Novel benzo[ b ]thiophene derivatives as new potential antidepressants with rapid onset of action

Article abstract of DOI:10.1021/jm2000773

We report benzo[b]thiophene derivatives synthesized according to a dual strategy. 8j, 9c, and 9e with affinity values toward 5-HT₇R and 5-HTT were selected to probe their antidepressant activity in vivo using the forced swimming text (FST). The results showed significant antidepressant activity after chronic treatment. 9c was effective in reducing the immobility time in FST even after acute treatment. These findings identify these compounds as a new class of antidepressants with a rapid onset of action.

Full text of DOI:10.1021/jm2000773

BRIEF ARTICLE
pubs.acs.org/jmc
Novel Benzo[b]thiophene Derivatives as New Potential
Antidepressants with Rapid Onset of Action
Luis Berrade,†,§ Bꢀarbara Aisa,‡ María J. Ramirez,‡ Silvia Galiano,† Salvatore Guccione,§ Lise Romꢀan Moltzau,||
Finn Olav Levy,|| Ferdinando Nicoletti,^,# Giuseppe Battaglia,# Gemma Molinaro,# Ignacio Aldana,†
Antonio Monge,† and Silvia Perez-Silanes*,†
†Unidad en Investigaciꢀon y Desarrollo de Medicamentos, Centro de Investigaciꢀon en Farmacobiología Aplicada (CIFA),
University of Navarra, C/Irunlarrea 1, 31080 Pamplona, Spain
‡Department of Pharmacology, University of Navarra, C/Irunlarrea 1, 31080 Pamplona, Spain
§Dipartimento di Scienze del Farmaco, University of Catania, V. le Andrea Doria 6 Ed, 2 Cittꢁa Universitaria, I-95125, Catania, Italy
Department of Pharmacology, University of Oslo and Oslo University Hospital, N-0316 Oslo, Norway
^I.R.C.C.S. Instituto Neurologico Mediterraneo Neuromed, Localitꢀa Camerelle, 86077 Pozzilli (IS), Italy
#Department of Physiology and Pharmacology, University of Rome Sapienza, Italy
S Supporting Information
b
ABSTRACT: We report benzo[b]thiophene derivatives synthesized according to a dual strategy. 8j, 9c, and 9e with affinity values
toward 5-HT7R and 5-HTT were selected to probe their antidepressant activity in vivo using the forced swimming text (FST). The
results showed significant antidepressant activity after chronic treatment. 9c was effective in reducing the immobility time in FST
even after acute treatment. These findings identify these compounds as a new class of antidepressants with a rapid onset of action.
’ INTRODUCTION
The most widely used treatment for depression is based on
selective serotonin reuptake inhibitors (SSRIs, e.g., citalopram,
escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline).
However, antidepressant treatments require several weeks for the
onset of action and exhibit limited efficacy. In this sense, new
directions for antidepressant treatment have been developed, and
dual action drugs could represent an advance over SSRIs.
Some years ago, dual action compounds (Figure 1), with
affinity for the 5-HT1A receptor and able to inhibit serotonin
Figure 1. Compounds with dual action, 5HT1A antagonists, and
serotonin reuptake inhibitors.
transporter, synthesized in our laboratory showed good anti-
depressant activity.1ꢀ3 A pharmacophore study was carried out,
SB-269970 and SB-656104-A are 5-HT7 receptor antagonists
that exhibit antidepressant-like activity.17 Moreover, recent stud-
ies suggest that selective blockade of 5-HT7R may have a
synergistic effect with the inhibition of 5-HT reuptake in animal
model of depression.16 Therefore, compounds inhibiting sero-
tonin reuptake and blocking the 5-HT7R could open new
horizons in the treatment of this disease. Other studies have
shown the antidepressant efficacy of dual 5-HT1/SSRIs
compounds.17 One of the most important advantages of these
compounds is that they may behave as novel antidepressant-like
agents with a faster onset of action.18
and the inhibition of serotonin reuptake was related to the
benzo[b]thiophene moiety and the affinity to 5-HT1A receptors
to the arylpiperazine group.4
Advances in the neurobiology of depression have suggested a
number of novel targets for antidepressant treatment, such as
5-HT7 receptors (5-HT7R),5 the most recent serotonin receptor
cloned in 1993.6ꢀ9 The fact that clinical effective antipsychotic
and antidepressant drugs present affinity for 5-HT7R10 and that
chronic administration of antidepressants down-regulates 5-HT7
receptor mediated responses and receptor binding in limbic
areas10,11 leads to the prediction that these receptors are likely
involved in depressive states and antidepressant responses. Abbas
et al.12 suggest that amisulpride exerts its antidepressant activity
through 5-HT7R. Pure 5-HT7 receptor antagonists could be
effective in the treatment of depression and might have advantages
over currently available options.13 The 5-HT7 receptor antagonism
seems capable of producing diverse antidepressant-like behavior-
al effects, affecting hippocampal neuronal morphology, and
enhancing hippocampal neurogenesis.14
’ CHEMISTRY
To obtain new dual compounds, 5-HT7 receptor antagonists
and serotonin reuptake inhibitors, a bibliographic revision
was carried out and it was observed that structures such as
Received: November 3, 2010
Published: April 06, 2011
r
2011 American Chemical Society
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|

Journal of Medicinal Chemistry
BRIEF ARTICLE
arylsulfonamides19ꢀ24 and arylamines22,23,25 presented high affi-
nity toward 5-HT7R. Therefore, two new molecules were
synthesized (Figure 2) in which the benzo[b]thiophene ring4
was fused with an arylsulfonamide for the compounds of series I
(6 and 7 of the Scheme 1) and with an arylamine for the
compounds of series II (8 and 9 of the Scheme 1).
The structures of the investigated compounds and their
synthesis are presented in Scheme 1. 1-(3-Benzo[b]thiophenyl)-
3-chloropropan-1-one precursor was synthesized by a FriedelꢀCraft
acylation of the corresponding benzo[b]thiophene precursor as
previously described.2 Benzo[b]thiophene is commercially available,
and 5-fluorobenzo[b]thiophene was prepared as reported.26 The
synthesis of the sulfonamides 2 was carried out by a nucleophilic
attack of the amine over different sulfonyl chlorides via SN2
mechanism. BOC-arylamines 3 were obtained by an Ar SN
reaction via Meisenheimer complex27 between a monoprotected
diamine and an aryl fluoride. Removal of the BOC group from 2
and 3 with HCl and acetic acid yielded 4 and 5. Compounds 6
and 8 were synthesized by a nucleophilic attack of the nitrogen
atom on the carbon carrying the chlorine atom via SN2 mechan-
ism. The hydroxyl derivatives 7 and 9 were obtained by reduction
of the carbonyl groups of 6 and 8 with NaBH4 in methanol. The
effect of the newly created stereogenic center in 7 and 9 on the
pharmacological profile should be evaluated in future studies.
The influence of the structural modifications on the affinity for
the targets was investigated, and the most interesting compounds
were pharmacologically evaluated in the forced swimming test
(FST), a pharmacological model for anxiety and depression.28
’ RESULTS AND DISCUSSION
All synthesized compounds were tested in competition bind-
ing experiments for the evalutation of their affinity for the
5-HT7R and SERT (Table 1).
Figure 2. General structures of the new arylsulfonamides and aryla-
mines synthesized.
Scheme 1. Synthesis of New Sulfonamides and Arylamines, Benzo[b]thiophene Derivativesa
a (i) Cl-SO2-Ar, CH2Cl2, EtN3; (ii) F-Ar, K2CO3, CH3CN, reflux 48 h; (iii) HCl, acetic acid, 2 h; (iv) THF, K2CO3, 72 h; (v) methanol, NaBH4, 0 ꢀC, 2 h.
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Table 1. Series II: Arylamine Derivative Affinity toward 5-HT7 Receptor and 5-HTT (Serotonin Transport Protein)a
BRIEF ARTICLE
5-HT7
agonism
5-HTT affinity, % displacement of [3H]5-HT
compd R1
R
amino
piperazine
Ar
pKi
10 μM
1 μM
8a
8b
8c
8d
8e
8f
H
H
H
F
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
p-nitrophenyl
<4.00
4.85
ND
33.2
ND
38.2
16.3
ND
63.1
58.0
76.5
36.6
97.9
45.6
45.4
62.8
ND
35.0
30.2
57.7
36.0
36.7
49.2
80.4
63.6
2.1
ND
5.4
0
piperazine
p-aminophenyl
p-cyanophenyl
p-nitrophenyl
ND
piperazine
<4.00
4.04
ND
piperazine
ND
H
H
H
H
H
H
H
H
H
H
F
homopiperazine
homopiperazine
homopiperazine
(R)-pyrrolidin-3-amine
3-amine-(S)-pyrrolidine
p-nitro-o-trifluoromethylphenyl <4.00
ND
ND
1.2
23.8
17.9
0
p-cyanophenyl
2-quinoxaline
p-nitrophenyl
p-nitrophenyl
4.82
5.02
ND
8g
8h
8i
ND
<4.00
<4.00
ND
ND
8j
3-amine- (S)-pyrrolidine p-nitro-o-trifluoromethylphenyl <4.00
ND
28.4
0
8k
8l
3-amine-(S)-pyrrolidine
p-cyanophenyl
<4.00
<4.00
5.04
5.14
5.32
4.27
4.90
5.06
6.58
<4.00
5.78
4.56
ND
3-amine-(R)-pyrrolidine p-nitrophenyl
ND
9.0
26.9
ND
3.1
11.1
43.5
0
8m
8n
8o
8p
9a
9b
9c
9d
9e
9f
4-amine-piperidine
4-amine-piperidine
4-amine-piperidine
piperidine
p-nitro-o-trifluoromethylphenyl
A/PAg
PAg
A/PA
ND
p-cyanophenyl
p-nitrophenyl
H
H
H
H
H
H
H
Morpholine
CꢀOH piperazine
p-cyanophenyl
A/IAg
PAg
A/IAg
ND
CꢀOH homopiperazine
CꢀOH homopiperazine
p-nitro-o-trifluoromethylphenyl
p-cyanophenyl
19.7
28.1
53.1
2.2
CꢀOH 3-amine-(R)-pyrrolidine p-nitrophenyl
CꢀOH 4-amine-piperidine
CꢀOH piperidine
p-cyanophenyl
A/IAg
ND
morpholine
a ND, no data; A, antagonist; Ag, agonist; PAg, partial agonist; IAg, inverse agonist.
Binding Assay to the 5-HT7R. Compounds from series I,
containing the arylsulfonamide moiety, showed in general low
affinity toward 5-HT7R, whereas the arylamine derivatives of
series II displayed the most interesting results of affinity toward
this receptor (Table 1).
affinity. This compound might be considered as prototypical for
the design of new antidepressant agents.
In Vivo Assays. Three compounds were selected for testing
antidepressant activity in the FST, which has predictive value for
antidepressant-like activity.28 8j was chosen because of its affinity
for SERT. 9c was found to be the best 5-HT7 receptor antagonist,
while 9e was one of the most interesting compounds because
it showed dual affinity. All compounds were tested at a dose of
10 mg/kg. For comparative purposes, fluoxetine (10 and 20 mg/kg,
ip) was also included in the experiment.
After acute administration, 9c (10 mg/kg, ip) but not fluox-
etine (10 or 20 mg/kg) was able to significantly reduce the
immobility time compared to controls (Figure 3). After chronic
treatment, 8j, 9c, and 9e showed antidepressant activity compar-
able to that of chronic fluoxetine (20 mg/kg, ip) treatment
(Figure 3).
The FST must be validated by testing the influence of the
compounds on motor behavior because an increase in motor
activity might account for changes in the immobility time in the
test. The results in the present study do not appear to be related
to unspecific effects of any of the drugs in motor activity because
no differences were found in total path length traveled in the
locomotor activity test (data not shown).
Binding Assay to 5-HT1A Receptor. The affinity for 5-HT1A
receptors was also checked because this receptor is known to
have a pharmacological profile similar to the 5-HT7 receptor and
it also plays a role in the antidepressant response. The pKi for the
reference 8-OH-DPAT was 8.9. The pKi values obtained for 9c,
9e, and 8j were 5.5, 6.8, and 7.3 respectively. These results show
that the affinity of these compounds for the 5-HT1A receptor
does not seem to be related to their antidepressant-like activity.
The 5-HT7 receptor affinity values revealed that the alcohol
derivatives 9 are the most suited compounds for interacting with
this target, especially the homopiperazinyl and aminopiperidinyl
compounds (9b,c,e). The influence of the different substituents
in the aromatic ring is not very clear, but it appears that products
containing a p-cyano group (9c,e) have more affinity toward this
target than those that hold any other residue. Accordingly, 9c,
containing a homopiperazine as central diamine and a p-cyano
group as substituent of the phenyl ring, is the most potent
compound, behaving as a 5-HT7R antagonist in adenylyl cyclase
assays and displaying pKi = 6.58 in 5-HT7 receptor binding
assays. For this reason, these compounds were chosen for the
study of antidepressant activity in vivo.
Binding Assay to the SERT. To evaluate the duality of our
compounds, weassessed their affinity for SERT. The displacement
of the radioligand [3H]5-HT by fluoxetine and our compounds
was compared. Some molecules from series I presented relevant
affinity for SERT (see Table 1 in Supporting Information), but the
arylamine derivatives from series II displayed the highest affinity
for this target (Table 1). As opposed to 5-HT7 receptor data, the
ketones 8 showed higher affinity for SERT than the alcohol
derivatives. Activity toward SERT was further studied for 8j, 9c,
and 9e. IC50 was 8.3 ( 2.24 μM for fluoxetine, 7.02 ( 3.05 μM for
8j, 3.66 ( 1.29 μM for 9e, and 57.81 ( 16.15 μM for 9c. On the
basis of the affinity values toward both targets, 9e was chosen as
one of the most interesting products because it showed dual
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BRIEF ARTICLE
Synthesis of 1-Benzo[b]thiophen-3-yl-3-[1-(4-nitro-2-trifluoro-
methylphenyl-(S)-pyrrolidin-3-ylamino)propan-1-one (8j).
A mixture of 1-(benzo[b]thiophen-3-yl)-3-chloropropan-1-one (1.24
g, 4.61 mmol), 1-(4-nitro-2-trifluoromethylphenyl)-(S)-pyrrolidin-3-
amine (1.52 g, 5.53 mmol), and K2CO3 (0.68 g, 6.91 mmol) was stirred
in THF for 72 h at room temperature. The solvent was removed under
reduced pressure, and the residue was dissolved in CH2Cl2 (40 mL), and
washed with water (3 ꢁ 30 mL). After evaporating to dryness under
reduced pressure, the residue was purified by column chromatography
(SP, silica gel), eluting with CH2Cl2/methanol 99:1 v/v. Yield: 18%. Mp
122ꢀ124 ꢀC. 1H NMR (400 MHz, CDCl3): δ 1.74(s, 1H, NH);
1.93ꢀ2.00 (m, 1H, H4ec pyrrolidine); 2.21ꢀ2.28 (m, 1H, H4ax
pyrrolidine); 3.04ꢀ3.10 (q, 1H, CH2-NH); 3.14ꢀ3.20 (m, 1H, CO-
CH2-CH2); 3.26 (t, 2H, CO-CH2, J = 5.9 Hz); 3.40 (dd, 1H, H2ec
pyrrolidine, J2ec,2ax = 10.3 Hz, J2ec,3 = 4.9 Hz,); 3.54ꢀ3.62 (m, 2H, H5);
3.68ꢀ3.74 (m, 1H, H3 pyrrolidine); 3.78 (dd, 1H, H2ax pyrrolidine,
0
0
0
J2ax,2ec = 10.3 Hz, J2ax,3 = 5.7 Hz,); 6.79 (d, 1H, H6 , J6 ,5 = 9.5 Hz); 7.45
(ddd, 1H, H5, J5,4 = 8.0 Hz, J5,6 = 7.1 Hz, J5,7 = 1.1 Hz); 7.51 (ddd, 1H,
H6, J6,7 = 8.3 Hz, J6,5 = 7.1 Hz, J6,4 = 1.2 Hz); 7.89 (ddd, 1H, H4, J4,5 = 8.0
0
0
0
0
0
Hz, J4,6 = 1.1 Hz, J4,7 = 0.7 Hz); 8.12 (dd, 1H, H5 , J5 ,6 = 9.5 Hz, J5 ,3
=
0
0
0
2.8 Hz); 8.33 (s, 1H, H2); 8.54 (d, 1H, H3 , J3 ,5 = 2.8 Hz); 8.75 (ddd,
1H, H7, J7,6 = 8.0 Hz, J7,5 = 1.2 Hz, J7,4 = 0.6 Hz) ppm. Anal. Calcd for
C22H20N3F3O3S: C, 57.01%; H, 4.35%; N, 9.07%. Found: C, 56.72%; H,
4.31%; N, 8.82%.
Figure 3. Antidepressant effect, measured as immobility time in the
Porsolt swimming test, after acute or chronic treatment with fluoxetine
(10 or 20 mg/kg) for 9c, 9e, 8j (all 10 mg/kg): acute treatment, one-way
ANOVA (F5,75 = 4217, p < 0.01) followed by Scheffe post hoc test, (/)
p < 0.05 vs control; chronic treatment, one-way ANOVA (F5,73 = 11 029,
p < 0.001) followed by Scheffe posthoc test, (/) p < 0.001 vs control, (†)
p < 0.05 vs fluxetine (10 mg/kg).
Synthesis of 4-[4-(3-Benzo[b]thiophen-3-yl-3-hydroxy-
propyl)[1,4]diazepan-1-yl]benzonitrile (9c). Sodium borohy-
dride (0.14 g, 3.84 mmol) was added little by little to a precooled
suspension (0 ꢀC, 5 min) of 4-[4-(3-benzo[b]thiophen-3-yl-3-
oxopropyl)[1,4]diazepan-1-yl]benzonitrile (0.50 g, 1.28 mmol) in
methanol (20 mL) over 30 min. The mixture was stirred until TLC
proved that the reaction did not go on (∼1 h). The solvent was removed
under reduced pressure, and the residue dissolved in dichloromethane
(40 mL) was washed with water (3 ꢁ 30 mL). The organic phase was
dried with anhydrous Na2SO4 and filtered. After evaporation of the
solvent to dryness under reduced pressure, the compound was purified
by preparative chromatography (SP, silica gel), eluting with CH2Cl2/
Compounds with higher affinity for this receptor do not show
great antidepressant effects in this test.
’ CONCLUSIONS
The thorough research carried out on new compounds with
antidepressant profiles resulted in the synthesis of 35 new
benzo[b]thiophene derivatives. Some of them have shown
acceptable affinity toward 5-HT7R, one of the serotonin recep-
tors that has been purportedly described as being involved in the
development of depression. The affinity for this target and for
SERT was studied, and three products were selected for perform-
ing in vivo assays.
The FST revealed that all three compounds possessed anti-
depressant activity after chronic treatment (15-day treatment) and
that one of them showed activity even after acute administration.
The results of this study indicate that 5-HT7 receptor antago-
nists have properties that are common to classical antidepressants
in the FST, suggesting that they may be of interest for the treatment
of depression. However, a note of caution should be considered at
this point, as dual activity of these compounds on SERT and
5HT1A receptors cannot be completely excluded as being purport-
edly involved in the biological effects of these compounds.
In addition, considering that SSRIs such as fluoxetine often
require several weeks to achieve clinical benefits in depressed
patients, the rapid onset of action of 9c suggests that 5-HT7
receptor antagonists may represent a new class of antidepressants
with beneficial effects over classical SSRIs.
1
methanol 95:5 v/v.Yield: 61%. Mp 41ꢀ43 ꢀC. H NMR (400 MHz,
DMSO-d6): δ 2.04ꢀ2.15 (m, 4H, CHOH-CH2 and H6 diazepane);
2.68ꢀ2.99 (m, 6H, CHOH-CH2-CH2 and H2 þ H7 diazepane);
3.54ꢀ3.63 (m, 2H, H5 diazepane); 3.70 (bs, 2H, H3 diazepane);
5.35ꢀ5.38 (dd, CHOH, JH,CH2 = 7.7 Hz, JH,OH = 3.0 Hz); 6.68 (d,
0
0
0
0
0
0
2H, H2 þ H6 , J2 ,3 = J6 ,5 = 8.8 Hz); 7.34ꢀ7.41 (m, 2H, H6 þ H5); 7.42
0
0
0
0
0
0
(s, 1H, H2); 7.49 (d, 1H, H3 þ H5 , J3 ,2 = J5 ,6 = 8.8 Hz); 7.79 (dd. 1H,
H4, J4,5 = 7.1 Hz, J4,6 = 1.5 Hz); 7.88 (dd, 1H, H7, J7,6 = 7.0 Hz, J7,5 = 1.5
Hz) ppm. Anal. Calcd for C23H25N3OS: C, 70.56%; H, 6.44%; N,
10.73%. Found: C, 70.58%; H, 6.78%; N, 10.44%.
Synthesis of 4-[4-(3-Benzo[b]thiophen-3-yl-3-hydroxy-
propylamino)piperidin-1-yl]benzonitrile (9e). Sodium borohydride
(0.51 g, 13.32 mmol) was added little by little to a precooled suspension
(0 ꢀC, 5 min) of 4-[4-(3-benzo[b]thiophen-3-yl-3-oxopropylami-
no)piperidin-1-yl]benzonitrile (1.19 g, 4.44 mmol) in methanol (30 mL)
over 30 min. The mixture was stirred until TLC proved that the reaction did
not go on (∼1 h). The solvent was removed under reduced pressure, and the
residue dissolved in dichloromethane (40 mL) was washed with water (3 ꢁ
30 mL). The organic phase was dried with anhydrous Na2SO4 and filtered.
After evaporation of the solvent to dryness under reduced pressure, the
compound was purified by column chromatography (SP, silica gel), eluting
with CH2Cl2/methanol 99:1. Yield: 56%. Mp 150ꢀ151 ꢀC. 1H NMR (400
MHz, CDCl3): δ 1.59ꢀ1.69 (m, 2H, H3ax þ H5ax piperidine); 2.16ꢀ2.19
(bs, 2H, H3ec þ H5ec piperidine); 2.92ꢀ2.98 (m, 3H, H2ax þ H6ax þ H4
piperidine); 3.25 (t, 2H, CHOH-CH2, J = 6.1 Hz); 3.41 (t, 2H, CHOH-
CH2-CH2, J = 6.1 Hz); 3.87 (d, 2H, H2ec þ H6ec piperidine, J2ec,2ax = J6ec,6ax
’ EXPERIMENTAL SECTION
All the compounds were chemically characterized by TLC, melting
point, IR, and 1H NMR spectra. To determine the purity of the
compounds, we used elemental microanalysis. The analytical results
for C, H, and N were within (0.4 of the theoretical values.
0
0
0
0
0 0
= 13.1 Hz); 5.51 (bs, 1H, NH); 6.87 (d, 2H, H2 þ H6 , J2 ,3 = J6 ,5 = 9.1
0
0
Hz); 7.42ꢀ7.53 (m, 4H, H5 þ H6 þ H3 þ H5 ); 7.88 (ddd, 1H, H4,
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BRIEF ARTICLE
J4,5 =7.8 Hz, J4,6 = 1.2 Hz, J4,7 =0.7Hz); 8.39(s, 1H, H2);8.73 (ddd, 1H, H7,
J7,6 = 8.2 Hz, J7,5 = 1.3 Hz, J7,4 = 0.7 Hz) ppm. Anal. Calcd for C23H25N3OS:
C, 70.56%; H, 6.44%; N, 10.73%. Found: C, 70.27%; H, 6.51%; N, 10.44%.
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5-HT7R inhibition and inactivation induce antidepressantlike behavior
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’ ASSOCIATED CONTENT
S
Supporting Information. Synthesis methods and char-
b
acterization data of all compounds and details of biological assay
procedures. This material is available free of charge via the Internet
at http://pubs.acs.org.
(15) Wesolowska, A.; Nikiforuk, A.; Stachowicz, K.; Tatarczynska, E.
Effect of the selective 5-HT7 receptor antagonist SB 269970 in animal
models of anxiety and depression. Neuropharmacology 2006, 51, 578–586.
(16) Wesolowska, A.; Tatarczynska, E.; Nikiforuk, A.; Chojnacka-
Wojcik, E. Enhancement of the anti-immobility action of antidepres-
sants by a selective 5-HT7 receptor antagonist in the forced swimming
test in mice. Eur. J. Pharmacol. 2007, 555, 43–47.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: þ34 948 425653. Fax: þ34 948 425652. E-mail:
sperez@unav.es.
(17) Bromidge, S. M.; Bertani, B.; Borriello, M.; Bozzolb, A.; Faedo,
S.; Gianotti, M.; Gordon, L. J.; Hilla, M.; Zucchelli, V.; Watson, J. W.;
Zonzini, L. 8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-
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(18) Mnie-Filali, O.; Lambꢀas-Se~nas, L.; Zimmer, L.; Haddjeri, N.
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produce rapid antidepressant responses or to hasten those obtained with
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