New 1-Aryl-3-(4-arylpiperazin-1-yl)propane Derivatives
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 427
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sphere. cAMP experiments were carried out with cultures
grown for 2-3 days in 8-well culture plates with 2 mL medium/
well.
F or sk olin -in d u ced cAMP for m a t ion : Cultures (about
7.5 × 104 cells/well) were washed with PBS and incubated for
10 min with 1 mL of PBS containing 0.5 mM isobutylmeth-
ylxanthine, 10 µM forskolin in the presence or absence of test
compounds. The medium was then aspirated and the reaction
stopped by addition of 600 µL ice-cold ethanol. Two hours later
ethanol was taken into an Eppendorf tube to be lyophilized
and the resulting pellet was resuspended in 100 µL of assay
buffer (Kit Amersham SPA, RPA 538) and cAMP was quanti-
fied by RIA. To study the antagonism to 8-OH-DPAT-induced
inhibition of forskolin-induced cAMP formation, test com-
pounds were preincubated 20 min before the addition of
forskolin and 8-OH-DPAT.
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F ST or P or solt Test.53 Mice were placed individually for
6 min into a glass cylinders (height 24 cm, diameter 13 cm)
containing 14 cm of water, maintained at 22-23 °C. This
procedure was repeated for 2 consecutive days. On the second
day, the animals were treated 30 min before water immersion
and the duration of immobility was recorded the second day
during the last 4 min of the 6-min testing period. A mouse
was considered to be immobile when it floated in an upright
position and made only small movements to keep its head
above water. The tricyclic antidepressant amitriptyline was
used as reference compound. Results were analyzed by using
the Student’s t-test.
Lea r n ed Help lessn ess Test. The test was performed as
previously described54 with minor modifications. Experimental
condition were as follows:
Help less in d u ction : On day 1, rats were placed individu-
ally in an operand conditioning chamber with a grid floor
connected to a scrambled shock generator (Coulbourn Instru-
ments). Each rat was then exposed to inescapable electric foot
shocks (1.1 mA, 10 s) every 30 s during 30 min.
Con d ition ed a void a n ce tr a in in g: Animals were placed
individually into a shuttle-box (Letica Instruments, Spain)
consisting of two compartments of the same size separated by
a door. Shocks delivered through the grid floor were termi-
nated as soon as the animal entered into the other compart-
ment. The assay consisted of 30 stimulus shock trials of 8 s
with a 30-s resting period between each trial. During the first
5 s of each trial, a light and a sound were on (conditioned
stimulus). If the animal did not cross within this period to the
other compartment, a shock (1 mA, 3-s maximal duration) was
delivered. Avoidance sessions were performed during 3 con-
secutive days and the number of escape failures and of
intertrial crossings were recorded.
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antidepressant therapy. Annu. Rep. Med. Chem. 1999, 34, 1-10.
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tors: Binding profiles and intrinsic activity. Pharmacol. Bio-
chem. Behav. 1991, 40, 1041-1051.
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Animals received either saline or treatment throughout the
4-day period. On day 1, the drug was given 6 h after exposure
to the inescapable shocks and on days 2-4 the drug was
administered twice a day, 30 min before shuttle-box exposure
and 6 h after. On each day of avoidance testing, differences
between control and treated rats were evaluated by the
Mann-Whitney U-test.
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K. V. Synthesis of 3-aryloxy-3-phenylpropanamines as possible
antidepressants. Ind. J . Chem. 1994, 33B, 393-396.
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(21) Klemm, K.; Pruesse, W.; Baron, L.; Kilian, U.; Sanders, K.
Pyridopyrimidintrione, verfahren zu ihrer herstellung, ihre
verwedung und sie enthaltende arzneimittel. Patent Application
DE3326118.
(22) Elworthy, T. R.; Ford, A. P.; Bantle, G. W.; Morgans, D. J . J r;
Ozer-RS.; Palmer, W. S.; Repke, D. B.; Romero, M.; Sandoval,
L.; Sjogren, E. B.; Talamas, F. X.; Vazquez, A.; Wu, H.;
Arredondo, N. F.; Blue, D. R., J r; DeSousa, A.; Gross, L. M.;
Kava, M. S.; Lesnick, J . D.; Vimont, R. L.; Williams, T. J .; Zhu,
Q. M.; Pfister, J . R.; Clarke, D. E. N-Arylpiperazinyl-N′-propyl-
amino derivatives of heteroaryl amides as functional uroselective
R-1-adrenoceptor antagonists J . Med. Chem. 1997, 40, 2674-
2687.
Ack n ow led gm en t. The authors are grateful to
VITA-INVEST S.A. for financial support and to the
Government of Navarra for predoctoral fellowships to
two of us (A.M.O. and R.T.). We also thank Sandra
Lizaso and Maria Espelosin for skillful technical as-
sistance.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, IR, com-
bustion analyses, and physical data of the prepared com-
pounds (mp, yield, purification method, and formula). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(23) Kuipers, W.; van Wijngaarden, I.; Kruse, C. G.; ter Horst-van
Amstel, M.; Tulp, M. Th. M.; Ijzerman A. P. N4-Unsubstituted
N1-arylpiperazines as high affinity 5-HT1A receptor ligands. J .
Med. Chem. 1995, 38, 1942-1954.
(24) Peglion, J . L.; Canton, H.; Bervoets, K.; Audinot, V.; Brocco, M.;
Gobert, A.; Le Marouille-Girardon, S.; Millan, M. J . Character-
ization of potent and selective antagonists at postsynaptic 5-HT1A
receptors in a serie of N4-substituted arylpiperazines. J . Med.
Chem. 1995, 38, 4044-4055.
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