N1-Azinylsulfonyl-1H-indoles: 5-HT6 Receptor Antagonists with Procognitive and Antidepressant-Like Properties

Article abstract of DOI:10.1021/acsmedchemlett.6b00056

A series of N1-azinylsulfonyl-3-(1,2,3,6,tetrahyrdopyridin-4-yl)-1H-indole derivatives was designed to obtain highly potent 5-HT₆ receptor ligands. The study allowed for the identification of 25 (4-{[5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}isoquinoline), a potent and selective 5-HT₆ receptor antagonist. The selected compound, was evaluated in vivo in a novel object recognition (NOR) and forced swim (FST) tests in rats, demonstrating distinct pro-cognitive and antidepressant-like properties (MED = 1 mg/kg and 0.1 mg/kg, i.p., respectively). Compound SB-742457, used as comparator, reversed memory deficits in NOR task in similar doses, while in FST it was active in 10-30-fold higher dose (3 mg/kg). In contrast to SB-742457, which was active in Vogel test (MED = 3 mg/kg), compound 25 displayed no anxiolytic activity.

Full text of DOI:10.1021/acsmedchemlett.6b00056

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Letter
N1-azinylsulfonyl-1H-indoles: 5-HT6 receptor antagonists
with pro-cognitive and antidepressant-like properties
Pawe# Zajdel, Krzysztof Marciniec, Grzegorz Sata#a, Vittorio Canale, Tomasz Kos, Anna
Partyka, Magdalena Jastrz#bska-Wi#sek, Anna Weso#owska, Agnieszka Basi#ska-
Ziobro#, Jacek Wójcikowski, W#adys#awa A. Daniel, Andrzej J. Bojarski, and Piotr Popik
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00056 • Publication Date (Web): 07 Apr 2016
Downloaded from http://pubs.acs.org on April 9, 2016
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Page 1 of 5
ACS Medicinal Chemistry Letters
N1-azinylsulfonyl-1H-indoles: 5-HT6 receptor antagonists with
pro-cognitive and antidepressant-like properties
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†
,
‡
†
≠
⊥
Paweł Zajdel, * Krzysztof Marciniec, Grzegorz Satała, Vittorio Canale, Tomasz Kos, Anna
§
§
§
#
Partyka, Magdalena JastrzębskaꢀWięsek, Anna Wesołowska, Agnieszka BasińskaꢀZiobroń, Jacek
Wójcikowski, Władysława A. Daniel, Andrzej J Bojarski, Piotr Popik
#
#
‡
±,≠
†
§
Department of Medicinal Chemistry, Department of Clinical Pharmacy, Jagiellonian University Medical College, 9
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Medyczna Street, 30ꢀ688 Krakow, Poland
⊥
Department of Organic Chemistry, Medical University of Silesia, 4 Jagiellońska Street, 41ꢀ200 Sosnowiec, Poland
±
Faculty of Health Sciences, Jagiellonian University Medical College, Michalowskiego 20, 31ꢀ126 Krakow, Poland
‡
#
≠
Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, Department of Behavioral
Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31ꢀ343
Krakow, Poland
KEYWORDS: isoquinoline/quinoline sulfonamides, 5ꢀHT receptor antagonist, Alzheimer’s disease, cognitive decline, novel
6
object recognition task, forced swim test, Vogel test
ABSTRACT: A series of N1ꢀazinylsulfonylꢀ3ꢀ(1,2,3,6,tetrahyrdopyridinꢀ4ꢀyl)ꢀ1Hꢀindole derivatives was designed to obtain highly
potent 5ꢀHT receptor ligands. The study allowed for the identification of 25 (4ꢀ{[5ꢀmethoxyꢀ3ꢀ(1,2,3,6ꢀtetrahydropyridinꢀ4ꢀyl)ꢀ1Hꢀ
6
indolꢀ1ꢀyl]sulfonyl}isoquinoline),
The selected compound, with good brain penetrability, was evaluated in vivo in a novel object recognition (NOR) and forced swim
FST) tests in rats, demonstrating distinct proꢀcognitive and antidepressantꢀlike properties (MED = 1 mg/kg and 0.1 mg/kg, i.p.,
a
potent
and
selective
5ꢀHT6
receptor
antagonist.
(
respectively). Compound SBꢀ742457, used as comparator, reversed memory deficits in NOR task in similar doses, while in FST
was active in 10–30 folds higher dose (3 mg/kg). In contrast to SBꢀ742457, which was active in Vogel test (MED = 3 mg/kg),
compound 25 displayed no anxiolytic activity.
The most devastating neurodegenerative form of dementia is
Alzheimer’s disease (AD). The number of AD patients was
estimated at 35.6 mln in 2012 and is expected to double every
twenty years to 65.7 mln in 2030 and 115.4 in 2050. Current AD
treatments provide only brief symptomatic relief and are based on
the use of acetylcholinesterase inhibitors and NMDA receptor
antagonist. One approach that has recently garnered significant
1
interest is selective 5ꢀHT receptor (5ꢀHT R) antagonism.
6
6
The 5ꢀHT R belongs to the Gꢀprotein coupled receptor
6
(GPCR) superfamily, and it stimulates adenylyl cyclase via Gs, as
well as extracellularꢀregulated kinase (ERK) signaling via the Srcꢀ
family
tyrosine
kinase
Fyn.
Furthermore,
Figure 1. 5ꢀHT R antagonists under clinical trials.
6
5
ꢀHT R activates mTOR Complex 1 (mTORC1) in the prefrontal
6
2
cortex which is related to cognitive deficits, and the receptor
constitutively activates Cdk5 to control cortical neurons migration
and promote neurite growth.
Almost exclusive localization of 5ꢀHT R in the cerebral
6
3
cortex, nucleus accumbens and hippocampus suggests that
compounds, which selectively affect this receptor might have
relatively few peripheral side effects.
Blockade of 5ꢀHT R enhances cognitive performance in a
6
4
,5
broad range of tasks in rodents and phase II clinical studies have
demonstrated efficacy of 5ꢀHT R antagonists
Iladopirdine = LuAE58054, SB742457, and AVNꢀ211, Figure 1)
A vast group of 5ꢀHT R ligands is based on an indole
6
6
10,11
scaffold.
Structureꢀactivity relationship studies within this
(
class revealed that incorporating the tryptamine aminoethyl group
into the constrained basic side chain of the tetrahydropyridynyl
moiety and the sulfonylation at the N1 position on the indole
in conjunction with donepezil in mildꢀtoꢀmoderate AD patients.
Currently, Iladopirdine is being evaluated in phase III clinical
6
trials. The proꢀcognitive effects of 5ꢀHT R antagonists are
6
scaffold is a good strategy for developing selective 5ꢀHT R
6
typically attributed to their ability to promote corticoꢀlimbic
release of acetylcholine, glutamate and monoamines.
Further, 5ꢀHT R antagonists might be effective in the
treatment of anxiety and depressive symptoms that often
7–8
antagonists. Many studies have investigated the effects of a kind
of central aromatic core (indole, azaindole, indazole, benzoxazine,
tetrahydroquinoline), localization and the nature of amino centers
6
12–14
(
tetrahydropyridine, piperazine, pyrrolidine).
However, the
accompany AD. The results of in vivo tests have indicated that 5ꢀ
type of arylsulfonyl moiety has not been extensively explored
considering azinyl (quinolinyl, isoquinolinyl) fragments.
Herein we report on the synthesis of N1ꢀazinylsulfonylꢀ3ꢀ
(1,2,3,6ꢀtetrahydropyridinꢀ4ꢀyl)ꢀ1Hꢀindoles, in vitro biological
evaluations, preliminary pharmacokinetic studies, and behavioral
profiling in animal model of memory cognitive decline, i.e., novel
HT R antagonists produce antidepressantꢀlike and anxiolyticꢀlike
6
15
9
responses in animal models.
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object recognition (NOR) test. Since biochemical data suggest
ArSO Cl, BTPP, CH Cl , 0°C, 2 h, 73%; iii) 1N HCl in MeOH,
2 2 2
1
2
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5
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9
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4
5
5
5
5
5
5
5
5
5
5
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that neurotransmitters deficits in AD contribute to aggressive
behavior, sleep disturbance and depression, the compounds were
also evaluated in the forced swim (FST) and Vogel tests to verify
their potential antidepressant and anxiolytic properties.
r.t.; iv) Alkyl bromide, K CO , KI, Acetone, 60°C, 48 h, 63–67%.
2 3
Table 1. The binding data of the synthesized compounds 11–
31 for 5ꢀHT R
6
Scheme 1.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
ꢀHT
6
a
Compd
Q
R
R
1
i
K [nM]
b
I
2ꢀNapthtyl
3ꢀQuinolinyl
6ꢀQuinolinyl
7ꢀQuinolinyl
3ꢀIsoquinolinyl
4ꢀIsoquinolinyl
3ꢀQuinolinyl
5ꢀQuinolinyl
7ꢀQuinolinyl
4ꢀIsoquinolinyl
2ꢀNapthtyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
27 ± 6
13 ± 3
20 ± 4
7 ± 2
12 ± 1
5 ± 1
11 ± 2
11 ± 3
9 ± 2
18 ± 3
19 ± 2
8 ± 1
Reagents and conditions: i) KOH, MeOH, 60°C, 12 h, 65–70%;
ii) ArSO Cl, BTPP, CH Cl , 0°C, 2 h, 70–75%; iii) 1N HCl in
11
12
2
2
2
H
MeOH, r.t.
H
1
3
14
15
16
17
18
19
H
The final compounds 11–31 and 34–38 were synthesized as
shown in Scheme 1 and 2.Condensation of differently substituted
indole derivatives 1–5 with NꢀBocꢀpiperidinone in presence of
potassium carbonate under refluxing methanol, yielded
intermediates 6–10. Next, strong, nonꢀionic, basic conditions
H
5ꢀCl
5ꢀCl
5ꢀCl
5ꢀCl
5ꢀMeO
5ꢀMeO
5ꢀMeO
5ꢀMeO
5ꢀMeO
involving phosphazene base P ꢀtꢀBuꢀtris(tetramethylene (BTPP)
1
b
II
in CH Cl were employed for the N1ꢀindole sulfonylation with the
2
2
1
6
respective quinolineꢀ/isoquinolinesulfonyl chlorides. Removal of
the Bocꢀprotecting group under stirring with a 1N HCl solution in
methanol gave the final compounds 11–31.
20
21
22
3ꢀQuinolinyl
5ꢀQuinolinyl
6ꢀQuinolinyl
7ꢀQuinolinyl
4 ± 1
14 ± 3
2 ± 0.4
6 ± 1
3 ± 0.2
37 ± 5
112 ± 9
22 ± 2
102 ± 12
18 ± 3
Alternatively, threeꢀstep procedure involving hydrogenation
of intermediate 8 over palladium on carbon, followed by the
treatment of intermediate 33 with azinylsulfonyl chloride, and
removal of Boc group in acidic conditions, yielded piperidine
analogs 34 and 35 (Scheme 2). On the other hand, condensation of
5ꢀMeOꢀindole with Nꢀmethylꢀpiperidone resulted in intermediate
32, which was subsequently sulfonylated to obtain compound 36.
Finally, the Nꢀalkyl tetrahydropyridinyl analogs 37 and 38 were
obtained by alkylation of compound 23 with the appropriate alkyl
bromide under biphasic conditions.
2
2
2
2
2
2
2
3
4
5
6
7
8
9
3ꢀIsoquinolinyl 5ꢀMeO
4ꢀIsoquinolinyl 5ꢀMeO
3ꢀQuinolinyl
6ꢀQuinolinyl
7ꢀQuinolinyl
3ꢀIsoquinolinyl
7ꢀQuinolinyl
3ꢀIsoquinolinyl
6ꢀCl
6ꢀCl
6ꢀCl
6ꢀCl
H
30
31
H
20 ± 2
a
Nꢀazinylsulfonyl derivatives 11–31 displayed high affinity for 5ꢀ
Mean K values ± SEM based on three independent binding experiments,
data from (13)
i
b
HT R (Table 1). Most importantly, replacement of naphthyl
6
13
moiety present in compounds I and II with azinyl fragment,
apart from improvement of physicochemical properties (logD,
The type of azinesulfonamide moiety (position of the sulfonamide
group in the α- or β-position of the azine moiety, and the
localization of the sulfonamide group in pyridine or benzene
rings) affected the receptor affinity, but the quantitative influence
logP, pKa), has increased affinity for 5ꢀHT R.Thus, the
6
contribution of the azinesulfonyl moiety to the compound affinity
for 5ꢀHT R was subsequently investigated.
6
of quinolinyl/isoquinolinyl moieties toward 5ꢀHT R was difficult
6
Scheme 2.
to establish. However, the 7ꢀquinolinyl fragment was the most
preferential among the quinoline set, and 4ꢀisoquinolinyl was
more preferable than its 3ꢀcounterpart.
Boc
N
R
N
H
N
The effect of indole substitution on affinity for 5ꢀHT Rs was
6
O
O
O
i
ii, iii
observed using 3ꢀquinolinyl, and 4ꢀquinolinyl derivatives, which
gave the following rank order: 5ꢀMeO > 5ꢀH > 5ꢀchloro > 6ꢀ
N
H
N
N
S
H
O
1
3
O
chloro. This is in contrast to data reported by Cole et al. where
chloro substituent in positionꢀ6 of indole core was well tolerated.
Further, introduction of methyl substituent in positionꢀ2 of the
N
8
3
,
R = Boc
2, R = CH3
33
23
ii
iv
indole, slightly decreased affinity for 5ꢀHT sites (11 vs 30, and
6
ii, iii
H
N
N
N
1
3 vs 31).
Yet another modification involving reduction of double bond
O
O
O
in 1,2,3,6ꢀtetrahydropyridinꢀ4ꢀyl giving N1ꢀazinylsulfonylꢀ3ꢀ
N
S
N
S
N
S
piperidinꢀ4ꢀyl derivatives, decreased affinity for 5ꢀHT Rs (23 vs
6
O
O
O
W
z
O
O
O
34, and 25 vs 35; Table 1, Table 2), which is in line with data
N
N
13
reported by others.
Y
X
Finally, as shown by the binding data outlined in Table 2,
alkyl substituents at the tetrahydropyridine nitrogen atom were
unfavorable. Introducing a small methyl substituent decreased
3
3
4, X = CH, Y = CH, W = N, z = 7
5, X = CH, Y = N, W = CH, z = 4
37, n = 1
38, n = 2
36
Reagents and conditions: i) H , Pd/C, MeOH, r.t., 2 h, 75%; ii)
2
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affinity for 5ꢀHT R up to 11ꢀfold, while compounds with
unbranched alkyl substituents (nꢀpropyl, nꢀbutyl) displayed even
100ꢀfold lower affinity. It thus seem, that alkyl substituents in this
position are not able to accommodate the restriction of the binding
site.
a
a
6
K [nM] K [nM]
%inh
i
b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Compd
23
5
ꢀHT
6
α
1
α
2C
H
1
M
1
5
M 5ꢀHT2C SerT
2 ± 0.4
3 ± 0.2
4.4
5.6
41 18
9
11 NT
18
15
4
6
2
5
40 21 15
0
3
Table 2. The binding data of the synthesized compounds 34–
38 for 5ꢀHT R
Subsequently, the effects of the selected 5ꢀHT
3 and 25 were determined on cytochrome P450 (CYP) enzyme
R antagonists
6
6
2
catalytic activity in human liver microsomes and metabolic
stability in rat in vitro assays (Table 5). Compounds 23 and 25
had no effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, and
moderately inhibited CYP3A4 activity. Compounds 23 and 25
were slowly metabolized in rat liver microsomes. Additionally,
compounds 23 and 25 were not mutagenic in an Ames test (Table
1ꢀSI).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
ꢀHT
6
a
Compd
Q
R
S/D
i
K [nM]
Table 4. The antagonist activity of selected compounds 23 and
3
3
3
3
4
5
6
7
7ꢀQuinolinyl
4ꢀIsoquinolinyl
7ꢀQuinolinyl
7ꢀQuinolinyl
7ꢀQuinolinyl
H
H
S
S
30 ± 4
24 ± 4
2
5 for 5ꢀHT R
6
a
K
b
values and percentage of inhibition were determined at Eurofins
Me
D
D
D
82 ± 10
247 ± 19
219 ± 24
Cerep.
nꢀpropyl
nꢀbutyl
Next, compounds 23 and 25 were submitted to the preliminary
38
Mean K
a
pharmacokinetic profiling after a single 3 mg/kg i.p. dose in male
Wistar rats. Experiments carried out 15, 30, and 90 min after drug
administration, showed the highest concentrations at 30 min (21.9
and 18.6 ng/g of brain tissue for 23 and 25, respectively). The data
indicated moderate bloodꢀbrain barrier penetration with a brain to
plasma concentration ratio within 0.1–0.6 in the investigated time
intervals, being higher for compound 25.
i
values ± SEM based on three independent binding experiments
Certain selected 5ꢀHT R ligands were subsequently examined
6
in a panel of serotonin (5ꢀHT , 5ꢀHT , 5ꢀHT ) and dopamine D
receptors demonstrating at least 70ꢀfold selectivity (Table 3).
In the next step, compounds 23 and 25 with the highest
1
A
2A
7
2
17
Many pieces of evidence suggest that 5ꢀHT R antagonists
6
Assay Type
23
25
modulate cognitive processes and their proꢀcognitive properties
may be beneficial for the treatment of Alzheimer’s disease. Thus,
compounds 23 and 25 were tested in a NOR test and doseꢀ
1
2
A2
C9
100
>100
>100
>100
20
100
>100
>100
>100
26
Cytochrome P450
inhibition, IC50 (ꢁM)
2
C19
dependently (MED 1 mg/kg, i.p.) ameliorated PCPꢀinduced
20,21
memory deficits in rats.
Compound SBꢀ742457 was used as a
2
D6
A4
model selective 5ꢀHT receptor antagonist and reversed memory
6
3
deficits and the effect reached statistical significance at doses
ranging from 0.3–1 mg/kg (i.p.) (Figure 2)
pH 7.4
pH 2.0
>5
>5
Solubility mg/mL
>5
>5
Microsomal stability
CLint [ꢁl/min/mg]
Rat
18
10
Table 5. Interaction of selected compounds 23 and 25 with
cytochrome P450 and their metabolic stability.
affinity for 5ꢀHT R were investigated in vitro for their functional
6
activity in cAMP assays, behaving as potent antagonists at h5ꢀ
In the next step of behavioral evaluation, the potential
18
HT Rs (Table 4). The same compounds were evaluated for their
6
antidepressant and anxiolytic activity of compounds 23 and 25
affinity for ‘‘offꢀtarget’’ receptor panel at CEREP and displayed
22,23
was evaluated in rats using a modified FST test
conflict drinking test, respectively.
and Vogel
24
weak affinity for adrenergic α1 and α , histamine H ,
2C
1
muscarinic M1 and M , serotonin 5ꢀHT receptors, and the
5
2C
serotonin transporter (SerT). Finally, neither 23 nor 25 displayed
agonist properties at 5ꢀHT2B receptors (<13% @ 1 μM) and did
not bind at hERG (@ 10 and 50 μM). These results suggested
a
low risk that the tested compounds would evoke
undesirable cardiovascular or CNS side effects. Interestingly,
compounds 23 and 25 displayed high to moderate affinity for
dopamine D receptors with K = 32 and 150 nM, respectively, but
a
K
i
[nM]
3
i
Compd
Q
R
did not exhibit antagonist properties in an in vitro functional
5ꢀHT 5ꢀHT 5ꢀHT2A 5ꢀHT7 D2
6
1A
19
test.
1
1
2
8
6ꢀQuinolinyl
7ꢀQuinolinyl
H
20
9
1872
1412
2589
1552
1003
3355
6660 1410
7322 1168
2352 302
6248 240
7832 3319
5ꢀCl
2467
2944
5036
5009
Table 3. The binding data of the selected compounds for 5ꢀ
HT , 5ꢀHT , 5ꢀHT , 5ꢀHT and D Rs
6
1A
2A
7
2
21
23
5ꢀQuinolinyl 5ꢀMeO
7ꢀQuinolinyl 5ꢀMeO
4ꢀIsoquinolinyl 5ꢀMeO
4
2
2
5
3
a
i
Mean K values (SEM ± 27%) based on two independent binding
experiments
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naphthyl fragment with quinolinyl or isoquinolinyl moieties
increased affinity for 5ꢀHT6 receptors. The most potent
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
compounds 23 and 25 behaved as 5ꢀHT R antagonists in the
6
cAMP assay and showed good selectivity over a panel of other
receptors tested. The lead compound 25 displayed good brain
penetration and was active in a NOR test in similar doses to SBꢀ
7
42457 (1 mg/kg), while in FST was active in 10–30 folds lower
dose. In contrast to SBꢀ742457, which was active in the Vogel test
MED = 3 mg/kg), compound 25 displayed no anxiolytic activity.
(
These data further support the potential utility of 5ꢀHT receptor
6
antagonists for the treatment of cognitive dysfunction and
accompanying affective disorders.
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Figure 2. Effects of compounds 23, 25 and SBꢀ742457 in the
novelꢀobject recognition test in rats. Data are presented as the
mean ± standard error of the mean of N = 7–12 animals per group.
*p <0.05 vs vehicle, **p <0.01 vs vehicle,***p <0.001 vs vehicle,
ASSOCIATED CONTENT
Supporting Information Available: characterization data for
final compounds, and full experimental procedures.
This material is available free of charge on the ACS Publications
website at DOI:
#
##p <0.001 vs PCP.
For comparison, the selective 5ꢀHT receptor antagonist, SBꢀ
6
742457, was tested under the same conditions. Both 23 and 25
and SBꢀ742457, significantly decreased the immobility time and
increased the climbing time of rats in the forced swim test (Figure
AUTHOR INFORMATION
Corresponding Author
3
). The literature data indicated that 5ꢀHT R antagonists enhance
6
*Eꢀmail: pawel.zajdel@uj.edu.pl; Fax +48 126205405; Tel: +48
the extracellular levels of dopamine (DA) and noradrenaline (NA)
without altering serotonin (5ꢀHT) neurotransmission in
1
26205450
25
Funding Sources
microdialysis in vivo study in rats. Moreover, the results of
behavioral studies in rats demonstrate that the antidepressantꢀlike
The study was financially supported by the project “Prokog”,
UDAꢀPOIG.01.03.01ꢀ12ꢀ063/09ꢀ00, coꢀfinanced by the European
Union from the European Fund of Regional Development
(EFRD), by the Polish Ministry of Science and Higher Education
(MNiSW), Grant No. N N405 671540, statutory activity from
Jagiellonian University Medical College (K/ZDS/004704), and by
statutory funds from the Institute of Pharmacology, Polish
Academy of Sciences.
effect of 5ꢀHT R antagonists in the FST is not related to 5ꢀHT
6
signaling but rather to activation of DA and NA systems.
Given the above, the antidepressantꢀlike effect of the tested
compounds remains in agreement with the previously published
23
data, which showed that noradrenergic systemꢀaffecting drugs
modify climbing behavior, without any significant changes in the
swimming. Notably, the tested compounds, 23 and 25 displayed
antidepressantꢀlike activity in relatively low doses (0.3 mg/kg for
Notes: The authors declare no competing financial interest.
2
3 and 0.1 and 0.3 mg/kg for 25) in the test, while SBꢀ742457
was active in 10–30ꢀfold higher dose (3 mg/kg). The
antidepressantꢀlike activity of both compounds and SBꢀ742457
seems specific, because they did not affect the rats locomotor
activity in the open field paradigm (data not shown). Further,
neither 23 nor 25 showed antiꢀanxiety properties in the Vogel
conflict drinking test. On the other hand, SBꢀ742457, which was
used as a reference, produced an antiꢀconflict effect at dose of 3
mg/kg (Table 3ꢀSI).
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