Arch. Pharm. Chem. Life Sci. 2007, 340, 299–303
New 1-Aryl-3-[(4-benzyl)piperidine-1-yl]propanes
303
pressure; the residue was triturated with n-hexane and allowed
to sit with the solvent in refrigerator over the night. The precipi-
tated product was filtered and dried.
Evaluation of the locomotor activity
The compounds were administered intraperitoneally (ip) at
doses of 0.1–30 mg/kg 30 min. before the locomotor activity test
(5 min.). Sertraline (20 mg/kg, ip) fluoxetine (30 mg/kg, ip) and
imipramine (20 mg/kg, ip) were employed as the standard anti-
depressant drug. The control groups received distilled water and
DMSO (1 mL/kg, ip)
3-[4-Benzylpiperidine-1-yl]-1-(4-substitutedphenyl)-1-(4-
trifluoromethylphenoxy)-propane 5, 6
3-(4-Benzylpiperidine-1-yl)-1-(4-substituted phenyl)propane-1-ol
(2.5 mmol) was dissolved in N,N-dimethylacetamide or DMSO
(25 mL) and heated to 758C. Sodium hydride (2.5 mmol) was
added and the reaction mixture was maintained at 758C for 2 h
to allow the formation of salt. After this period of time, 4-chloro-
1-trifluoromethylbenzen (2.5 mmol) was added and the result-
ing mixture was poured onto crushed ice. It was then extracted
with diethyl ether (4610 mL), washed with brine (3610 mL)
and dried with anhydrous sodium sulphate. The solvent was
removed under reduced pressure and recrystallized from a suit-
able solvent.
Statistical analysis
All results are expressed as the mean lS.E.M. The data were ana-
lysed by student-t test. The level of significance was defined as
p a 0.05.
References
[1] D. T. Wong, K. W. Perry, F. P. Bymaster, Nat Revs Drug
Discov 2005, 4, 764–774.
Pharmacology
Animals
[2] P. Celada, M. V. Puig, M. A. Bosch, A. Adell, F. Artigas, J.
Psychiatry Neurosci. 2004, 29, 252–265.
Male Balb/c mice weighing 25–35 g were housed collectively in
groups of ten in polycarbonate cages. They were maintained on
a 12 h light/dark cycle (lights on 08:00/20:00 h) in a temperature
controlled (20 l 28C) laboratory. Food and water were available
ad libitum. These conditions were maintained constant through-
out the experiments. All procedures in this study are in accord-
ance with the Guide for the Care and Use of Laboratory Animals
as adopted by the National Institutes of Health.
[3] A. Hemeryck, F. M. Belpaire, Curr Drug Metab 2002, 3, 13–
37.
[4] J. Martinez-Esparza, A. M. Oficialdegui, S. Perez-Silanes,
B. Heras, et al., J. Med. Chem. 2001, 44, 418–428.
[5] A. Labbate, J. B. Grimes, G. W. Arana, Biol. Psychiatry 1998,
43, 904–907.
[6] K. Takeuchi, T. J. Kohn, N. A. Honigschmidt, V. P. Rocco,
et al., Bioorg. Med. Chem. Lett. 2003, 13, 3939–3942.
Forced swimming test
[7] K. Takeuchi, T. J. Kohn, N. A. Honigschmidt, V. P. Rocco,
FST consisted of placing mice into individual plexiglass cylin-
ders (16 cm diameter) containing 23–258C water, 11 cm deep;
mice could not support themselves by touching the bottom with
their paws. Two swimming sessions were conducted: an initial
15-min pretest followed 24 h later by a 6-min test. After an initial
2-min period of vigorous activity, each animal assumed an
immobile posture. The total duration of immobility was
recorded during last 4 min of the 6-min testing period. Follow-
ing each swimming session, the mice were removed from the
cylinders, dried with paper towels, placed in heated cages for
30 min and then returned to their home cages. Test sessions
were videotaped for later scoring. A single observer, who was
blind to the treatment conditions, did all the behavioural scor-
ing.
et. al., Bioorg. Med. Chem. Lett. 2003, 13, 1903–1905.
[8] K. Takeuchi, T. J. Kohn, N. A. Honigschmidt, V. P. Rocco,
et al., Bioorg. Med. Chem. Lett. 2003, 13, 2393–2397.
[9] V. P. Rocco, P. G. Spinazze, T. J. Kohn, N. A. Honigsch-
midt, et al., Bioorg. Med. Chem. Lett. 2004, 14, 2653–2656.
[10] K. Takeuchi, T. J. Kohn, N. A. Honigschmidt, V. P. Rocco,
et al., Bioorg. Med. Chem. Lett. 2006, 16, 2347–2351.
[11] L. Orus, S. Perez-Silanes, A. M. Oficialdegui, J. Martinez-
Esparza, et al., J. Med. Chem. 2002, 45, 4128–4139.
[12] N. T. Hatzenbuhler, D. A. Evrard, B. L. Harrison, D. Huryn,
et al., J. Med. Chem. 2006, 49, 4785–4789.
[13] D. Zhou, B. L. Harrison, U. Shah, T. H. Andree, et al., Bio-
org. Med. Chem. Lett. 2006, 16, 1338–1341.
Locomotor activity test
[14] A. M. Oficialdegui, J. Martinez, S. Perez, B. Heras, et al.,
Farmaco 2000, 55, 345–353.
Spontaneous locomotor activity was measured in an activity
cage (Ugo Basile, Varese, Italy) having dimensions of 39628626
cm. The values indicate pulses recorded by the apparatus as the
stainless steel bars tilt in response to animal movements. The
activity of each mouse was automatically recorded for 5 min.
[15] J. Martinez, S. Perez, A. M. Oficialdegui, B. Heras, et al,
Eur. J. Med. Chem. 2001, 36, 55–61.
[16] P. Willner, Psychopharmacology 1984, 83, 1–16.
[17] M. Bourin, Fundam. Clin. Pharmacol. 1990, 4, 49–64.
Evaluation
Evaluation of the antidepressant-like effect
[18] R. Porsolt, G. Anton, N. Blavet, M. Jalfe, Eur. J. Pharmaco.
1978, 47, 379–391.
The compounds were administered intraperitoneally (ip) at
doses of 0.1–30 mg/kg 30 min. before the forced swimming test.
Sertraline (20 mg/kg, ip), fluoxetine (30 mg/kg, ip) and imipr-
amine (20 mg/kg, ip) were employed as the standard antidepres-
sant drugs. The control groups received sterile distilled water
and DMSO (1 mL/kg, ip)
[19] F. Borsini, A. Meli, Psychopharmacology 1988, 94, 147–160.
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim