Y. Charton et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2188–2193
2193
1H, NH+), 8.65 (m, 1H), 8.5 (m, 1H), 8.00 (m, 1H), 7.85
(m, 1H), 4.50 (s, 2H), 2.85 (s, 6H), 1.5–1.10 (m, 4H).
Other pharmaceutical properties are exemplified for
compound 1a. Thus 1a increased in a dose-dependant
manner (microdialysis, freely moving rats), the release
of cortical ACh (Fig. 2).10 This effect is indicative of
an agonist character. Moreover a positive effect on
memory was observed in the social recognition test in
Wistar rats (Fig. 3).11
1
Compound 1c: H NMR (DMSO d6-300 MHz) d 8.9 (sb,
3H, NH3þ), 8.65 (d, J = 2.0 Hz, 1H), 8.5 (d, J = 6.0 Hz,
1H), 8.10 (dd, J = 7.6, 2 Hz, 1H), 7.9 (m, 1H), 4.35 (s, 2H),
1.15–0.95 (m, 4H).
1
Compound 5a: H NMR (DMSO d6-300 MHz) d 9.7 (sb,
2H, NH2þ), 8.4 (m, 2H), 7.8 (m, 1H), 4.35 (s, 2H), 2.7 (s,
3H), 1.4–1.0 (m, 4H).
Compound 6a: 1H NMR (DMSO d6, 300 MHz) d 9.75 (sb,
2H, NH2þ), 8.25 (d, J = 2 Hz, 1H), 8.00 (d, J = 2 Hz, 1H),
4.35 (s, 2H), 2.65 (s, 3H), 1.3–0.95 (m, 4H).
Further pharmacological characterization of the above
compounds is ongoing and will be reported in due time.
7. For labeling of a7 nicotinic subtype rat brain cell mem-
branes (500 lg/ml) were incubated with [125I]a-bungaro-
toxine (2 nM) for 5 h at 37 °C. Non-specific binding was
determined by incubation of membrane preparations with
1 lM a-bungarotoxine Marks, M. J.; Stitzel, J. A.; Collins,
A. C. Pharmacol. Exp. Ther. 1985, 235, 619.
8. For labeling of a4b2 receptors, rat brain cell membranes
(250 lg/ml), were incubated with [3H]cytisine for 2 h at
room temperature. Non-specific binding was assessed by
the incubation of membrane preparations with 10 lM
S(ꢀ) nicotine Pabreza, L. A.; Dhawan, S.; Kellar, K. Mol.
Pharmacol. 1990, 39, 9.
Acknowledgments
We gratefully acknowledge the Cerebral Pathology
Division and the Chemistry Research Division A teams
as well as Dr. J.P. Bouchet and Mrs. C. Schaeffer for
analytical data and Mrs. D. Rostagni for the skillful typ-
ing of the manuscript.
References and notes
9. For labeling of muscarinic receptors (M2/M4) rat brain cell
membranes (250 lg/ml) were incubated with [3H]oxotre-
morine (2 nM) for 2 h at room temperature non-specific
binding being determined by incubation of membrane
preparations with 1 lM atropine Lockhart, B.; Closier,
M.; Howard, K.; Stewart, C.; Lestage, P. Naunyn Schmi-
edeberg Arch. Pharmacol. 2001, 363, 429.
1. (a) Jensen, A. A.; Frølund, B.; Liljefors, T.; Krogsgaard-
Larsen, P. J. Med. Chem. 2005, 48, 4705; (b) Romanelli,
N.; Gratteri, P.; Guandalini, L.; Martini, E.; Bonaccini, C.
ChemMedChem 2007, 2, 746.
2. (a) Dani, J. A. Biol. Psychiatry 2001, 49, 166; (b) Rezvani,
A. H.; Levin, E. D. Biol. Psychiatry 2001, 49, 258.
3. (a) Levin, E. D.; Bradley, A.; Addy, N.; Sigurani, N.
Neuroscience 2002, 109, 757; (b) Gatto, G. J.; Bohme, G.
A.; Caldwell, W. S.; Letchworth, S. R.; Traina, V. M.;
Obinu, M. C.; Laville, M.; Reibaud, M.; Pradier, L.;
Dunbar, G.; Bencherif, M. CNS Drug Rev. 2004, 10, 147;
(c) de Fiebre, C. M.; Meyer, E. M.; Henry, J. C.;
Muraskin, S. I.; Kem, W. R.; Papke, R. L. Mol.
Pharmacol. 1995, 47, 164; (d) Astles, P. C.; Baker, S. R.;
Boot, J. R.; Broad, L. M.; Dell, C. P.; Keenan, M. Curr.
Drug Targets CNS Neurol. Disord. 2002, 1, 337; (e)
Kitagawa, H.; Takenouchi, T.; Azuma, R.; Wesnes, K. A.;
Kramer, W. G.; Clody, D. E.; Burnett, A. L. Neuropsy-
chopharmacology 2003, 28, 542.
10. ACh levels: A guide-cannula was stereotaxically implanted
in the prefrontal cortex (AP: +3.3, L: ꢀ0.6, V: ꢀ0.5
relative to bregma). After 5–7 days of recovery, the
microdialysis probe (CMA11, 4 mm length, ; 0.23 mm)
was lowered in the guide-cannula. The dialysis probe was
continuously perfused at a flow rate of 1 ll/min with an
artificial cerebrospinal fluid (composition in mM: NaCl
147, KCl 2.7, MgCl2 1, CaCl2 1.2, adjusted at pH 7.4 with
2 mM phosphate buffer). Two hours after probe implan-
tation (stabilization period) in the rat prefrontal cortex,
dialysates were collected every 30 min and analyzed by
HPLC coupled to electrochemical detection. The first four
dialysates were considered as baseline. Drug administra-
tion began at the end of the baseline. Data are expressed in
percentage of the mean value of the baseline samples.
11. Social recognition: Adult male Wistar rats placed in their
standard home cages were exposed twice to a juvenile rat
(25–30 days old) in two 5 min sessions separated by a
retention interval of 120 min. Manual chronometric eval-
uation of exploration times (s) of the juvenile rats was
performed through a video-camera system. Decrease of
the exploration time toward the juvenile rate on the 2nd
session indicated that the adult rat recognized the juvenile
(increase of memory retention).
4. Goldstein, S.; Guillonneau, C.; Charton, Y.; Lockhart, B.;
Lestage, P. Eur. Patent 117081 A1, 2002; Chem. Abstr.
2002, 136, 86 625.
5. Lockhart, B.; Bonhomme, N.; Lebrun, C.; Roger, A.;
Guillonneau, C.; Charton, Y.; Goldstein, S.; Lestage, P.
Pharmacologist 2002, 44, A97.
6. Selected data: Compound 1a: 1H NMR (DMSO d6-
300 MHz) d 9.85 (sb, 2H, NH2þ), 8.65 (d, J = 2.0 Hz, 1H),
8.5 (d, J = 6.0 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.9 (m,
1H), 4.45 (s, 2H), 2.65 (s, 3H), 1.35–1.00 (m, 4H).
Compound 1b: 1H NMR (DMSO d6-300 MHz) d 11.4 (sb,