparation of the
intermediate benz-fused myosmine. Reduction of the
intermediate with NaBH4 gave 9. Methylation of 9 via
an Eschweiler–Clarke reaction resulted in 1f. Adapting
the method of Gerlach18 the optical isomers (À)1f
(½aD28=À131.5ꢀ; c 0.92, CH3OH) and (+)1f (½a2D8=
+126.5ꢀ; c 0.64, CH3OH) were obtained by optical
resolution of racemic 1f using the (+)di-O,O0-p-toluyl-
l-tartaric acid and (À)di-O,O0-p-toluyl-d-tartaric acid,
respectively.
Analogues 8b, 8d, and 8f were synthesized from
the substituted pyridin-3-ols19,20 or quinolin-3-ols.21
Although reported, 5-bromopyridin-3-ol was prepared
using a new approach: 3,5-dibromopyridine was treated
with the sodium salt of 4-methoxybenzyl alcohol in
DMF followed by deprotection in TFA to give the
desired intermediate. 6-Bromopyridine-3-ol was synthe-
sized using the Naumann and Langhals21 method for
the preparation of quinoline-3-ol. The desired ethers
were obtained via Williamson synthesis using dibromo-
ethane22 and aminated with N-methylethylamine to give
the final products.
12. Lee, J.; Davis, C. B.; Rivero, R. A.; Reitz, A. B.; Shank,
P. Bioorg. Med. Chem. Lett. 2000, 10, 1063.
13. Balboni, G.; Marastoni, M.; Merighi, S.; Borea, P. A.;
Tomatis, R. Eur. J. Med. Chem. 2000, 35, 979.
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B.; Damaj, M. I.; Glennon, R. A. Eur. J. Med. Chem. 1999,
34, 177.
15. Dukat, M.; Dowd, M.; Damaj, M. I.; Martin, B. R.; El-
Zahabi, M.; Glennon, R. A. Eur. J. Med. Chem. 1999, 34, 31.
16. Dukat, M.; Damaj, I. M.; Young, R.; Vann, R.; Collins,
A. C.; Marks, M. J.; Martin, B. R.; Glennon, R. A. Eur. J.
Pharmacol. 2002, 435, 171.
17. Ide, A.; Matsumori, K.; Watanabe, H. Nippon Kagaku
Zasshi 1970, 91, 578; Chem. Abstr. 1970, 73, 130860y.
18. Gerlach, H. Helv. Chim. Acta 1966, 49, 2481.
19. Ziegler, F. E.; Bennett, G. B. J. Am. Chem. Soc. 1973, 95,
7458.
Derivative 3b was prepared from 5-bromonicotinic acid
by a previously reported method.23 In the case of 3d and
3f, 2-bromo-5-methylpyridine and 3-methylquinoline,
respectively, were brominated with NBS followed by N-
alkylation. Sodium methoxide was used to synthesize
3c, 8c, and 8e from the corresponding bromo analogues
3b, 8b, and 8d, respectively.
20. Lin, N.-H.; Gunn, D. E.; Li, Y.; He, Y.; Bai, H.; Ryther,
K. B.; Kuntzweiler, D.; Donnelly-Roberts, L.; Anderon, D. J.;
Campbell, J. E.; Sullivan, J. P.; Arneric, S. P.; Holladay, M. W.
Bioorg. Med. Chem. Lett. 1998, 8, 249.
21. Naumann, C.; Langhals, H. Synthesis 1990, 279.
22. Miura, Y.; Takaku, S.; Fujimura, Y.; Hamana, M. Het-
erocycles 1992, 34, 1055.
The binding assay was performed as previously reported
using rat brain homogenates with [3H]nicotine as
radioligand.16 Correlations were obtained using Lotus
Freelance Graphics (Cambridge, MA, USA).
23. Dukat, M.; Fiedler, W.; Dumas, D.; Damaj, I.; Martin,
B. R.; Rosecrans, J. A.; James, J. R.; Glennon, R. A. Eur. J.
Med. Chem. 1996, 31, 875.
Acknowledgement
This work was supported in part by DA 05274.