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L. Scipione et al. / Bioorg. Med. Chem. Lett. 18 (2008) 309–312
17. Passive avoidance performance test was carried out
Acknowledgments
according to the step-through method described by
Giovannini (Behaviour Brain Research 1999, 104: 147–
155). The time elapsed between the rat was placed in the
light and it entered the dark compartment is recorded as
Training Trial latency time (TT). Amnesia was induced in
rats with scopolamine (0.5 mg/kg) given subcutaneously
1 h before Training Trial. Rats received intraperitoneally
the compounds under study (4-AP, 3a, 4a, 4d) or vehicle
(saline) 30 min after scopolamine treatment. Compound 1
was given 15 min before Training Trial. In a second set of
experiments 1 was combined with 4-AP following the same
experimental protocol. Retention trial was performed 24 h
later, following a similar procedure, except that the electric
shock was not given. The latency time to enter the dark
compartment was measured up to a cut off time of 180 s
and indicated as Retention Trial latency time (RT).
Experiments were done in compliance with the recom-
mendations of the EEC 886/609/CEE and in accordance
with the national laws (DL 116/92).
This work was financially supported by PRIN funding
`
of Italian ‘Ministero dell’Universita e della Ricerca’.
The Authors thank Dr. Giuseppe Domenichini for skil-
ful technical support.
Supplementary data
Supplementary data associated with this article can be
References and notes
1. Bartus, R. T.; Dean, R. L., III; Beer, B.; Lippa, A. S.
Science 1982, 217, 408.
2. Whitehouse, P. J.; Price, D. L.; Struble, R. G. Science
1982, 215, 1237.
18. Youdim, M. B. H.; Buccafusco, J. J. J. Neural. Transm.
2005, 112, 519.
19. Compounds 3a–d were prepared following a common
procedure: 4-AP (5.2 mmol) was dissolved in 50 mL of
anhydrous benzene, then 18.7 mmol of anhydrous TEA
was added. The solution was kept under stirring at rt and
10 mL of benzene, containing 3.2 mmol of triphosgene,
was added dropwise. The solution was refluxed for 5 h.
The produced TEA HCl was filtered off, the solution was
added with 5.2 mmol of freshly distilled 2-dimethylami-
noethanol and stirred overnight. To the benzene solution,
50 mL of saturated Na2CO3 was added under stirring; the
organic layer was separated and the alkaline solution was
extracted with 5 portions (20 mL each) of chloroform. The
recombined organic fractions were evaporated to give an
oily residue which was chromatographed on silica gel
column using 1:1 methanol/ethylacetate as eluent, collect-
ing the product with lower Rf. Compounds 4a–d were
prepared following a common procedure: 3.0 mmol of
compounds 3a–d was dissolved in 30 mL of anhydrous
ethanol and 6.0 mmol of iodomethane was added. The
solution was stirred for 5–6 days at rt and then Et2O was
added (100 mL). The obtained yellow solid was separated
and crystallized from MeOH/Et2O. Compounds 5b–d were
prepared following a common procedure: compounds 3b–
d (1.0 mmol) were dissolved in 15 mL of anhydrous
ethanol and cooled in an ice bath. The solution was
saturated for 15 min with gaseous HCl and then 10 mL of
Et2O was added. The white crystalline precipitate was
collected, washed with Et2O and crystallized from MeOH/
Et2O. For all compounds elemental analyses are within
3. Perry, E. K.; Perry, R. H.; Blessed, G.; Tomlinson, B. E.
Neuropath. Appl. Neuro. 1978, 4, 273.
4. Gil-Bea, F. J.; Garcia-Alloza, M.; Dominguez, J.; Marcos,
B.; Ramirez, M. J. Neurosci. Lett. 2005, 375, 37.
5. Mohs, R. C.; Doody, R. S.; Morris, J. C.; Ieni, J. R.;
Rogers, S. L.; Perdomo, C. A.; Pratt, R. D. Neurology
2001, 57, 481.
6. Olin, J.; Schneider, L. Cochrane database of systematic
reviews 2001, 4, CD001747.
7. Birks, J. Cochrane Database of Systematic Reviews 2006, 1,
CD005593.
8. Carelli, V.; Liberatore, F.; Scipione, L.; Rotiroti, D.;
Rispoli, V.; Cardellini M, Patent IT MI 2000 A000898
(2000), EP 1925883.(2001); Carelli, V.; Liberatore, F.;
Scipione, L.; Rotiroti, D.; Rispoli, V.; Cardellini, M.
Chem. Abst. 2001, 135, 344212m.
9. Rispoli, V.; Rotiroti, D.; Carelli, V.; Liberatore, F.;
Scipione, L.; Marra, R.; Giorgioni, G.; Di Stefano, A.
Neurosci. Lett. 2004, 356, 199.
10. Rispoli, V.; Rotiroti, D.; Carelli, V.; Liberatore, F.;
Scipione, L.; Marra, R.; Tortorella, S.; Bi Rienzo, B.
Pharmacol. Biochem. Behav. 2004, 78, 667.
11. Rispoli, V.; Marra, R.; Costa, N.; Scipione, L.; Rotiroti,
D.; De Vita, D.; Liberatore, F.; Carelli, V. Pharmacol.
Biochem. Behav. 2006, 84, 453.
12. Papke, R. L.; Bencherif, M.; Lippiello, P. Neurosci. Lett.
1996, 213, 201.
13. Alkondon, M.; Pereira, E. F. R.; Cortes, W. S.; Maelicke,
A.; Albuquerque, E. X. Eur. J. Neurosci. 1997, 9, 2734.
14. Breese, C. R.; Adams, C.; Logel, J.; Drebing, C.; Rollins,
Y.; Barnhart, M.; Sullivan, B.; Demasters, B. K.; Freed-
man, R.; Leonard, S. J. Comp. Neurol. 1997, 387 3, 385.
15. Davidson, M.; Zemishlany, J. H.; Mohs, R. C. Biol.
Psychiatry 1988, 23, 485.
16. Smith, C. P.; Bores, G. M.; Petko, W.; Li, M.; Selk, D. E.;
Rush, D. K.; Camacho, F.; Winslow, J. T.; Fishkin, R.;
Cunningham, D. M.; Brooks, K. M.; Roehr, J.; Hartman,
H. B.; Davis, L.; Vargas, H. M. J. Pharmacol. Exp. Ther.
1997, 280, 710.
1
0.4%. H, 13C NMR and analytical data are reported in
supplementary material.
20. Ellman, G. L.; Courtney, K. D.; Andres, V.; Featherstone,
R. M. Biochem. Pharmacol. 1961, 7, 88.
21. Dixon, M. Biochem. J. 1953, 55, 170.
22. Recanatini, M.; Cavalli, A.; Belluti, F.; Piazzi, L.;
Rampa, A.; Bisi, A.; Gobbi, S.; Valenti, P.; Andrisano,
V.; Bartolini, M.; Cavrini, V. J. Med. Chem. 2000, 43,
2007.
23. Bartolini, M.; Bertucci, C.; Cavrini, V.; Andrisano, V.
Biochem. Pharmacol. 2003, 65, 407.