1874
P. A. Crooks et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1869–1874
which was <50% of the uptake in the absence of
choline. These results suggest that a significant com-
ponent of NONI uptake occurs via the blood–brain
barrier choline transporter.
13. Paton, W.; Zaimis, E. J. Nature (London) 1948, 162, 810.
14. Barlow, R. B.; Ing, H. R. Brit. J. Pharmacol. 1948, 3, 298.
1
1
1
1
5. Crooks, P. A.; Ravard, A.; Wilkins, L. H.; Teng, L. H.;
Buxton, S. T.; Dwoskin, L. P. Drug Dev. Res. 1995, 36, 91.
6. Dwoskin, L. P.; Wilkins, L. H.; Pauly, J. R.; Crooks, P. A.
Ann. N.Y. Acad. Sci. 1999, 868, 617.
7. Wilkins, L. H.; Haubner, A.; Ayers, J. T.; Crooks, P. A.;
Dwoskin, L. P. J. Pharmacol. Exp. Ther. 2002, 301, 1088.
8. Wilkins, L. H.; Grinevich, V. P.; Ayers, J. T.; Crooks,
P. A.; Dwoskin, L. P. J. Pharmacol. Exp. Ther. 2003, 304,
400.
5. Summary
In summary, rotameric restriction of N-n-alkylnicoti-
nium iodides eliminates inhibitory activity at both
a4b2* and a7* nAChRs, and affords high affinity and
selectivity for nAChRs mediating nicotine-evoked
dopamine release from striatum. Thus, conformational
restriction of N-n-alkyl analogues of nicotine appears to
be a useful approach in the development of subtype-
selective inhibitors for nAChRs mediating nicotine-
evoked dopamine release.
19. Wilkins, L. H.; Pauly, J. R.; Crooks, P. A.; Dwoskin, L. P.
Soc. Neurosci. Abstr. 1997, 23, 477.
2
0. Xu, R.; Dwoskin, L. P.; Grinevich, V. P.; Sumithran, S. P.;
Crooks, P. A. Drug Dev. Res. 2002, 55, 173.
2
1. Allen, D. D.; Lockman, P. R.; Roder, K. E.; Dwoskin,
L. P.; Crooks, P. A. J. Pharmacol. Exp. Ther. 2003, 304,
1
268.
2
2
2
2. Zhu, J.; Crooks, P. A.; Ayers, J. T.; Sumithran, S. P.;
Dwoskin, L. P. Drug Dev. Res. 2003, 60, 270.
3. Glassco, W.; Suchocki, J.; Martin, G. C.; May, E. L. J.
Med. Chem. 1993, 36, 3381.
4. Vernier, J. M.; Holsenback, H.; Cosford, N. D. P.; Whit-
ten, J. P.; Menzaghi, F.; Reid, R.; Rao, T. S.; Sacaan,
A. I.; Lloyd, G. K.; Suto, C. M.; Chavez- Noriega, L. E.;
Washburn, M. S.; Urrutia, A.; Macdonald, I. A. Biorg.
Med. Chem. Lett. 1998, 8, 2173.
References and notes
1
2
3
. Lloyd, G. K.; Williams, M. J. Pharmacol. Exp. Ther.
2000, 292, 461.
. Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med.
Chem. 1997, 40, 4169.
. Lin, N.; Meyer, M. D. Exp. Opin. Ther. Patents 1998, 8,
25. Berg-Nielsen, K.; Skattebol, L. Acta Chem. Scand. Ser. B
1978, 32, 553.
991.
4
5
. Schmitt, J. D. Curr. Med. Chem. 2000, 7, 749.
. Tønder, J. E.; Olesen, P. H. Curr. Med. Chem. 2001, 8,
26. Dwoskin, L. P.; Zahniser, N. R. J. Pharmacol. Exp. Ther.
1986, 239, 442.
6
51.
27. Miller, D. K.; Sumithran, S. P.; Dwoskin, L. P. J. Phar-
macol. Exp. Ther. 2002, 302, 1113.
28. Reuben, M.; Clarke, P. B. Neuropharmacology 2000, 39,
290.
6
. Glennon, R. A.; Dukat, M. In Neuronal Nicotinic Recep-
tors; Arneric, S. P.; Brioni, J. D., Eds.; Wiley-Liss: New
York, 1999; p 271.
7
8
. Ortells, M.; Lunt, G. G. Trends in Neurosci. 1995, 18, 121.
. Lukas, R. J.; Changeux, J. P.; Novere, N. L.; Albu-
querque, E. X.; Balfour, D. J.; Berg, D. K.; Bertrand, D.;
Chiappinelli, V. A.; Clarke, P. B. S.; Collins, A. C.; Dani,
J. A.; Grady, S. R.; Kellar, K. J.; Lindstrom, J. M.;
Marks, M. J.; Quik, M.; Taylor, P. W.; Wonnacott, S.
Pharmacol. Rev. 1999, 51, 397.
29. Zumstein, A.; Karduck, W.; Starke, K. Naunyn-Schmie-
deberg’s Arch. Pharmacol. 1981, 316, 205.
30. Bradford, M. M. Anal. Biochem. 1976, 72, 248.
31. Takasato, Y.; Rapoport, S. I.; Smith, Q. R, Am. J. Physiol.
1984, 247, 484.
32. Allen, D. D.; Smith, Q. R. Neurosci. Lett. 1999, 277, 198.
33. Allen, D. D.; Smith, Q. R. J. Neurochem. 2001, 76, 1032.
34. Smith, Q. R.; Momma, S.; Aoyagi, M.; Rapoport, S. I. J.
Neurochem. 1987, 49, 1651.
9
. Everett, A. J.; Lowe, L. A.; Wilkinson, S. Chem. Commun.
Chem. Soc. London 1970, 1020.
1
0. Koelle, G. B. In The Pharmacological Basis of Thera-
peutic, 5th Edn; Goodman, L. S., Gilman, A., Eds.;
MacMillan Pub. Co.: New York, 1975; p 565.
35. Sheridan, R. P.; Nilakantan, R.; Dixon, J. S.; Venkatar-
aghavan, R. J. Med. Chem. 1986, 29, 899.
36. Smith, Q. R. In Implications of the Blood-Brain Barrier
and its Manipulation; Neuwelt, E. A., Ed.; Plenum Press:
New York, 1989; Vol. 1, p 85.
37. Ayers, J. T.; Dwoskin, L. P.; Deaciuc, A. G.; Grinevich,
V. P.; Zhu, J.; Crooks, P. A. Bioorg. Med. Chem. Lett.
2002, 12, 3067.
1
1
1. Khromov-Borisov, N.; Michelson, M. Pharmacol. Rev.
1966, 18, 1051.
2. Michelson, M.; Zaimal, E. In Acetylcholine, An Approach
to the Molecular Mechanism of Action; Pergammon Press:
Oxford, 1973; p 243.