Arene- and quinoline-sulfonamides as novel 5-HT7 receptor ligands

Article abstract of DOI:10.1016/j.bmc.2011.09.044

Novel arene- and quinolinesulfonamides were synthesized using different solutions and a solid-support methodology, and were evaluated for their affinity for 5-HT_1A, 5-HT_2A, 5-HT₆, and 5-HT ₇ receptors. Compound

Full text of DOI:10.1016/j.bmc.2011.09.044

Bioorganic & Medicinal Chemistry 19 (2011) 6750–6759
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Arene- and quinoline-sulfonamides as novel 5-HT7 receptor ligands
Paweł Zajdel a, , Krzysztof Marciniec , Andrzej Maslankiewicz , Maria H. Paluchowska ,
⇑
b
b
c
´
Grzegorz Satała c, Anna Partyka d, Magdalena Jastrze˛bska-Wie˛sek d, Dagmara Wróbel d,
Anna Wesołowska , Beata Duszynska , Andrzej J. Bojarski , Maciej Pawłowski
a Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
d
c
c
a
´
b
´
Department of Organic Chemistry, Medical University of Silesia, 4 Jagiellonska Street, 41-200 Sosnowiec, Poland
c Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Sme˛tna Street, 31-343 Kraków, Poland
d Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel arene- and quinolinesulfonamides were synthesized using different solutions and a solid-support
methodology, and were evaluated for their affinity for 5-HT1A, 5-HT2A, 5-HT6, and 5-HT7 receptors. Com-
pound 54 (N-Ethyl-N-[4-(1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-2-yl)butyl]-8-quinolinesulfona-
mide) was identified as potent 5-HT7 antagonist (Ki = 13 nM, KB = 140 nM) with good selectivity over
5-HT1A, 5-HT2A, 5-HT6 receptors. In the FST in mice, it reduced immobility in a manner similar to the
selective 5-HT7 antagonist SB-269970.
Received 24 August 2011
Revised 22 September 2011
Accepted 23 September 2011
Available online 29 September 2011
Keywords:
Sulfonamides
Ó 2011 Elsevier Ltd. All rights reserved.
Arylpiperazines/tetrahydroisoquinolines/
perhydroisoquinolines
Solid-phase synthesis
5-HT7 receptor antagonist
Depression
1. Introduction
O
S
N
O
Of the 14 serotonin receptors (5-HTR), a recently identified
5-HT7 subtype has focused considerable attention. Since its cloning
in 1993 by several independent laboratories a number of informa-
tion has been gathered. A physiological role of 5-HT7 receptor in
CNS has been established in the control of circadian rhythms, ther-
moregulation, learning and memory and neuroendocrine regula-
tion; suggested functions in the periphery are related to the
control of smooth muscles cells.1 These data followed by identifica-
tion of pharmacological tools allowed to outline therapeutical
potential of 5-HT7 receptor in depression, anxiety, epilepsy, pain,
migraine, and cognition.2,3 The obtained data were further sup-
ported by the discovery that several psychotropic drugs displayed
a relatively high affinity and antagonistic activity at 5-HT7R.4
Moreover, it was suggested that this mechanism may, at least in
part, account for their therapeutic antidepressant properties
observed in the clinic.5–7
O
O
OH
N
S
N
SB-269970
1
Ki(5-HT7) = 1.2 nM
Ki(5-HT7) = 8 nM
O
O
O
O
S
S
N
H
N
N
N
O
N
O
2
3
Ki(5-HT7) = 360 nM
Ki(5-HT7) = 19 nM
Figure 1. Representatives of the sulfone/sulfonamide class of 5-HT7 receptor
ligands.
Herein, we report on the design and synthesis of a new series of
arene- and their bioisosteric quinoline-sulfonamides as 5-HT7
receptor ligands, followed by their pharmacological evaluation in
an animal model of depression.
Among several classes of 5-HT7R ligands a pre-eminent position
is held by aromatic sulfonamides and sulfones connected to aryl-
or alkyl-amine fragments via an aliphatic spacer of different length
(Fig. 1).8–11
2. Chemistry
As a first step we designed and synthesized a series of THIQ
derivatives of N-unsubstituted (11–17) and N-(
kyl)substituted (18–21) arenesulfonamides. The synthesis of both
x-aminoal-
⇑
Corresponding author. Tel.: +48 12 620 54 50; fax: +48 12 620 54 05.
E-mail address: mfzajdel@cyf-kr.edu.pl (P. Zajdel).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.09.044

P. Zajdel et al. / Bioorg. Med. Chem. 19 (2011) 6750–6759
6751
O
O
O
S
S
i
H2N
N
Ar
N
H
N
H2N
n
i
N
N
N
H
N
N
n
n
n
4 - 10
11 - 17
4 - 10
41 - 44
ii
ii, iii
O
z
O
O
O
iii
S
N
N
H
Ar
N
R
N
n
n
N
n
Ar = phenyl, 1- or 2-naphthyl
n = 0, 1, 2
R = (CH2)2NH2, (CH2)3NH2
45 - 48
49 - 55
18 - 21
Amine = THIQ, PHIQ, 2-MPP
z = 3, 6, 8
Scheme 1. The synthesis of N-substituted sulfonamide derivatives: Reagents and
conditions: (i) ArSO2Cl, H2O/OH-, 60 °C; (ii) N-(2-bromoethyl)- or N-(3-chloropro-
pyl)phthalimide, toluene, NaOH/K2CO3, TBAB, reflux; (iii) N2H4, EtOH, H+.
n = 1, 2, 3
Scheme 3. The synthesis of N-substituted quinolinesulfonamide derivatives:
Reagents and conditions: (i) Ac2O, NaHCO3, RT, 6 h; (ii) LiAlH4, anh. THF, reflux,
12 h, 94%; (iii) quinolinesulfonyl chloride, Et3N, DCM, 5 h.
those series started with coupling of a primary amine with arene-
sulfonyl chloride (Scheme 1).
Introduction of an N-(x-aminoalkyl) fragment to the sulfon-
for native 5-HT1A, 5-HT2A and adrenergic a1 receptors as well as
for cloned human 5-HT6 and 5-HT7 receptors. This was accom-
plished by displacement of [3H]-8-OH-DPAT from rat hippocampus
for 5-HT1AR, and [3H]-ketanserin and [3H]-prazosin from rat cortex
amide nitrogen atom was achieved by alkylation with an appropri-
ate phthalimide derivative and subsequent deprotection with
hydrazine to yield compounds 18–21.
For the synthesis of a next series of compounds (28–40) we em-
ployed the previously elaborated method using a BAL linker, and
TBDPSi-protected aminoalcohols as synthons for diversification of
the polymethylene linker length.12 Quinolinesulfonyl chlorides
were synthesized according to the previously reported method.13
Solid-phase work-flow started by attaching the TBDPSi-protected
3-aminopropan-1-ol and 4-aminobutan-1-ol to resin 22 (Scheme
2). Subsequent sulfonylation of the resin bound product 23, fol-
lowed by silyl protection removal with TBAF and mesylation,
yielded the key intermediate 26 for the introduction of secondary
amines on the resin. Then, it was readily converted into the
amine-bound product 27. Final sulfonamides 28–40 were cleaved
from the resin under acidic treatment.
for 5-HT2AR and
a
1R, respectively.14,15 Displacement of [3H]-LSD
and [3H]-5-CT from the cloned human receptor stably expressed
in HEK293 cells was used in 5-HT6R and 5-HT7R binding
experiments.16
The functional activity of the selected compounds 54 and 55 at
5-HT7 receptors was determined at CEREP (Le Bois l’Eveque, 86600
Celle L’Evescault, France) according to previously published
methods.17
3.2. Pharmacological experiments
The potential antidepressant-like activity of compounds 54 and
55 was evaluated in the mouse forced swim test (FST) and their
activity was compared with that of SB-269970.18 The effect of
the tested compounds on the spontaneous locomotor activity of
mice was also investigated.
The synthetic procedures for the last series of N-alkylated quino-
line-sulfonamides proceeded according to Scheme 3. The acetylation
ofprimaryaminesandthe reductionofacetamide derivatives yielded
their respective secondary amines which were further sulfonylated
with quinolinesulfonyl chloride to give the final products 49–55.
4. Results and discussion
3. Pharmacology
Following the finding that compounds containing 1,2,3,4-tetrahy-
droisoquinoline (THIQ) and 2-methoxyphenylpiperazine (2-MPP)
may be a source of 5-HT7 receptor ligands,19–23 we first evaluated a
3.1. In vitro biological evaluation
series of THIQ derivatives of N-unsubstituted (11–17) and N-(x-ami-
noalkyl)substituted (18–21) arenesulfonamides for 5-HT7 and
Radioligand binding assays were employed for determination of
the affinity and selectivity profile of the synthesized compounds
O
i
ii
iii
HN
O
N
O
N
OH
H
z
O
z
O
Si
Ph
S
Si
Ph
S
n
n
n
Ph
Ph
N
N
O
O
22
23
25
24
PS resin
with BAL type linker
iv
O
z
O
S
vi
v
N
H
N
N
OMs
N
N
z
O
n
z
O
S
S
N
n
n
N
N
O
O
28 - 40
26
27
Amine = 2-MPP, THIQ, THTP, PHIQ
n = 1,2
z = 3, 6, 7, 8
Scheme 2. Solid-phase synthesis for sulfonamide derivatives 28–40: Reagents and conditions: (i) TBDPSiO(CH2)3NH2 or TBDPSiO(CH2)4NH2, NaBH3CN, 1%AcOH/DMF, 60 °C,
15 h; (ii) Quinolinesulfonyl chloride, TEA, DCM, RT, 2 Â 2 h; (iii) 1 M TBAF/THF, 12 h; (iv) MeSO2Cl, Py, RT, 1 h; (v) secondary amine, anh. DMSO, 50 °C, 5 h; (vi) TFA/DCM, (80/
20, v/v), 2 h.

6752
P. Zajdel et al. / Bioorg. Med. Chem. 19 (2011) 6750–6759
Table 1
2-Naphthalenesulfonamides containing 2-MPP fragments were
previously described in the literature as multi-receptor ligands
with high affinity for 5-HT1A receptors.27 In comparison with these
data, replacement of the 2-naphthyl ring with nitrogen-containing
aromatic heterocycles differently influenced the 5-HT1A receptor
affinity of the tested quinolinesulfonamides 28–32; the rank order
of 5-HT1A binding was 3-quinolinyl >6-quinolinyl >8-quinolinyl. It
seemed that the nitrogen atom in the distal aromatic ring was
unfavorable for an interaction with 5-HT1A receptors. The impact
of the nitrogen position on the affinity for 5-HT7 receptors was dif-
ferent: 8-quinolinyl >3-quinolinyl >6-quinolinyl. It was also
observed that within the 2-MPP series, sulfonamides with four
methylene linker displayed a decreased affinity for 5-HT1A recep-
tors compared to their three methylene homologs (30 vs 29, and
32 vs 31); on the other hand, an increased linker length was ben-
eficial for 5-HT7 receptor binding.
It was recently reported that substitution of the sulfonamide
nitrogen mimicked the steric and lipophilic effects of the pyrroli-
dine fragment of the SB-series (e.g., SB-269970), being essential
for 5-HT7 selectivity.10 N-alkylation of the sulfonamide may also
improve the bioavailability, while suppression of the hydrophilic
bond seems to be beneficial to brain permeation. Thus, as a succes-
sive step, we designed a series of the selected N-alkylated sulfon-
amide derivatives 49–55. We chose 2-MPP and PHIQ as
secondary amines to be bridged via tetramethylene and penta-
methylene spacers with the quinolinesulfonamide fragment, since
a longer spacer might also increase selectivity.29
As expected, in the case of 2-MPP derivatives introduction of
N-ethyl sulfonamide fragment increased affinity for 5-HT7 receptors
from two to fivefold (e.g., 29 vs 50; 30 vs 51, Tables 2 and 3). How-
ever, this modification did not increase selectivity for 5-HT7 recep-
tors. A kind of quinolinyl moiety did not influence 5-HT7 receptor
affinity of the N-substituted sulfonamides containing 2-MPP. With
regard to the influence of the kind of quinolinyl moiety on 5-HT1A
receptor affinity, it was found that within N-alkylated sulfonamides
the rank order remained similar to that observed for unsubstituted
derivatives 28–32 (3-quinolinyl >6-quinolinyl >8-quinolinyl). In
consequence, N-ethyl sulfonamide derivatives containing 2-MPP
were classified as dual 5-HT1A/5-HT7 ligands.
N-Alkylation of the PHIQ containing sulfonamide 40 resulted in
54, which displayed high affinity for 5-HT7 receptors, and good
selectivity for 5-HT1A ones (S ratio—84). Unfortunately, elongation
of the spacer up to pentamethylene unit (55) slightly decreased
5-HT7R affinity and the 5-HT7/5-HT1A selectivity ratio. These two
interesting compounds (54 and 55) exhibited high 5-HT7 receptor
affinity and good selectivity over the 5-HT1A one, were also evalu-
ated for a1 receptors, since affinity of antidepressant drugs for
these sites is considered as undesirable action, for example, cardio-
vascular effects (Table 3).30
Binding affinities of the arene-sulfonamides 11–21 for 5-HT7 receptors
O
O
S
Ar
N
R
N
n
11 - 21
Compd
n
Ar
R
Ki SEM (nM)
5-HT7
11
12
13
14
15
16
17
18
19
20
21
0
0
1
1
2
2
2
0
1
1
2
2-Naphthyl
Phenyl
2-Naphthyl
Phenyl
2-Naphthyl
Phenyl
1-Naphthyl
Phenyl
H
H
H
H
H
H
H
78
773 94
80
270 19
64
8
6
5
94 11
296 31
3010 570
267 16
335 28
235 14
(CH2)3NH2
(CH2)2NH2
(CH2)3NH2
(CH2)3NH2
Phenyl
Phenyl
Phenyl
5-HT1A receptors. Introduction of the aminoalkyl fragment was sug-
gested by preliminary docking to our 5-HT7R homology models,24
where potential interactions with Arg7.36 and/or Glu7.35 were
observed. It was found, that 2-naphthalenesulfonamides 11, 13 and
15 demonstrated almost the same affinity for the 5-HT7 receptor,
regardless of the spacer length. Their binding constant values ranged
between 64 and 80 nM (Table 1). Interestingly, 2-naphthyl deriva-
tives (11, 13, 15) were always more active than their benzenesulfon-
amideanalogs (12, 14, 16). Among the benzenesulfonamides studied,
compound 16 with a tetramethylene spacer had the highest 5-HT7R
affinity (Ki = 94 nM), whereas its trimethylene (14) and ethylene
(12) analogs exhibited significantly lower affinities (Ki = 270 and
773 nM, respectively). The introduction of aminoalkyl substituents
into the sulfonamide moiety of compounds 12, 14 and 16 was not a
profitable structure modification; their N-substituted analogs
18–21 showed a weaker 5-HT7 receptor affinity (Ki = 235–3010 nM).
Inviewofliteraturedatabioisostericreplacementofnaphthylring
with quinolinyl moiety may be beneficial for creation of additional
hydrogen bonds in the receptor binding site being advantageous for
ligand-receptor interaction25,26 or may improve compound aqueous
solubility facilitating compound bioavailability.27,28
As the following step, only three and four methylene linkers were
used for a seriesof quinolinesulfonamides;besidesTHIQ, compounds
with its bioisostere 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (THTP),
the saturated analog perhydroisoquinoline (PHIQ), and 2-MPP were
prepared.
In general, the new quinolinesulfonamides 28–40 displayed
high-to-low binding affinities for 5-HT7 (Ki = 55–1255 nM) and
5-HT1A (Ki = 3.7–4310 nM) receptors and practically did not bind
to 5-HT6 ones (Table 2). Of the tested compounds, only 29 and
33 exhibited affinity lower than 1000 nM for 5-HT2AR. As regards
amine fragments, the sulfonamides containing 2-MPP (28–32)
showed the highest affinity for 5-HT7 receptors (Ki <156 nM), being
simultaneously devoid of selectivity for 5-HT1AR (Ki <53 nM). The
replacement of 2-MPP with THIQ and THTP decreased the affinity
for both those subtypes (Ki = 88–506 nM), while the introduction
of the fully saturated cycloaliphatic amine moiety—PHIQ (com-
pounds 38–40), dramatically shifted 5-HT1AR and 5-HT7R affinity
At the successive stage, effects of the selected compounds 54
and 55 on intracellular cAMP levels were studied in CHO cells
which stably expressed the human 5-HT7 receptor.17 The obtained
results indicated that the compounds tested behaved like antago-
nists at the h5-HT7R with KB = 140 nM and KB = 1.3
and 55, respectively.
lM for 54
Those compounds were further pharmacologically evaluated in
a mouse model of depression. Compound 54, administered in a
dose of 10 mg/kg, significantly reduced—by 22%—the immobility
time of mice, whereas its analog 55, given in doses of up to
20 mg/kg produced no effect in the FST in mice (Table 4). Com-
pound 54 showed antidepressant-like activity similar to that of
the selective 5-HT7 receptor antagonist SB-269970, which exerted
its effect characteristic of antidepressants in one medium dose
(10 mg/kg), decreasing mouse immobility time by 33%. Those ef-
fects seemed to be specific, since 54 and SB-269970, used in a dose
evoking antidepressant-like activity, did not change the locomotor
to a l-molar range.
Replacement of the 2-naphthyl ring of the THIQ derivative 15
with its b-position quinolinyl analogs, 3-quinolinyl or 6-quinolinyl,
yielded compounds 33 and 34, which were 3.5 times less potent
5-HT7 ligands. Interestingly, the change of the 1-naphthyl ring of
compound 17 to 8-quinolinyl (its
compound 35 which displayed a threefold higher affinity for
a-position counterpart) gave
5-HT7 receptors.

P. Zajdel et al. / Bioorg. Med. Chem. 19 (2011) 6750–6759
6753
Table 2
Binding affinities of the quinolinesulfonamides 28–40 for 5-HT receptors
O
z
O
S
N
N
n
N
H
28 - 40
Compd
Ar
n
Aminea
Ki SEM (nM)
5-HT2A
Sb
5-HT1A
5-HT6
5-HT7
79
156 26
132 18
90
55
228 12
224 26
88
506829
334 48
995 70
1420 242
1255 189
28
29
30
31
32
33
34
35
36
37
38
39
40
3-Quinolinyl
6-Quinolinyl
6-Quinolinyl
8-Quinolinyl
8-Quinolinyl
3-Quinolinyl
6-Quinolinyl
8-Quinolinyl
3-Quinolinyl
7-Quinolinyl
3-Quinolinyl
6-Quinolinyl
8-Quinolinyl
2
1
2
1
2
2
2
2
2
2
2
1
2
2-MPP
2-MPP
2-MPP
2-MPP
2-MPP
THIQ
THIQ
THIQ
THTP
THTP
PHIQ
3.7 0.6
NTc
NT
8
0.05
0.1
0.3
0.4
0.9
1.3
1
3.0
1.9
1.4
1.5
3.0
2.8
18
40
37
53
305 18
233 18
271 32
986 118
483 47
2
5
3
7
825 74
NT
2842 140
NT
2159 254
NT
1640 94
NT
7
4
590 62
1518 130
8635 1245
8246 1678
1462 126
17390 1620
17480 3700
NT
41858718
7
1082 190
2652 320
1449 208
4310 945
3565 720
NT
NT
NT
PHIQ
PHIQ
NT
NT
a
b
c
2-MPP—2-methoxyphenylpiperazine; THIQ—1,2,3,4-tetrahydroisoquinoline; THTP—4,5,6,7-tetrahydrothieno[3,2-c]pyridine; PHIQ—perhydroisoquinoline.
5-HT1A/5-HT7 selectivity.
NT = not tested.
Table 3
Receptor binding profile of the N-ethyl sulfonamide derivatives
O
z
O
S
N
N
n
N
49 - 55
Compd
Ar
n
Aminea
Ki SEM (nM)
Sb
5-HT1A
5-HT2A
NTc
1321 98
NT
5-HT6
5-HT7
a1
49
50
51
52
53
54
55
3-Quinolinyl
6-Quinolinyl
6-Quinolinyl
8-Quinolinyl
3-Quinolinyl
8-Quinolinyl
8-Quinolinyl
2
1
2
2
2
2
3
2-MPP
2-MPP
2-MPP
2-MPP
PHIQ
9.3
25
21
30
1
2
1
4
NT
1920 186
NT
38
29
41
37
3
3
6
4
NT
NT
NT
0.2
0.9
0.5
0.8
1.7
NT
NT
NT
325 57
1099 113
313 42
5093 980
6281 1394
1790 222
14460 2950
1950 215
4587 580
187 23
NT
155 12
92
PHIQ
PHIQ
13
33
1
5
84.5
9.5
8
a
b
c
2-MPP—2-methoxyphenylpiperazine; PHIQ—perhydroisoquinoline.
5-HT1A/5-HT7 selectivity.
NT = not tested.
activity of mice measured during the time equal to the observation
period in FST (i.e., from 2 to 6 min), and during 30-min experimen-
tal sessions (Table 2-SM). Our data on SB-269970 are in line with
the results obtained by other authors31–33 who found that SB-
269970 used in a single, medium dose (10 mg/kg) shortened the
time of mouse immobilization in both the tail suspension and
the FST models. Both compound 54 and SB-269970 evoked
U-shaped dose-response curves. The cause of such activity is
difficult to explain.
A limited number of data concerning the in vivo activity of ana-
log 54 do not permit us to find an explanation for the loss of an
antidepressant-like effect after administration of its higher dose
(20 mg/kg). It is noteworthy that SB-269970 can produce U-shaped
dose-response effects in the animal models used to predict anxio-
lytic-like activity in mice and rats.32 Similarly, the decrease in rat
body temperature induced by the 5-HT1A/7 receptor agonist 8-hy-
droxy-2-(di-n-propylamino)tetralin was inhibited by SB-269970,
which showed a tendency to develop a bell-shaped dose-response
relationship.34 It is hypothesized that the potential antidepressant
activity of 54 may result from the blockade of 5-HT7 receptors,
since sulfonamide 54 is a fairly selective 5-HT7 receptor antagonist
(Table 4).
5. Conclusions
Summing up, the paper presents the synthesis of two series of
novel arene- (11–17) and quinoline- (28–40) sulfonamides and
their N-alkylated analogs 18–21 and 49–55. The study reveals that
5-HT7 receptor affinity benefits from the increased distance be-
tween the basic center (embedded in PHIQ) and the terminal Ar
group, as well as from the introduction of a hydrophobic fragment
to the nitrogen of the sulfonamide group. The study also demon-
strates that the kind of substitution and localization of the nitrogen
atom in the aromatic ring of sulfonamide moiety affect 5-HT7 and

6754
P. Zajdel et al. / Bioorg. Med. Chem. 19 (2011) 6750–6759
Table 4
All other analyses were carried out using a Acquity UPLC BEH
C18, 50 Â 2.1 mm reversed-phase column. A flow rate of 0.3 mL/
min and a gradient of (5–95)% B over 5 min was used. Eluent A:
water/0.1% HCO2H; eluent B: acetonitrile/0.1% HCO2H. Nitrogen
was used for both nebulizing and drying gas. LC/MS data were ob-
tained by scanning the first quadrupole in 0.5 s in a mass range
from 100 to 700 m/z; 10 scans were summed up to produce the fi-
nal spectrum.
Elemental analyses were found within 0.4% of the theoretical
values.
Melting points (mp) were determined with a Buchi apparatus
and are uncorrected.
Effects of the tested compounds on immobility time in the forced swim test in mice
Treatment (mg/kg)
n
Immobility time (s)
Mean SEM
Tween
54 (5)
54 (10)
54 (20)
9
9
8
8
165.2 9.6
155.2 12.1
128.1 6.2*
182.3 11.1
F(3,30) = 4.012
P <0.05
Tween
55 (5)
55 (10)
55 (20)
9
8
9
9
165.2 9.6
144.8 5.6
158.6 8.6
181.2 9.9
F(3,30) = 3.368
P <0.05
Column chromatography separations were carried out on col-
umn with Merck Kieselgel 60 or Aluminium oxide 90, neutral
(70–230 mesh). Purification of compounds synthesized on solid
support was performed on silica gel (irregular particles 40–
Tween
9
165.2 9.6
136.1 13.1
110.8 10.4**
139.3 8.1
F(3,34) = 5.172
P <0.01
SB-269970 (5)
SB-269970 (10)
SB-269970 (20)
10
10
10
63 lm, Merck Kieselgel 60) filled synthesis reactors. The yields of
the final compounds, after chromatographic purification, were cal-
culated on the basis of the initial loading of the starting resins and
are the overall yields of all reaction steps starting from these
resins.
The following abbreviations were used: CHCl3—chloroform;
DCM—dichloromethane; DMF—dimethylformamide; TBAB—tetra-
n-butylammonium bromide; TBAF—tetra-n-butylammonium fluo-
ride; TFA—trifluoroacetic acid. The other abbreviations used were
recommended by the IUPAC-IUB Commission (Eur. J. Biochem.
1984, 138, 9–37).
n—number of mice per group.
*
P <0.05.
**
P <0.01 versus respective tween group (Bonferroni post-hoc test).
5-HT1A receptor affinity and selectivity. We have identified and
pharmacologically evaluated the N-ethyl-substituted quinoline-
sulfonamide 54 (5-HT7R antagonist), which significantly reduces
the duration of immobility in mice, when given in a dose compara-
ble to that of SB-269970. The preliminary results concerning 54 as
a potential antidepressant agent with 5-HT7 receptor antagonistic
activity are promising enough to warrant further detailed mecha-
nistic studies.
6.2. General procedure for the preparation of compounds 11–17
(Method A)
The starting N-(
were synthesized by published procedures.35,36 To the appropriate
-( -aminoalkyl-1,2,3,4-tetrahydroisoquinoline (6 mmol) and so-
x-aminoalkyl)-1,2,3,4-tetrahydroisoquinolines
N
x
dium hydroxide (7.2 mmol) in 20 cm3 of water arylsulfonyl chlo-
ride (7.2 mmol) was added at the room temperature portionwise.
The reaction mixture was stirred at 60 °C for 30 min then cooled
down and after neutralization to pH = 7 (4 M HCl) was extracted
with CHCl3 (3 Â 30 cm3). The combined extracts were washed with
water and dried (K2CO3). The solvent was evaporated and the sul-
fonamides were separated by column chromatography using SiO2
and CHCl3 followed by CHCl3/MeOH = 49/1. Free bases were then
converted into the hydrochloride salts in acetone by treatment
with excess of Et2O saturated with gaseous HCl.
6. Experimental
6.1. Materials and methods
Solution and solid-phase organic transformations and resin
washes were carried out at ambient temperature, unless indicated
otherwise. Organic solvents (from Aldrich and Chempur) were of
reagent grade and were used without purification. BAL linker resin
(loading 1.1 mmol/g) was purchased from Iris Chemicals. All other
reagents were from Aldrich.
Purity of the synthesized compounds was confirmed by TLC
performed on Merck silica gel 60 F254aluminium sheets (Merck,
Darmstadt, Germany). Spots were detected by their absorption un-
der UV light (k = 254 nm).
Analytical HPLC were run on a Waters Alliance HPLC instrument,
equipped with a ChromolithSpeedROD column (4.6 Â 50 mm).
Standard conditions were eluent system A (water/0.1% TFA), system
B (acetonitrile/0.1% TFA). A flow rate of 5 mL/min and a gradient of
(0–100)% B over 3 min were used. Detection was performed on a
PDA detector. Retention times (tR) are given in minutes.
1H NMR Spectra were recorded at 300 MHz (Varian BB 200
spectrometer) or at 60 MHz (Varian EM-360 L) using TMS
(0.00 ppm) and chloroform-d1, DMSO-d6, or chloroform-d1 mixed
with methanol-d4 (2–10%); J values are in hertz (Hz), and splitting
patterns are designated as follows: s (singlet), d (doublet), t (trip-
let), m (multiplet).
6.2.1. N-[2-(1,2,3,4-Tetrahydroisoquinolin-2-yl)ethyl]-2-
naphthalenesulfonamide (11)
Colorless crystals (53% yield), mp 107–172 °C; 1H NMR
(60 MHz, CDCl3) d (ppm): 2.3–3.2 (m, 6H), 3.1 (t, J = 6 Hz, 2H),
3.35 (s, 2H), 6.8 (b s, 1H), 6.95–7.3 (m, 4H), 7.45–8.1 (m, 6H),
8.45 (s, 1H). 11ÁHCl: colorless crystals, mp 223–225 °C. Anal.
(C21H22N2SO2ÁHCl) C, H, N.
6.2.2. N-[2-(1,2,3,4-Tetrahydroisoquinolin-2-yl)ethyl]
benzenesulfonamide (12)
Pale yellow oil (39% yield); 1H NMR (60 MHz, CDCl3) d (ppm):
2.3–2.9 (m, 6H), 3.1 (t, J = 6 Hz, 2H), 3.4 (s, 2H), 5.25 (b s, 1H),
6.8–7.2 (m, 4H), 7.4–7.7 (m, 3H), 7.8–8.1(m, 2H). 12ÁHCl: colorless
crystals, mp 213–215 °C. Anal. (C17H20N2SO2ÁHCl) C, H, N.
6.2.3. N-[3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)propyl]-2-
naphthalenesulfonamide (13)
Mass spectrometry analyses—Samples were prepared in aceto-
nitrile/water (10/90 v/v) mixture. The LC/MS system consisted of
a Waters Acquity UPLC, coupled to a Waters TQD mass spectrom-
eter (electrospray ionization mode ESI-triple quadrupole (QqQ)).
Yellow oil (32% yield); 1H NMR (60 MHz, CDCl3) d (ppm): 1.3–1.9
(m, 2H), 2.2–2.9 (m, 6H), 3.1 (t, J = 6 Hz, 2H), 3.4 (s, 2H), 6.6–7.3
(cluster, 5H), 7.3–8.0 (m, 6H), 8.35 (s, 1H). 13ÁHCl: colorless crystals,
mp 203–205 °C. Anal. (C22H24N2SO2ÁHCl) C, H, N.

P. Zajdel et al. / Bioorg. Med. Chem. 19 (2011) 6750–6759
6755
6.2.4. N-[3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)propyl]
6.3.3. N-(3-Aminopropyl)-N-[3-(1,2,3,4-tetrahydroisoquinolin-
benzenesulfonamide (14)
2-yl)propyl]benzenesulfonamide (20)
Colorless crystals (65% yield), mp 114–116 °C; 1H NMR (60 MHz,
CDCl3) d (ppm): 1.5–1.9 (m, 2H), 2.3–2.9 (cluster, 6H), 3.1 (t, J = 6 Hz,
2H), 3.5 (s, 2H), 6.4 (b s, 1H), 6.8–7.3 (m, 4H), 7.3–7.6 (m, 3H), 7.6–8.0
(m, 2H). 14ÁHCl: colorless crystals, mp 206–208 °C. Anal.
(C18H22N2SO2ÁHCl) C, H, N.
Pale yellow oil (100% yield); 1H NMR (60 MHz, CDCl3) d (ppm):
1.4–1.9 (m, 4H), 2.1 (s, 2H), 2.3–3.0 (cluster, 8H), 3.25 (t, J = 7 Hz,
4H), 3.55 (s, 2H), 7.1 (s, 4H), 7.3–7.7 (m, 3H), 7.7–8.0 (m, 2H).
20ÁC4H4O4Á1.4H2O: colorless crystals, mp 143–145 °C. Anal.
(C22H29N3SO2ÁC4H4O4Á1.4H2O) C, H, N.
6.2.5. N-[4-(1,2,3,4-Tetrahydroisoquinolin-2-yl)butyl]-2-
naphthalenesulfonamide (15)
6.3.4. N-(3-Aminopropyl)-N-[4-(1,2,3,4-tetrahydroisoquinolin-
2-yl)butyl]benzenesulfonamide (21)
Pale yellow oil (58% yield); 1H NMR (60 MHz, CDCl3) d (ppm):
1.35–1.9 (m, 4H), 2.2–3.1 (cluster, 8H), 3.5 (s, 2H), 6.8–8.0 (cluster,
11H), 8.3 (s, 1H). 15ÁHCl: colorless crystals, mp 146–148 °C. Anal.
(C23H26N2SO2Á0.9HCl) C, H, N.
Pale yellow oil (67% yield); 1H NMR (60 MHz, CDCl3) d (ppm):
1.3–1.9 (m, 6H), 2.2 (s, 2H), 2.3–3.0 (cluster, 8H), 3.0–3.45 (m,
4H), 3.55 (s, 2H), 7.1 (s, 4H), 7.4–7.7 (m, 3H), 7.7–8.0 (m, 2H).
21Á2HClÁH2O: colorless crystals, mp 58–60 °C. Anal. (C22H31N3SO2Á-
C4H4O4Á2H2O) C, H, N.
6.2.6. N-[4-(1,2,3,4-Tetrahydroisoquinolin-2-yl)butyl]
benzenesulfonamide (16)
6.4. General procedures for manual solid-phase synthesis of
compounds 28–40
Pale yellow oil (74% yield); 1H NMR (60 MHz, CDCl3) d (ppm):
1.4–1.9 (m, 4H), 2.4–3.2 (cluster, 8H), 3.65 (s, 2H), 6.7 (s, 1H),
6.8–7.7 (cluster, 9H). 16ÁHCl: colorless crystals, mp 146–148 °C.
Anal. (C19H24N2SO2ÁHCl) C, H, N.
6.4.1. Preparation of amine-bound resin (23) via reductive
amination
The BAL resin (2 g, 1.1 mmol) was divided into two reactors and
was swelled in CH2Cl2 for 1 h, followed by DMF washes (3 Â 10 mL).
Then O-tert-butyldiphenylsilyl-3-aminopropanol hydrochloride37
(1.92 g, 5.5 mmol, 5 equiv) and O-tert-butyldiphenylsilyl-4-amin-
obutanolhydrochloride12 (2.0 g, 5.5 mmol, 5 equiv) were added
(solubilized in a mixture of 1%AcOH in DMF, 2 mL each) to a resin.
Subsequently, a resin was treated with a suspension of sodium cya-
noborohydride ([NaBH3CN] = 0.34 g, 5.5 mmol, 5 equiv) in a 1%
AcOH in 8 mL of DMF.38 The reactors were heated overnight at
60 °C. The resin was drained and washed with a mixture of 10%
AcOH in DMF (1 Â 10 mL), DMF (3 Â 10 mL), MeOH (2 Â 10 mL),
and CH2Cl2 (3 Â 10 mL). The amine resin product 3 was air-dried.
6.2.7. N-[4-(1,2,3,4-Tetrahydroisoquinolin-2-yl)butyl]-1-
naphthalenesulfonamide (17)
Pale yellow oil (67% yield); 1H NMR (60 MHz, CDCl3) d (ppm):
1.15–1.75 (m, 4H), 2.2–3.2 (cluster, 8H), 3.55 (s, 2H), 6.9–7.7 (clus-
ter, 8H), 7.8–8.3 (m, 3H), 8.6 (d, J = 8 Hz, 1 H). 17ÁHCl: colorless
crystals, mp 205–207 °C. Anal. (C23H26N2SO2ÁHCl) C, H, N.
6.3. General procedure for the preparation of compounds 18–21
(Method B)
To the slightly warm (60 °C) mixture of appropriate sulfon-
amide (5 mmol), finely powdered sodium hydroxide (0.35 g),
potassium carbonate (0.35 g), TBAB (0.5 mmol) in toluene
6.4.2. Sulfonylation of amine resin (23) with quinolinesulfonyl
chlorides
(30 mL) N-(x-bromoalkyl)phthalimide (20% excess) in 10 mL of
solvent was added dropwise with stirring. After the addition was
completed (1 h) stirring was continued at the reflux for 17 h. The
inorganic precipitate was filtered off and washed carefully with
toluene. The filtrate was combined with washings, washed with
water until neutral, dried (MgSO4) and evaporated. The residue
without purification was treated with hydrazine (100% excess) in
EtOH (10 mL) and refluxed for 1 h. The reaction mixture was
cooled down and treated with additional amount of ethanol
(10 mL) and concentrated HCl (0.6 mL). Then the reaction mixture
was refluxed for 4 h and left overnight at the room temperature.
The precipitate was filtered off and the solvent was evaporated.
The residue was purified by column chromatography (Al2O3,
CHCl3/CH3OH = 19/1). Free bases were then converted into the
hydrochloride (19) or fumarate (18, 20, 21) salts in acetone.
The amine resin (0.1 g) was distributed to 5 mL polypropylene
reactors. To the resin was added a solution of triethylamine in
CH2Cl2 (0.33 M, 2 mL, 0.66 mmol, 6 equiv), followed by addition
of quinolinesulfonyl chloride (75 mg, 0.33 mmol, 3 equiv). Sulfony-
lation was allowed to proceed at ambient temperature for 3 h.
After draining of the resin and washing with CH2Cl2 (3 Â 10 mL),
the reaction was repeated. Then, the resin was drained again and
washed with DMF (3 Â 10 mL), MeOH (2 Â 10 mL), and CH2Cl2
(3 Â 10 mL).
6.4.3. Deprotection of the silyl ether with TBAF
The resin attached product 24 was swelled in CH2Cl2 for 30 min,
then the drained resin was treated with THF (2 Â 4 mL). Subse-
quently to the resin was added TBAF/THF (1 M, 2 mL, 18 equiv),
and the reaction was allowed to proceed for 16 h. The drained resin
was washed with THF (3 Â 4 mL), CH2Cl2 (3 Â 4 mL), and air dried.
6.3.1. N-(3-Aminopropyl)-N-[2-(1,2,3,4-tetrahydroisoquinolin-
2-yl)ethyl]benzenesulfonamide (18)
Pale yellow oil (32% yield); 1H NMR (60 MHz, DMSO-d6) d
(ppm): 1.4–1.9 (m, 2H), 2.3–3.4 (cluster, 10H), 3.1–3.4 (m, 4H),
3.6 (s, 2H), 7.1 (s, 4H), 7.5–7.8 (m, 3H), 7.8–8.0 (m, 2H).
18ÁC4H4O4Á1.5H2O: colorless crystals, mp 123–125 °C. Anal.
(C20H27N3SO2ÁC4H4O4Á1.5H2O) C, H, N.
6.4.4. Mesylation of alcohol
The alcohol resin 25 was swelled in CH2Cl2 for 30 min, and then
it was treated with a mixture of mesyl chloride (MsCl) in anhy-
drous pyridine (1 M, 2 mL, 2 mmol, 18 equiv), and rotated at room
temperature for 1 h. The drained resin product 26 was washed
with DMF (3 Â 4 mL), H2O (1 Â 4 mL), MeOH (2 Â 4 mL), and
CH2Cl2 (3 Â 4 mL).
6.3.2. N-(2-Aminoethyl)-N-[3-(1,2,3,4-tetrahydroisoquinolin-2-
yl)propyl]benzenesulfonamide (19)
Pale yellow oil (100% yield); 1H NMR (60 MHz, CDCl3) d (ppm):
1.4 (b s, 2H), 1.5–2.1 (m, 2H), 2.35–3.1 (cluster, 8H), 3.1–3.5
(m, 4H), 3.65 (s, 2H), 7.15 (s, 4H), 7.5–7.8 (m, 5H). 19Á2HClÁH2O:
colorless crystals, mp 148–150 °C. Anal. (C20H27N3SO2Á2HClÁH2O)
C, H, N.
6.4.5. N-Alkylation
The mesyl resin 26 was swelled in CH2Cl2 for 30 min, and to the
resin was added a solution of secondary amine—2-MPP, THIQ, PHIQ
in anhydrous DMSO (1 M, 2 mL, 2 mmol, 18 equiv), and the reac-

6756
P. Zajdel et al. / Bioorg. Med. Chem. 19 (2011) 6750–6759
tion was heated to 80 °C for 6 h. The resulting resin product 27 was
drained, washed with a mixture of 10% AcOH in DMF (2 Â 4 mL),
H2O (1 Â 4 mL), DMF (3 Â 4 mL), MeOH (2 Â 4 mL), and CH2Cl2
(3 Â 4 mL), and air-dried.
1H), 8.04–8.07 (m, 1H), 8.27–8.30 (m, 1H), 8.44–8.47 (m, 1H),
9.02–9.04 (m, 1H). MS calcd for [M+H]+: C24H30N4O3S m/z: 454.2,
found 455.3.
6.4.12. N-[4-(1,2,3,4-Tetrahydroisoquinolin-2-yl)butyl]-3-
quinolinesulfonamide (33)
6.4.6. Cleavage from the resin
The resin product was cleaved from the resin by the treatment
with 80%TFA/CH2Cl2 (1.5 mL) over 2 h, washed with CH2Cl2 and the
filtrates were collected and evaporated with a stream of nitrogen
on Eva parallel evaporator. The crude residue was re-dissolved in
CH2Cl2 or CH2Cl2/MeOH mixture, and purified using silica gel col-
umns and mixture CH2Cl2/MeOH, to elute a pure product. The com-
pounds were generally obtained as light yellow oil.
Yellow oil, 21.2 mg (48% yield) following chromatographic puri-
fication over silica gel with CH2Cl2/MeOH (9/1.15); initial LC/MS
purity 91%, tR = 1.04. 1H NMR (300 MHz, DMSO) d (ppm): 1.41–
1.43 (m, 4H), 2.27–2.29 (m, 2H), 2.49–2.51 (m, 2H), 2.66–2.70 (t,
2H), 2.86–2.88 (m, 2H), 3.39 (br s, 2H), 6.94–6.97 (m, 1H), 7.02–
7.08 (m, 3H), 7.26–7.78 (td, 1H), 7.91–7.96 (m, 2H), 8.10–8.14
(dd, 1H),8.19–8.22 (dd, 1H), 8.83–8.84 (d, 1H), 9.15–9.16 (d, 1H).
MS calcd for [M+H]+: C22H25N3O2S m/z: 395.2, found 396.4.
6.4.7. N-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-3-
quinolinesulfonamide (28)
6.4.13. N-[4-(1,2,3,4-Tetrahydroisoquinolin-2-yl)butyl]-6-
quinolinesulfonamide (34)
Yellow oil, 32 mg (64% yield) following chromatographic purifi-
cation over silica gel with CH2Cl2/MeOH (9/1); initial LC/MS purity
98%, tR = 1.10.1H NMR (300 MHz, DMSO) d (ppm): 1.35–1.37 (m,
4H), 2.17–2.19 (m, 2H), 2.33–2.47 (m, 4H), 2.81–2.87 (m, 6H),
3.73 (s, 3H), 6.78–6.92 (m, 4H), 7.90–7.97 (m, 2H) 7.72–7.77 (m,
1H), 8.11–8.13 (d, 1H), 8.22–8.25 (d, 1H), 8.86–8.86 (m, 1H),
9.17–9.18 (m, 1H). MS calcd for [M+H]+: C24H30N4O3S m/z: 454.2,
found 455.4.
Yellow oil, 23 mg (53% yield) following chromatographic purifi-
cation over silica gel with CH2Cl2/MeOH (9/1); initial LC/MS purity
93%, tR = 0.82. 1H NMR (300 MHz, DMSO) d (ppm): 1.43–1.48 (m,
2H), 1.74–1.81 (m, 2H), 2.80–2.86 (m, 2H), 2.94–2.98 (m, 1H),
3.05–3.15 (m, 4H), 3.18–3.23 (d, 1H), 3.57 (br s, 1H), 4.14–4.22
(q, 1H), 4.39–4.44 (dd, 1H), 7.14–7.21 (m, 4H), 7.79–7.82 (m, 1H),
8.15–8.18 (d, 1H), 8.30–8.34 (d, 1H),8.62 (s, 1H), 8.82 (br s, 1H),
9.14–9.15 (m, 1H). MS calcd for [M+H]+: C22H25N3O2S m/z: 395.2,
found 396.4.
6.4.8. N-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl}-6-
quinolinesulfonamide (29)
6.4.14. N-[4-(1,2,3,4-Tetrahydroisoquinolin-2-yl)butyl]-8-
quinolinesulfonamide (35)
Yellow oli, 29 mg (60% yield) following chromatographic purifi-
cation over silica gel with CH2Cl2/MeOH (9/1); initial LC/MS purity
94%, tR = 0.87. 1H NMR (300 MHz, CDCl3) d (ppm): 1.67–1.71 (m,
2H), 2.47–2.51 (m, 2H), 2.63 (br s, 4H), 3.13–3.17 (m, 6H), 3.86
(s, 3H), 6.85–7.05 (m, 5H), 7.52–7.56 (dd, 1H, J = 8.2 Hz,
J = 4.4 Hz), 8.05–8.09 (dd, 1H, J = 8.9 Hz, J = 2.0 Hz), 8.21–8.29 (m,
2H), 8.42–8.43 (d, 1H), 9.04–9.06 (dd, 1H, J = 4.4 Hz, J = 1.8 Hz).
MS calcd for [M+H]+: C23H28N4O3S m/z: 440.2, found 441.3.
Yellow oil, 21.5 mg (49% yield) following chromatographic puri-
fication over silica gel with CH2Cl2/MeOH (9/1.1); initial LC/MS
purity 96%, tR = 0.98. 1H NMR (300 MHz, DMSO) d (ppm): 1.37–
1.44 (m, 2H), 1.66–1.76 (m, 2H), 2.81–2.83 (m, 2H), 2.96–3.07
(m, 3H), 3.17–3.21 (d, 2H), 3.55–4.07 (m, 2H), 4.12–4.19 (m, 1H),
4.37–4.41 (m, 1H), 7.14–7.32 (m, 4H), 7.69–7.78 (m, 2H), 8.28–
8.33 (m, 2H), 8.54–8.58 (m, 1H), 9.08–9.10 (dd, 1H, J = 4.4 Hz,
J = 1.8 Hz). MS calcd for [M+H]+: C22H25N3O2S m/z: 395.2, found
396.4.
6.4.9. N-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-6-
quinolinesulfonamide (30)
Yellow oil, 29 mg (58% yield) following chromatographic purifi-
cation over silica gel with CH2Cl2/MeOH (9/1); initial LC/MS purity
97%, tR = 0.90. 1H NMR (300 MHz, DMSO) d (ppm): 1.40–1.47 (m,
2H), 1.64–1.69 (m, 2H), 2.79–2.86 (m, 2H,), 2.98–3.08 (m, 6H),
3.41–3.44 (m, 4H), 3.77 (s, 3H), 6.85–7.03 (m, 4H), 8.00–8.15 (m,
1H) 7.79–7.84 (m, 1H), 8.18–8.18 (d, 1H), 8.31–8.34 (d, 1H),
8.61–8.62 (d, 1H), 8.81–8.83 (d, 1H), 9.14–9.16 (dd, 1H, J = 4.4 Hz,
J = 1.5 Hz). MS calcd for [M+H]+: C24H30N4O3S m/z: 454.6, found
455.7.
6.4.15. N-[4-(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-5-
yl)butyl]-3-quinolinesulfonamide (36)
Yellow oil, 26 mg (59% yield) following chromatographic purifi-
cation over silica gel with CH2Cl2/MeOH (9/1); initial LC/MS purity
94%, tR = 0.87. 1H NMR (300 MHz, CDCl3) d (ppm): 1.65–1.71 (m,
4H), 2.55–2.59 (m, 2H, J = 10.8 Hz, J = 5.4 Hz), 2.84–2.88 (m, 2H,
J = 11.5 Hz, J = 5.7 Hz), 2.99–3.06 (m, 4H), 3.49 (s, 2H), 6.65–6.66
(d, 1H), 7.11–7.13 (d, 1H), 7.61–7.66 (t, 1H), 7.81–7.86 (t, 2H),
8.13–8.16 (d, 1H), 8.30–8.31 (m, 1H), 8.96–8.97 (d, 2H). ESI
[M+H]+: C20H23N3O2S2 m/z 402.13, found 402.0.
6.4.10. N-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl}-8-
quinolinesulfonamide(31)
6.4.16. N-[4-(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-5-
yl)butyl]-7-quinolinesulfonamide (37)
Yellow oil, 30 mg (62% yield) following chromatographic purifi-
cation over silica gel with CH2Cl2/MeOH (9/1); initial LC/MS purity
93%, tR = 1.01.1H NMR (300 MHz, CDCl3) d (ppm): 1.68–1.72 (m,
2H), 2.36–2.40 (m, 2H), 2.55 (br s, 4H), 2.95–3.06 (m, 6H), 3.86
(s, 3H), 6.84–7.02 (m, 5H), 7.53–7.58 (m, 1H), 7.64–7.69 (t, 1H),
8.04–8.07 (m, 1H), 8.27–8.30 (m, 1H), 8.44–8.47 (m, 1H), 9.02–
9.04 (m, 1H). MS calcd for [M+H]+: C23H28N4O3S m/z: 440.2, found
441.2.
Yellow oil, 27 mg (61% yield) following chromatographic purifi-
cation over silica gel with CH2Cl2/MeOH (9/1); initial LC/MS purity
93%, tR = 0.86. 1H NMR (300 MHz, CDCl3) d (ppm): 1.43–1.53 (m,
2H), 1.70–1.81 (m, 2H), 2.80–2.89 (m, 2H), 2.96–3.25 (m, 4H),
3.62–3.65 (m, 1H), 3.91 (m, 1H), 4.05–4.12 (m, 1H), 4.36–4.45
(m, 1H), 6.87–6.91 (m, 1H), 7.45–7.46 (d, 1H), 7.76–7.80 (q, 1H),
7.97–8.01 (dd, 1H), 8.06–8.10 (t, 1H, J = 11.2 Hz, J = 5.6 Hz), 8.27–
8.30 (d, 1H), 8.48 (s, 1H), 8.61–8.63 (d, 1H), 9.10–9.11 (m, 1H).
MS calcd for [M+H]+: C20H23N3O2S2 m/z 401.1, found 402.1.
6.4.11. N-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-8-
quinolinesulfonamide (32)
6.4.17. N-[4-(1,2,3,4,4a,5,6,7,8,8a-Decahydroisoquinolin-2-
yl)butyl]-3-quinolinesulfonamide (38)
Yellow oil, 21 mg (47% yield) following chromatographic purifi-
cation over silica gel with CH2Cl2/MeOH (9/1.3); initial LC/MS pur-
ity 89%, tR = 1.10. 1H NMR (300 MHz, CDCl3) d (ppm): 0.88–3.11
Yellow oil, 29 mg (58% yield) following chromatographic purifi-
cation over silica gel with CH2Cl2/MeOH (9/1); initial LC/MS purity
d (ppm): 1.68–1.72
(m, 2H), 2.36–2.48 (m, 4H), 2.55 (br s, 4H), 2.95–3.06 (m, 6H),
3.86 (s, 3H), 6.84–7.02 (m, 5H), 7.53–7.58 (m, 1H), 7.64–7.69 (t,
92%, tR = 1.09.1H NMR (300 MHz, CDCl3)

P. Zajdel et al. / Bioorg. Med. Chem. 19 (2011) 6750–6759
6757
(cluster 22H), 3.11–3.18 (m, 2H), 7.65–7.71 (t, 1H), 7.85–7.91 (m,
1H), 7.94–7.96 (d, 1H), 8.18–8.21 (d, 1H), 8.69 (s, 1H), 9.25–9.26
(d, 1H). MS calcd for [M+H]+: C22H31N3O2S m/z: 401.2, found 402.4.
(1.1 g, 93% yield). tR = 0.73. 1H NMR (300 MHz, CDCl3) d (ppm)
0.79–3.34 (cluster, 26H), 3.80 (s, 3H), 6.17 (bs s, 1H). MS calcd
for [M+H]+: C16H30N2O m/z: 266.2, found 267.3.
6.4.18. N-[3-(1,2,3,4,4a,5,6,7,8,8a-Decahydroisoquinolin-2-
yl)propyl]-6-quinolinesulfonamide (39)
6.6. General method for preparation of secondary amines 45–48
(Method D)
Yellow oil, 24.8 mg (58% yield) following chromatographic puri-
fication over silica gel with CH2Cl2/MeOH (9/1.3); initial LC/MS
purity 92%, tR = 0.90. 1H NMR (300 MHz, CDCl3) d (ppm) 0.88–
3.11 (cluster, 20H), 3.11–3.14 (m, 2H), 7.52–7.55 (m, 1H), 8.06–
8.09 (m, 1H), 8.21–8.29 (m, 2H), 8.42 (s, 1H), 9.04–9.06 (m, 1H).
MS calcd for [M+H]+: C21H29N3O2S m/z: 387.2, found 388.3.
Acetamides (1 mmol) were dissolved in anh. THF (10 mL); sub-
sequently a suspension of LiAlH4 in THF (2 N solution, 2 mmol) was
added dropwise under argon atmosphere. The reaction mixture
was warmed to reflux for 3–6 h. An excess of reactants was decom-
posed by addition of few drops of AcOEt, NaOH (1 N water solution,
1 equiv), and water. After filtration of the salts over Celite, a clear
solution was dried over Na2SO4 and concentrated in vacuo. This
yielded secondary amines, which were used without further
purification.
6.4.19. N-[4-(1,2,3,4,4a,5,6,7,8,8a-Decahydroisoquinolin-2-
yl)butyl]-8-quinolinesulfonamide (40)
Yellow oil, 21 mg (47% yield) following chromatographic purifi-
cation over silica gel with CH2Cl2/MeOH (9/1.2); initial LC/MS pur-
ity 90%, tR = 1.09.1H NMR (300 MHz, CDCl3) d (ppm): 0.84–3.52
(cluster 24H), 6.53 (br s, 1H), 7.59–7.69 (m, 2H), 8.07–8.10 (m,
1H), 8.29–8.32 (d, 1H, J = 7.9 Hz), 8.39–8.42 (d,1H, J = 7.2 Hz), 9.06
(s, 1H). MS calcd for [M+H]+: C22H31N3O2S m/z: 401.2, found 402.3.
6.6.1. Ethyl-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}
amine (45)10
Obtained from 41 (1.0 g, 3.43 mmol), as yellow oil (0.88 g, 91%
yield). tR = 0.62. 1H NMR (300 MHz, CDCl3) d (ppm): 1.09–1.34 (t,
3H), 1.66–1.78 (m, 3H), 2.41–2.49 (m, 2H), 2.62–2.79 (m, 8H),
3.09 (br s, 4H), 3.86 (s, 3H), 6.84–7.02 (m, 4H). MS calcd for
[M+H]+: C16H27N3O m/z: 277.2, found 278.2.
6.5. General method for preparation of acetamides 41–44
(Method C)
Primary amines (1 mmol) obtained according to the method de-
scribed by Gabriel were dissolved in a mixture of CH2Cl2 and satu-
rated aqueous NaHCO3 (20 mL/10 mL).35 Then to a vigorously
stirred mixture, an acetic anhydride (1.5 mmol) was added in sev-
eral portions. After addition of the acetic anhydride, a mixture was
additionally stirred for 6 h at room temperature. Then, the layers
were separated, inorganic phase was washed with CH2Cl2
(2 Â 30 mL). The combined organic fractions were washed with
brine, dried over Na2SO4, and evaporated in vacuum.
6.6.2. Ethyl-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}
amine (46)
Obtained from 42 (1.0 g, 3.27 mmol), as yellow oil (0.92 g, 96%
yield). tR = 0.64. 1H NMR (300 MHz, CDCl3) d (ppm) 1.13–1.20 (m,
3H), 1.52–1.63 (m, 4H), 2.41–2.56 (m, 2H), 2.61–2.75 (m, 8H),
3.10 (br s, 4H), 3.19–3.22 (t, 1H), 3.86 (s, 3H), 6.84–7.03 (m, 4H).
MS calcd for [M+H]+: C17H29N3O m/z: 291.2, found 292.2.
6.6.3. Ethyl-[4-(1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-2-
yl)butyl]amine (47)
6.5.1. N-{3-[4-(2-Methoxyphenyl)piperazyn-1-yl]propyl}
acetamide (41)10
Obtained from 43 (1.2 g, 4.75 mmol), as yellow oil (1 g, 91%
yield). tR = 0.63. 1H NMR (300 MHz, CDCl3) d (ppm): 0.82–3.16
(cluster,30H). MS calcd for [M+H]+: C15H30N2 m/z: 238.2, found
239.2.
Obtained from 3-[4-(2-methoxyphenyl) piperazin-1-yl]propyl-
1-amine (1.5 g, 6 mmol), as yellow oil, that crystalized upon stand-
ing (1.60 g, 92% yield). tR = 0.71. 1H NMR (300 MHz, CDCl3) d
(ppm): 2.03–2.06 (m, 3H), 2.11–2.19 (m, 2H), 3.08–3.12 (m, 4H),
3.39–3.62 (m, 8H), 3.86 (s, 3H), 6.87–7.10 (m, 4H), 7.27–7.41 (m,
1H). MS calcd for [M+H]+: C16H25N3O2 m/z: 291.2, found 292.1.
6.6.4. Ethyl-[5-(1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-2-
yl)pentyl]amine (48)
Obtained from 44 (1.0 g, 3.43 mmol), as yellow oil (0.86 g, 91%
yield). tR = 0.66. 1H NMR (300 MHz, CDCl3) d (ppm): 0.82–3.16
(cluster, 32H). MS calcd for [M+H]+: C16H32N2 m/z: 252.2, found
253.2.
6.5.2. N-{4-[4-(2-Methoxyphenyl)piperazyn-1-yl]butyl}
acetamide (42)
Obtained from 4-[4-(2-methoxyphenyl) piperazin-1-yl]butyl-1-
amine (1.2 g, 4.5 mmol), as yellow oil, that crystalized upon stand-
ing (1.32 g, 95% yield). tR = 0.75. Mp 58–60 °C. 1H NMR (300 MHz,
CDCl3) d (ppm): 1.56–1.76 (m, 4H), 1.97 (s, 3H), 2.43–2.48 (t,
2H), 2.68 (br s, 4H), 3.12 (br s, 4H), 3.24–3.31 (m, 2H), 3.86 (s,
3H), 6.19 (s, 1H), 6.85–7.04 (m, 4H). MS calcd for [M+H]+:
6.7. General method for preparation of sulfonamides 49–55
(Method E)
Secondary amines (0.64 mmol, 1 equiv) obtained according to
the method D were dissolved in a mixture of CH2Cl2 (generally
10 mL), followed by addition of triethylamine (1.3 mmol, 2 equiv).
Then the mixture was cooled down (ice bath), and quinolinesulfo-
nyl chloride (0.77 mmol, 1.2 equiv) was added, and the mixture
was stirred for 2–5 h. After evaporation of the solvent, the crude
product was purified on silica gel column chromatography using
CH2Cl2/MeOH (9/0.7) for compounds 49–52, and CH2Cl2/MeOH
(9/1.2) for compounds 53–55. The free base was converted to its
hydrochloride salt by treatment with 4 N HCl in dioxane.
C17H27N3O2 m/z: 305.2, found 306.2.
6.5.3. N-[4-(1,2,3,4,4a,5,6,7,8,8a-Decahydroisoquinolin-2-
yl)butyl]acetamide (43)
Obtained from 4-(octahydro-isoquinolin-2-yl)-butyl-1-amine
(1.26 g, 6 mmol), as yellow oil (1.37 g, 91% yield). tR = 0.72. 1H
NMR (300 MHz, CDCl3) d (ppm) 0.79–3.34 (cluster, 24H), 3.82 (s,
3H), 6.14 (bs s, 1H). MS calcd for [M + H]+: C15H28N2O m/z: 252.2,
found 253.3.
6.7.1. N-Ethyl-N-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}-
3-quinolinesulfonamide (49)
Obtained from amine 46, as yellow oil, 0.29 g (89% yield).
tR = 1.24. 49ÁHCl: mp 182–184 °C. 1H NMR (300 MHz, DMSO)
d(ppm) 1.03–1.08 (t, 3H), 1.55–1.62 (m, 2H), 1.69–1.75 (m, 2H),
6.5.4. N-[5-(1,2,3,4,4a,5,6,7,8,8a-Decahydroisoquinolin-2-
yl)pentyl]acetamide (44)
Obtained from 5-(octahydro-isoquinolin-2-yl)-pentyl-1-amine
(1 g, 4.4 mmol), as yellow oil, that crystalized upon standing

6758
P. Zajdel et al. / Bioorg. Med. Chem. 19 (2011) 6750–6759
3.07–3.10 (m, 6H), 3.19–3.29 (m, 4H), 3.40–3.47 (m, 4H), 3.78 (s,
3H), 6.86–7.04 (m, 4H), 7.75–7.81 (m, 1H), 7.94–7.99 (m, 1H),
8.13–8.16 (d, 1H), 8.26–8.29 (d, 1H),8.98–8.99 (d, 1H),9.20–9.21
(d, 1H), 10.97 (br s, 1H+). MS calcd for [M+H]+: C26H34N4O3S m/z:
482.2, found 483.2. Anal. (C26H34N4O3SÁHCl) C, H, N.
8.25–8.28 (dd, 1H, J = 8.2 Hz, J = 1.3 Hz), 8.34–8.37 (dd, 1H,
J = 7.4 Hz, J = 1.3 Hz), 8.50–8.53 (dd, 1H, J = 8.5 Hz, J = 1.5 Hz),
9.05–9.06 (dd, 1H, J = 4.1 Hz, J = 1.8 Hz), 10.2 (br s, 1H+). MS calcd
for [M+H]+: C25H37N3O2S m/z: 443.3, found 444.4. Anal.
(C25H37N3O2SÁHCl)C, H, N.
6.7.2. N-Ethyl-N-{3-[4-(2-methoxyphenyl)piperazin-1-
yl]propyl}-6-quinolinesulfonamide (50)
7. In vitro pharmacology
Obtained from amine 45, as an oil, 0.25 g (82% yield). tR = 1.10.
50ÁHCl: mp 190–192 °C. 1H NMR (300 MHz, DMSO) d (ppm): 1.02–
1.06 (t, 3H),2.02–2.06 (m, 2H), 3.09–3.32 (m, 10H), 3.44–3.52 (m,
4H), 3.78 (s, 3H), 6.86–7.01 (m, 4H), 7.85–7.89 (m, 1H), 8.19–
8.22 (d, 1H), 8.33–8.36 (d, 1H), 8.74 (s, 1H), 8.88–8.91 (d, 1H),
9.19–9.20 (d, 1H), 11.22 (br s, 1H+). MS calcd for [M+H]+:
7.1. Radioligand binding experiments
Compounds were tested in competition binding experiments
for native 5-HT1A, 5-HT2A and adrenergic a1 receptors as well as
for cloned human 5-HT6 and 5-HT7 receptors, according to the pre-
viously published procedures.14–16 The binding parameters are
summarized in Table 1-SM. Following incubation, the receptor
preparations were rapidly filtered under vacuum through GF/B
glass fiber filters; the filters were washed extensively with an ice
cold buffer using a harvester. Bound radioactivity was measured
by scintillation counting using a liquid scintillation cocktail. Com-
pounds (7–9 concentrations) were tested in triplicate. The inhibi-
tion constants (Ki) were calculated from the Cheng–Prusoff
equation.39 Results are expressed as means of at least three sepa-
rate experiments.
C
25H32N4O3S m/z: 468.2, found 469.2. Anal. (C25H33ClN4O3SÁHCl)
C, H, N.
6.7.3. N-Ethyl-N-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}-
6-quinolinesulfonamide (51)
Obtained from amine 46, as an oil, 0.28 g (86% yield). tR = 1.26.
51ÁHCl: mp 198–200 °C. 1H NMR (300 MHz, DMSO) d (ppm): 1.02–
1.06 (t, 3H), 1.56–1.58 (m, 2H), 1.73 (br s 2H), 3.11 (br s 6H), 3.18–
3.28 (m, 4H), 3.44–3.46 (m, 4H), 3.78 (s, 3H), 6.86–7.013 (m, 4H),
7.87–7.91 (m, 1H), 8.19–8.22 (m, 1H), 8.36–8.39 (d, 1H), 8.73–
8.74 (d, 1H), 8.92–8.95 (d, 1H), 9.20–9.21 (d, 1H), 11.12 (br s,
1H+). MS calcd for [M+H]+: C26H34N4O3S m/z: 482.2, found 483.2.
Anal. (C26H34N4O3SÁHCl) C, H, N.
7.2. Effects on adenylate cyclase activity
Adenylate cyclase activity is expressed as the percentage of the
maximal effect obtained with 300 nM serotonin. The compounds
were tested in 5 concentrations at 10À4–10À9 in the h5-HT7 antag-
onist effect. For the antagonists, the apparent dissociation con-
stants (KB) were calculated using the modified Cheng Prusoff
equation (KB = IC50/(1+(A/EC50A)), where A = concentration of refer-
ence agonist in the assay, and EC50A = EC50 value of the reference
agonist).
6.7.4. N-Ethyl-N-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}-
8-quinolinesulfonamide (52)
Obtained from amine amine 46, as pale oil 0.2 g (81% yield).
tR = 1.28. 52ÁHCl: mp 184–186 °C. 1H NMR (300 MHz, DMSO) d
(ppm): 0.90–0.95 (t, 3H), 1.49–1.54 (m, 2H), 1.70 (br s, 2H),
3.05–3.07 (m, 6H), 3.33–3.46 (8H, m), 3.78 (s, 3H), 6.86–7.04 (m,
4H), 7.66–7.76 (m, 2H), 8.26–8.29 (m, 1H), 8.35–8.38 (m, 1H),
8.51–8.54 (m, 1H), 9.07–9.09 (m, 1H), 10.84 (br s, 1H+). MS calcd
for [M+H]+: C26H34N4O3S m/z: 482.2, found 483.2. Anal.
(C26H34N4O3SÁHCl) C, H, N.
8. In vivo pharmacology
8.1. Subjects
6.7.5. N-Ethyl-N-[4-(1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-
2-yl)butyl]-3-quinolinesulfonamide (53)
The experiments were performed on male Albino Swiss mice
(22–26 g) purchased from a licensed breeder Staniszewska (Ilkow-
ice, Poland). Mice were kept in groups of ten to Makrolon type 3
cages (dimensions 26 Â 15 Â 42 cm) in an environmentally con-
trolled, experimental room (ambient temperature 21 1 °C; rela-
tive humidity 50–60%; 12:12 light:dark cycle, lights on at 8:00).
They were allowed to acclimatize with the environment for one
week before commencement of the experiments. Standard labora-
tory food (Ssniff M-Z) and filtered water were freely available. All
the experimental procedures were approved by the Local Ethics
Commission at the Jagiellonian University in Kraków.
Obtained from amine 47, as yellow oil 0.32 g (78% yield).
tR = 1.31. 53ÁHCl: mp 172–174 °C. 1H NMR (300 MHz, DMSO) d
(ppm): 0.89–0.92 (m, 5H), 1.17–1.21 (m, 3H), 1.44–1.62 (cluster,
11H), 2.81 (br s, 2H), 3.30–3.39 (m, 8H),7.67–7.73 (t, 1H), 7.88–
7.93 (m, 1H), 7.9–7.96 (d, 1H), 8.21–8.24 (d, 1H), 8.70 (s, 1H),
9.24–9.26 (m, 1H) 11.02 (br s, 1H+). MS calcd for [M+H]+:
C
H, N.
24H35N3O2S m/z: 429.2, found 430.2. Anal. (C24H35N3O2SÁHCl) C,
6.7.6. N-Ethyl-N-[4-(1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-
2-yl)butyl]-8-quinolinesulfonamide (54)
8.2. Experimental procedures
Obtained from amine 46, as yellow 0.34 g (78% yield). tR = 1.24.
54ÁHCl: mp 167–169 °C. 1H NMR (300 MHz, DMSO) d (ppm): 0.91–
0.94 (m, 5H), 1.19–1.24 (m, 3H), 1.45–1.64 (cluster, 11H), 2.83 (br
s, 2H), 3.32–3.41 (m, 8H),7.68–7.78 (m, 2H), 8.27–8.32 (m, 2H),
8.52–8.56 (d, 1H), 9.08–9.10 (d, 1H), 10.98 (br s, 1H+). MS calcd
for [M+H]+: C24H35N3O2S m/z: 429.2, found 430.2. Anal.
(C24H35N3O2SÁHCl) C, H, N.
All the experiments were conducted in the light phase between
09.00 and 14.00 h. Each experimental group consisted of 7–10 ani-
mals/dose, and the animals were used only once in each test. The
experiments were performed by an observer unaware of the treat-
ment administered.
8.3. Forced swim test in mice
6.7.7. N-Ethyl-N-[5-(1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-
2-yl)pentyl]-8-quinolinesulfonamide (55)
The experiment was carried out according to the method of
Porsolt et al.18 Briefly, mice were individually placed in a glass cyl-
inder (25 cm high; 10 cm in diameter) containing 6 cm of water
maintained at 23–25 °C, and were left there for 6 min. A mouse
Obtained from amine 47, as yellow oil 0.23 g (86% yield).
tR = 1.29. 55ÁHCl: mp 178–180 °C. 1H NMR (300 MHz, DMSO) d
(ppm): 0.89–0.94 (m, 5H), 1.18–1.23 (m, 5H), 1.44–1.63 (cluster,
11H), 2.83 (br s, 2H), 3.31–3.40 (m, 8H), 7.75–7.65 (m, 2H),

P. Zajdel et al. / Bioorg. Med. Chem. 19 (2011) 6750–6759
6759
6. Abbas, A. I.; Hedlund, P. B.; Huang, X. P.; Tran, T. B.; Meltzer, H. Y.; Roth, B. L.
Psychopharmacology 2009, 205, 119.
was regarded as immobile when it remained floating on the water,
making only small movements to keep its head above it. The total
duration of immobility was recorded during the last 4 min of a
6-min test session.
7. Ishibashi, T.; Horisawa, T.; Tokuda, K.; Ishiyama, T.; Ogasa, M.; Tagashira, R.;
Matsumoto, K.; Nishikawa, H.; Ueda, Y.; Toma, S.; Oki, H.; Tanno, N.; Saji, I.; Ito,
A.; Ohno, Y.; Nakamura, M. J. Pharmacol. Exp. Ther. 2010, 334, 171.
8. Lovell, P. J.; Bromidge, S. M.; Dabbs, S.; Duckworth, D. M.; Forbes, I. T.; Jennings,
A. J.; King, F. D.; Middlemiss, D. N.; Rahman, S. K.; Saunders, D. V.; Collin, L. L.;
Hagan, J. J.; Riley, G. J.; Thomas, D. R. J. Med. Chem. 2000, 43, 342.
9. Raubo, P.; Beer, M. S.; Hunt, P. A.; Huscroft, I. T.; London, C.; Stanton, J. A.;
Kulagowski, J. J. Bioorg. Med. Chem. Lett. 2006, 16, 1255.
10. Vermeulen, E. S.; van Smeden, M.; Schmidt, A. W.; Sprouse, J. S.; Wikström, H.
V.; Grol, C. J. J. Med. Chem. 2004, 47, 5451.
11. Yoon, J.; Yoo, E. A.; Kim, J. Y.; Pae, A. N.; Rhim, H.; Park, W. K.; Kong, J. Y.; Park
Choo, H. Y. Bioorg. Med. Chem. 2008, 16, 5405.
8.4. Locomotor activity in mice
The locomotor activity was recorded with an Opto M3 multi-
channel activity monitor (MultiDevice Software v.1.3, Columbus
Instruments). The mice were individually placed in plastic cages
(22 Â 12 Â 13 cm), and then the crossings of each channel (ambu-
lation) were counted from 2 to 6 min, that is, the time equal to the
observation period in the forced swim test and during 30-min
experimental sessions. The cages were cleaned up with 70% etha-
nol after each mouse.
12. Zajdel, P.; Subra, G.; Pawłowski, M.; Martinez, J. QSAR Comb. Sci. 2007, 26, 215.
13. Marciniec, K.; Mas´lankiewicz, A.; Pawłowski, M.; Zajdel, P. Heterocycles 2007,
71, 1975.
14. Bojarski, A. J.; Cegła, M. T.; Charakchieva-Minol, S.; Mokrosz, M. J.; Mac´kowiak,
M.; Misztal, S.; Mokrosz, J. L. Pharmazie 1993, 48, 289.
15. Leopoldo, M.; Berardi, F.; Colabufo, N. A.; De Giorgio, P.; Lacivita, E.; Perrone, R.;
Tortorella, V. J. Med. Chem. 2002, 45, 5727.
16. Paluchowska, M. H.; Bugno, R.; Tatarczyn´ ska, E.; Nikiforuk, A.; Lenda, T.;
8.5. Drugs
Chojnacka-Wójcik, E. Bioorg. Med. Chem. 2007, 15, 7116.
17. Adham, N.; Zgombick, J. M.; Bard, J.; Branchek, T. A. J. Pharmacol. Exp. Ther.
1998, 287, 508.
18. Porsolt, R. D.; Bertin, A.; Jalfre, M. Arch. Int. Pharmacodyn. Ther. 1977, 229, 327.
19. Lopez-Rodriguez, M. L.; Porras, E.; Morcillo, M. J.; Benhamu, B.; Soto, L. J.;
Lavandera, J. L.; Ramos, J. A.; Olivella, M.; Campillo, M.; Pardo, L. J. Med. Chem.
2003, 46, 5638.
20. Medina, R. A.; Sallander, J.; Benhamu, B.; Porras, E.; Campillo, M.; Pardo, L.;
Lopez-Rodriguez, M. L. J. Med. Chem. 2009, 52, 2384.
21. Leopoldo, M.; Berardi, F.; Colabufo, N. A.; Contino, M.; Lacivita, E.; Niso, M.;
The following drugs were used: (2R)-1-[(3-hydroxyphenyl)sul-
fonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl] pyrrolidine (hydrochlo-
ride, SB-269970, Tocris UK) and compounds 54, 55. SB-2699710,
54, 55 were suspended in a 1% aqueous solution of Tween 80
immediately before administration. All the compounds were
administered intraperitoneally at a volume of 10 ml/kg and were
given 30 min before the test. Control animals received a vehicle
injection according to the same schedule.
Perrone, R.; Tortorella, V. J. Med. Chem. 2004, 47, 6616.
22. Zajdel, P.; Subra, G.; Verdie, P.; Gabzdyl, E.; Bojarski, A. J.; Duszyn´ ska, B.;
Martinez, J.; Pawłowski, M. Bioorg. Med. Chem. Lett. 2009, 19, 4827.
23. Leopoldo, M.; Lacivita, E.; Berardi, F.; Perrone, R.; Hedlund, P. B. Pharmacol.
Ther. 2011, 129, 120.
8.6. Statistics
24. Kołaczkowski, M.; Nowak, M.; Pawłowski, M.; Bojarski, A. J. J. Med. Chem. 2006,
49, 6732.
All the data are presented as the mean SEM. The statistical sig-
nificance of the results was evaluated by a one-way ANOVA, fol-
lowed by Bonferroni Comparison Test.
25. Butini, S.; Gemma, S.; Campiani, G.; Franceschini, S.; Trotta, F.; Borriello, M.;
Ceres, N.; Ros, S.; Coccone, S. S.; Bernetti, M.; De Angelis, M.; Brindisi, M.; Nacci,
V.; Fiorini, I.; Novellino, E.; Cagnotto, A.; Mennini, T.; Sandager-Nielsen, K.;
Andreasen, J. T.; Scheel-Kruger, J.; Mikkelsen, J. D.; Fattorusso, C. J. Med. Chem.
2009, 52, 151.
Acknowledgments
26. Graulich, A.; Leonard, M.; Resimont, M.; Huang, X.-P.; Roth, B. L.; Liegeois, J.-F.
Aust. J. Chem. 2010, 63, 56.
27. Resimont, M.; Liegeois, J.-F. Bioorg. Med. Chem. Lett. 2010, 20, 5199.
28. Chen, J.; Ding, K.; Levant, B.; Wang, S. Bioorg. Med. Chem. Lett. 2006, 16, 443.
29. Perrone, R.; Berardi, F.; Colabufo, N. A.; Lacivita, E.; Leopoldo, M.; Tortorella, V.
J. Med. Chem. 2003, 46, 646.
30. Rosenzweig-Lipson, S.; Beyer, C. E.; Hughes, Z. A.; Khawaja, X.; Rajarao, S. J.;
Malberg, J. E.; Rahman, Z.; Ring, R. H.; Schechter, L. E. Pharmacol. Ther. 2007,
113, 134.
The authors wish to thank Professor G. Nowak, Ms. M. Wolak
and A. Siwek for their determination of the a1 receptor affinity of
compounds. This study was partly supported by the Polish Minis-
try of Science and Higher Education (MNiSW), grant no. NN405
378437. Radioligand binding experiments were financially sup-
ported by the Norwegian Financial Mechanism as part of the Pol-
ish-Norwegian Research Fund, grant no. PNRF-103-AI-1/07.
31. Hedlund, P. B.; Huitron-Resendiz, S.; Henriksen, S. J.; Sutcliffe, J. G. Biol.
Psychiatry 2005, 58, 831.
32. Wesołowska, A.; Nikiforuk, A.; Stachowicz, K.; Tatarczyn´ ska, E.
Neuropharmacology 2006, 51, 578.
Supplementary data
33. Wesołowska, A.; Tatarczyn´ ska, E.; Nikiforuk, A.; Chojnacka-Wójcik, E. Eur. J.
Pharmacol. 2007, 555, 43.
34. Hedlund, P. B.; Kelly, L.; Mazur, C.; Lovenberg, T.; Sutcliffe, J. G.; Bonaventure, P.
Eur. J. Pharmacol. 2004, 487, 125.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2011.09.044.
´
´
´
35. Mokrosz, J. M.; Deren-Wesołek, A.; Tatarczynska, E.; Duszynska, B.; Bojarski, A.
J.; Mokrosz, M. J.; Chojnacka-Wójcik, E. J. Med. Chem. 1996, 39, 1125.
36. Mokrosz, M. J.; Bojarski, A. J.; Duszyn´ ska, B.; Tatarczyn´ ska, E.; Kłodzin´ ska, A.;
References and notes
´
Deren-Wesołek, A.; Charakchieva-Minol, S.; Chojnacka-Wójcik, E. Bioorg. Med.
Chem. 1999, 7, 287.
1. Hedlund, P. B.; Sutcliffe, J. G. Trends Pharmacol. Sci. 2004, 25, 481.
2. Hedlund, P. B. Psychopharmacology 2009, 206, 345.
37. Kupihar, Z.; Schmel, Z.; Kele, Z.; Penke, B.; Kovacs, L. Bioorg. Med. Chem. 2001, 9,
1241.
38. Zajdel, P.; Król, J.; Grychowska, K.; Pawlowski, M.; Subra, G.; Nomezine, G.;
Martinez, J.; Bojarski, A. J.; Zhou, Z.; O’Donnell, M. J.; Scott, W. L. Molecules
2011, 16, 4104.
3. Roberts, A. J.; Hedlund, P. B. Hippocampus 2011. doi:10.1002/hipo.20938.
4. Roth, B. L.; Craigo, S. C.; Choudhary, M. S.; Uluer, A.; Monsma, F. J., Jr.; Shen, Y.;
Meltzer, H. Y.; Sibley, D. R. J. Pharmacol. Exp. Ther. 1994, 268, 1403.
5. Mnie-Filali, O.; Lambás-Senas, L.; Zimmer, L.; Haddjeri, N. Drugs News Perspect.
2007, 20, 613.
39. Cheng, Y.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099.