C. Manera et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6505–6510
6509
Table 2. Effect of AM630 on antinociception induced by derivative 2 in the mouse hot-plate test
Treatment 1 po
Treatment 2 po
No. of mice
Licking latency (s)
After treatment
Before pre treatment
15 min
30 min
45 min
CMC
CMC
CMC
AM630 0.6ꢀm1 g kgꢀ1
2 30 mg kgꢀ1
2 50 mg kgꢀ1
AM630 0.6 mg kgꢀ1
12
14
10
10
13
10
14.8 0.6
15.2 0.4
14.5 0.8
14.4 0.6
15.1 0.5
16.2 0.7
15.5 0.7
16.6 0.6
17.1 0.9
16.6 0.8
19.2 0.6
18.1 0.7
16.8 0.6
18.0 0.4
18.5 1.0
19.5 1.0
22.5 0.9*
19.2 0.4^
14.7 0.5
16.3 0.4
16.7 0.6
17.4 0.6
18.2 0.7
17.6 0.6
CMC
CMC
2 10 mg kg
*
CMC
2 50 mg kgꢀ1
* P < 0.05 versus CMC-treated mice.
^ P < 0.05 versus 2-treated mice. AM-630 and 2 were administered simultaneously.
2. Iwamura, H.; Suzuki, H.; Ueda, Y.; Kaya, T.; Inaba, T.
J. Pharmacol. Exp. Ther. 2001, 296, 420.
Table 3. Effect of 2 on motor coordination in the mouse rotarod test
3. Ofek, O.; Karsak, M.; Leclerc, N.; Fogel, M.; Frenkel, B.;
Wright, K.; Tam, J.; Attar-Namdar, M.; Kram, V.;
Shohami, E.; Mechoulam, R.; Zimmer, A.; Bab, I. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 696.
Treatment
po
No. of
mice
No. of falls
After treatment
30 min 45 min
Before
treatment
15 min
4. Sanchez, C.; de Ceballos, M. L.; del Pulgar, T. G.; Rueda,
D.; Corbacho, C.; Velasco, G.; Galve-Roperh, I.; Huff-
man, J. W.; Ramon y Cajal, S.; Guzman, M. Cancer Res.
2001, 61, 5784.
CMC
12
3.3 0.2 0.8 0.2 0.3 0.2 0.2 0.2
4.0 0.7 0.7 0.2 0.2 0.2 0.2 0.2
2 50 mg kgꢀ1 13
5. McKallip, R. J.; Lombard, C.; Fisher, M.; Martin, B. R.;
Ryu, S.; Grant, S.; Nagarkatti, P. S.; Nagarkatti, M.
Blood 2002, 100, 627.
6. Pertwee, R. G. Pharmacol. Ther. 2002, 95, 165.
7. Stella, N. Glia 2004, 48, 267.
duced by the activation of opioid and GABAergic acti-
vation (data not shown) suggesting that dose is selective
for CB neurotransmission.
8. Ramirez, B. G.; Blazquez, C.; Gomez del Pulgar, T.;
Guzman, M.; de Ceballos, M. L. J. Neurosci. 2005, 25,
1904.
9. Kim, K.; Moore, D. H.; Makriyannis, A.; Abood, M. E.
Eur. J. Pharmacol. 2006, 542, 100.
10. Valenzano, K. J.; Tafesse, L.; Leeb, G.; Harrison, J. E.;
Boulet, J. M.; Gottshall, S. L.; Mark, L.; Pearson, M. S.;
Miller, W.; Shan, S.; Rabadi, L.; Rotshteyn, Y.; Chaffer,
S. M.; Turchin, P. I.; Elsemore, D. A.; Toth, M.;
Koetzner, L.; Whiteside, G. T. Neuropharmacology 2005,
48, 658.
11. Malan, T. P., Jr.; Ibrahim, M. M.; Lai, J.; Vanderah, T.
W.; Makriyannis, A.; Porreca, F. Curr. Opin. Pharmacol.
2003, 3, 62.
However, AM630, at doses higher than the one men-
tioned above, could not be used since it caused an
impairment of behavioral parameters (data not shown).
It is interesting to note that 2 at the antinociceptive dose
did not modify mouse motor coordination evaluated in
the rotarod test (see Table 3).
The lack of any impairment in the motor coordination of
animals was demonstrated by the reduction of number of
falls from the rotating rod before and 15, 30, 45, and
60 min after the beginning of the rotarod session.
12. Ferrarini, P. L.; Calderone, V.; Cavallini, T.; Manera, C.;
Saccomanni, G.; Pani, L.; Ruiu, S.; Gessa, G. L. Bioorg.
Med. Chem. 2004, 12, 1921.
13. Manera, C.; Benetti, V.; Castelli, M. P.; Cavallini, T.;
Lazzarotti, S.; Pibiri, F.; Saccomanni, G.; Tuccinardi, T.;
Vannacci, A.; Martinelli, A.; Ferrarini, P. L. J. Med.
Chem. 2006, 49, 5947.
14. Tuccinardi, T.; Ferrarini, P. L.; Manera, C.; Ortore, G.;
Saccomanni, G.; Martinelli, A. J. Med. Chem. 2006, 49,
984.
In conclusion, the new 1,8-naphthyridine and quinoline
derivatives synthesized and characterized confirmed the
main suggested structural requisites for the CB2 interac-
tion. Moreover, compound 2 showed a high CB2 affinity
and CB2 versus CB1 selectivity and possessed antinoci-
ceptive effects, thus encouraging deeper studies on these
classes of CB2 agonists.
15. All compounds prepared in this work were characterized
by 1H NMR and MS spectra and were found to be in
agreement with their structures.
16. Shah, K. J.; Coats, E. A. J. Med. Chem. 1977, 20, 1001.
17. Carboni, S.; Da Settimo, A.; Bertini, D.; Ferrarini, P. L.;
Livi, O.; Mori, Cl.; Tonetti, I. o. Gazzetta Chimica Italiana
1972, 102, 253.
Supplementary data
Supplementary data associated with this article can be
18. Kaslow, C. E.; Clark, Wx. R. J. Org. Chem. 1953, 18, 55.
19. For CB1 and CB2 receptor binding assays, the new
compounds were tested using membranes from HEK-293
cells transfected with either the human CB1 or CB2
receptor and [3H]-(ꢀ)-cis-3-[2-hydroxy-4-(1,1-dimethyl-
heptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexanol
([3H]CP-55,940) (Kd = 0.31 nM for CB2 and 0.18 nM for
References and notes
1. Ibrahim, M. M.; Porreca, F.; Lai, J.; Albrecht, P. J.; Rice,
F. L.; Khodorova, A.; Davar, G.; Makriyannis, A.;
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Natl. Acad. Sci. U.S.A. 2005, 102, 3093.