Arylsulfonamide derivatives of (aryloxy)ethylpiperidines as selective 5-HT7 receptor antagonists and their psychotropic properties

Article abstract of DOI:10.1039/c5md00166h

A series of alkyl/arylsulfonamide derivatives of (aryloxy)ethylpiperidines as highly potent 5-HT₇ receptor antagonists has been developed through structure-based design on the previously identified compound PZ-766. This resulted in highly poten

Full text of DOI:10.1039/c5md00166h

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Arylsulfonamide derivatives of (aryloxy)
ethylpiperidines as selective 5-HT7 receptor
Cite this: DOI: 10.1039/c5md00166h
antagonists and their psychotropic properties†
Paweł Zajdel, a Vittorio Canale,a Anna Partyka,b Krzysztof Marciniec,c Rafał Kurczab,d
*
Grzegorz Satała,d Agata Siwek,e Magdalena Jastrzębska-Więsek,b Anna Wesołowska,b
Tomasz Kos,f Piotr Popikf and Andrzej J. Bojarskid
A series of alkyl/arylsulfonamide derivatives of (aryloxy)ethylpiperidines as highly potent 5-HT7 receptor
antagonists has been developed through structure-based design on the previously identified compound
PZ-766. This resulted in highly potent antagonist 10 IJ3-fluoro-N-IJ1-{2-ij(propan-2-yl)phenoxy]ethyl}-
piperidin-4-yl)-benzenesulfonamide) which was more active in vivo than PZ-766 and SB-269970 in forced
swim test in mice (MED = 2.5 mg kg−1), and displayed comparable effects to SB-269970 in four-plate test
in mice (MED = 1.25 mg kg−1) and novel object recognition test in rats (MED = 1 mg kg−1). The results high-
light the antidepressant, anxiolytic and pro-cognitive potential of the arylsulfonamide derivatives of
(aryloxy)ethylpiperidines with 5-HT7 receptor antagonist properties and warrant further studies to explore
their therapeutic potential for the treatment of CNS disorders.
Received 21st April 2015,
Accepted 18th May 2015
DOI: 10.1039/c5md00166h
www.rsc.org/medchemcomm
suspension tests;3–6 moreover, the response was faster than
the effect produced by fluoxetine.7 It was additionally
Introduction
G-protein-coupled 5-HT7 receptors IJ5-HT7Rs) are the most
recently identified members of the serotonin receptor family.1
Their widespread distribution in the CNS, correlated with
important functional roles, has focused interest in these sites
as potentially important targets for the treatment of depres-
sion.2 This was confirmed by the fact that blockade of the
5-HT7Rs was effective in rodent models of depression and
increased the latency to rapid eye movement (REM) sleep and
decreased REM duration. The selective 5-HT7R antagonists
SB-269970 and JNJ-18038683, as well as classical selective-
serotonin reuptake inhibitors (SSRI), produced an antidepressant-
like effect decreasing immobility in forced swim and tail
supported by the fact, that the antidepressant properties of
the clinically established antipsychotic drugs – amisulpride
and aripiprazole – were mediated by the 5-HT7Rs.8,9 More-
over, it was recently found that 5-HT7R antagonists may be
responsible for specific anti-anxiety-like effects as well as for
improvement of cognitive decline or neurological disor-
ders.10,11 Finally, 5-HT7R antagonism appears capable of
affecting hippocampal neuronal morphology, and enhancing
hippocampal neurogenesis.12,13
Initial efforts in the design of 5-HT7R antagonists were
focused on arylsulfonamide and arylsulfone derivatives of
alkylamines (Fig. 1).14,15 Subsequently, pyrazoloij3,4-d]azepine,
arylpiperazine and arylpiperidine cores, followed with
their isosteric tetrahydroisoquinoline analogs, emerged as
privileged structures for the development of 5-HT7 receptors
antagonists.6,16–20
Our research team has recently reported on the design,
synthesis, and biological evaluation of arylsulfonamide deriv-
atives of (aryloxy)ethylpiperidines as 5-HT7R antagonists.
Among them, a potent compound PZ-766, which displayed
nanomolar affinity for the 5-HT7Rs and high selectivity over
the 5-HT1ARs was identified.21,22
Herein, we designed and synthesized a focused library of
alkyl/arylsulfonamide derivatives of IJ(2-isopropylphenoxy/2-
phenylphenoxy)ethyl)piperidines based on the lead com-
pound PZ-766, and studied their affinity for the 5-HT7 recep-
tors and other related 5-HTRs, dopamine D2 receptors, as
a Department of Medicinal Chemistry, Jagiellonian University Medical College,
9 Medyczna Street, 30-688 Krakow, Poland. E-mail: pawel.zajdel@uj.edu.pl;
Fax: +48 126205405; Tel: +48 126205450
b Department of Clinical Pharmacy, Jagiellonian University Medical College,
9 Medyczna Street, 30-688 Krakow, Poland
c Department of Organic Chemistry, Medical University of Silesia, 4 Jagiellońska
Street, 41-200 Sosnowiec, Poland
d Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy
of Sciences, 12 Smętna Street, 31-343 Kraków, Poland
e Department of Pharmacobiology, Jagiellonian University Medical College,
9 Medyczna Street, 30-688 Krakow, Poland
f Department of Behavioral Neuroscience and Drug Development, Institute of
Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków,
Poland
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5md00166h
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Fig. 1 Chemical structure of the 5-HT7R antagonist.
well as for off-targets, i.e. adrenergic α1, and β1, histamine
H1, muscarinic M1 receptors regarded as potential sources of
cardiovascular and/or CNS side effects. This study also aimed
to evaluate the in vivo behavioral effects of selected com-
pounds in mice models of depression and anxiety (forced
swim test – FST and four-plate test – FPT, respectively). Fol-
lowing recent reports suggesting the efficacy of 5-HT7R antag-
onists in overcoming cognitive impairment in affective disor-
ders, pro-cognitive properties of selected compounds were
further tested in the novel object recognition (NOR) task in
rats.
Structure–activity relationships (SAR) within the evaluated
compounds confirmed that sterically hindered substituents
are allowed in the ortho position on the (aryloxy)ethyl frag-
ment (Table 1). The importance of the presence of an aro-
matic ring in the sulfonamide fragment was evidenced by the
moderate affinity for 5-HT7Rs and low selectivity over
5-HT1ARs of compounds 8 and 18 with alkylsulfonyl moiety.
These results are in line with those of molecular modeling,
indicating that compound PZ-766 and its isobutyl (8), and
phenyl (9) analogs had similar binding modes, involving a
salt-bridge with Asp3.32 and interactions of the (aryloxy)ethyl
amine fragment (CH–π or π–π) with the side chain of
Phe6.51. However, the higher affinity of PZ-766 can be
explained by polar contacts formed with the side chain of
Glu7.35 and the guanidinium group of Arg7.36, and addition-
ally, hydrophobic interactions with the lipophilic side chain
of Leu7.39 (Fig. 2).21,23 These interactions increased the stabi-
lization of the receptor–ligand complex of the fluorine analog
in comparison to the unsubstituted and isobutyl analogs.
Moreover, it has to be noted that the alkyl analog was the
worst scored among all the studied compounds.
Results and discussion
The antagonists reported in this study were synthesized
according to Scheme 1. Treatment of phenols 1–2 with 1,2-
dibromoethane under biphasic conditions yielded (aryloxy)
ethyl bromides 3–4. These intermediates were subsequently
used for the alkylation of the Boc-protected 4-amino-piperi-
dine. The final alkyl/arylsulfonamides 8–28 were obtained
upon treatment of deprotected intermediates 5–6 with the
selected alkyl/arylsulfonyl chlorides.
The influence of the type, position, and number of halo-
gen atoms in the arylsulfonyl moiety was not clear, but it
Scheme 1 Synthesis of the alkyl/arylsulfonamide derivatives of (aryloxy)ethylpiperidines. Reagents and conditions: i) 1,2-dibromoethane, K2CO3,
KI, IJCH3)2CO, 60 °C, 48–72 h; ii) 4-IJBoc-N-amino)-piperidine, K2CO3, KI, IJCH3)2CO, 60 °C, 48–72 h; iii) TFA/CH2Cl2 IJ90/10; v/v), 2 h; iv) alkyl/
arylsulfonyl chloride, CH2Cl2, 0 °C, 2–6 h.
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Table 1 The binding data of the synthesized compounds for the 5-HT7 and 5-HT1ARs
Ki [nM]a
Compd
R2
R1
5-HT7
5-HT1A
5-HT1A/5-HT7
7 (PZ-766)b
8
9
4-F-phenyl
Isobutyl
Phenyl
3-F-phenyl
3-Cl-phenyl
3,4-DiF-phenyl
2,5-DiF-phenyl
5-Cl-2-thienyl
1-N-Methyl-4-pyrazyl
4-Isoquinolinyl
5-Quinolinyl
Isobutyl
Phenyl
4-F-phenyl
3-F-phenyl
3-Cl-phenyl
3,4-DiF-phenyl
2,5-DiF-phenyl
5-Cl-2-thienyl
1-N-Methyl-4-pyrazyl
4-Isoquinolinyl
5-Quinolinyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
0.3
200
42
9
8
28
8
24
19
21
7
44
49
7
36
6
7
436
278
249
356
178
373
208
455
616
103
232
74
279
159
368
234
313
183
190
321
74
1453
1
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
40
22
14
26
19
32
5
33
2
6
23
10
33
45
26
16
17
8
7
12
19
9
Phenyl
Phenyl
8
102
13
a
Ki values are means of three independent binding experiments (SEM ≤ 19%). b Data taken from ref. 21.
appears that monohalogenation was sufficient for obtaining
higher affinity for the 5-HT7Rs and selectivity over the
5-HT1ARs.
The SAR involving the type of arylsulfonyl moiety was fur-
ther explored by introducing five-membered heterocycles
(high scoring building blocks in the VCL–VS method with the
5-HT7R homology model) and azinyl fragments.21 Although
this modification varied the affinity for the 5-HT7Rs, no
significant improvement in selectivity over the 5-HT1ARs was
obtained.
Further evaluation of the compounds with the highest
affinity for the 5-HT7 receptors and selectivity over the
5-HT1ARs in extended biological assays confirmed their
moderate-to-low affinity for the 5-HT6, dopamine D2 and
adrenergic α1 receptors (Table 2).24
Having identified 7, 10, 13, 15, 17, 22 and 23 as potent
5-HT7R antagonists in the cAMP assay (Table 2),25 they were
further evaluated in vivo in the mouse FST and FPT to
study their potential antidepressant and anxiolytic activity;
Table 2 The binding data of selected compounds for 5-HT1A, 5-HT6,
5-HT7, D2 and α1 Rs and their functional 5-HT7R antagonist properties
Ki [nM]a
Antag
Ki [nM]a
Compd
5-HT7
5-HT1A
5-HT6
D2
51
102
147
140
104
85
α1
629
979
589
389
712
7 (PZ-766)
0.3
9
8
19
7
6
12nMb
26 nM
84%c
436
356
208
616
232
234
313
240
471
324
641
233
276
199
10
13
15
17
22
23
85%c
96%c
95%c
2019
2541
7
4.6 nMc
63
a
Ki values are means of three independent binding experiments
b
Fig. 2 The binding mode of the structural analogs with different
substituents at the sulfonamide fragments (PZ-766 is green, and
compounds 8 and 9 are in cyan and yellow, respectively).
(SEM ≤ 19%). Kb = 1 nM for 7 in assay performed at Eurofins
c
Cerep. Kb value or
% inhibition of control agonist response
(serotonin 300 nM) at 10−6 M; performed at Eurofins Cerep.
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SB-269970, the selective 5-HT7R antagonist, was used as a
reference.26
Compounds 7 (5 mg kg−1), 10 (2.5 mg kg−1), 15 (20 mg
kg−1), 17 (1.25 and 2.5 mg kg−1), 22 (5 and 10 mg kg−1) and
23 (20 mg kg−1) significantly reduced the immobility time of
mice in the range of 18–33% in FST (Fig. 3). Compound 13
administered at a dose of 10 mg kg−1 showed a tendency to
decrease the immobility time of the animals, but the results
did not reach
a significant level. The potency of the
antidepressant-like activity of compounds 10 and 23 was sim-
ilar to that of the selective 5-HT7 receptor antagonist SB-
269970, which exerted its characteristic antidepressant effect
at one medium dose (10 mg kg−1), decreasing mouse immo-
bility time by 33%. It is worth noting that the active dose of
compound 10 is four times lower than the active dose of the
reference compound. Moreover, the results obtained demon-
strate that the majority of the investigated compounds as well
as SB-269970 showed U-shaped dose–response curves (Fig. 3).
The reason for such activity is difficult to explain, but it usu-
ally occurs with ligands interacting with just one 5-HT recep-
tor subtype.27–29
Depression and anxiety are the most common severe men-
tal diseases affecting a huge percentage of the population.30
In many cases, depressive and anxiety disorders are concomi-
tant, which is associated with greater severity of symptoms,
slower or even reduced response for treatment.31 For this rea-
son, two compounds (7 and 10), which showed the strongest
antidepressant effect in the Porsolt's test, were investigated
in the FPT (Fig. 4). Only compound 10 displayed anxiolytic-
like properties (1.25 mg kg−1) increasing the number of
punished crossings by 75%. This effect was similar to that
produced by SB-269970 (1 mg kg−1). Active doses of the inves-
tigated compounds and SB-269970 had no influence on
spontaneous locomotor activity measured during the time
equal to the observation period in FST and FPT (i.e., from
2 to 6 min and 1 min 15 s, respectively) (data not shown),
Fig. 4 Effects of the active compounds 7, 10 and SB-269970 on the
number of punished crossing in mice in the four-plate test. The data
are presented as the mean standard error of the mean of N = 8–10
animals per group. *p < 0.05, **p < 0.01, compared with the respec-
tive vehicle group, followed by the Bonferroni's comparison test after a
significant analysis of variance. ^Data taken from ref. 29.
thus the antidepressant and/or anxiolytic effects of those
compounds appeared to be specific.
Because 5-HT7Rs modulate cognitive processes involved in
consolidation performance in object recognition, they were
also regarded as promising targets for the treatment of
Fig. 3 Effects of the active compounds 7, 10, 13, 15, 17, 22, 23, and SB-269970 on the immobility time of mice in the forced swim test. The data
are presented as the mean standard error of the mean of N = 7–12 animals per group. *p < 0.05, **p < 0.01 vs. control group.
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Fig. 5 Effects of the active compounds 7, 10, 17, 22 and SB-269970 in the novel-object recognition test in rats. The data are presented as
the mean standard error of the mean of N = 7–12 animals per group. *p < 0.05 vs. vehicle, ***p < 0.001 vs. vehicle, ##p < 0.01 vs. PCP,
###p < 0.001 vs. PCP.
memory dysfunction – episode-related and age-related defi-
cits.32,33 This appears to be highly important because depres-
sive disorders are often accompanied by cognitive decline.
Thus pro-cognitive properties may have some benefit in
regard to the treatment of depression.
The efficacy of SB-269970 was recently demonstrated in
the phencyclidine (PCP) and ketamine-induced NOR task in
rats.34,35 Consistent with these reports, and similar to SB-
269970, acute administration of 7, 10, 17, and 22 dose-
dependently ameliorated PCP-induced memory deficits in
rats (Fig. 5). All the tested compounds reversed episodic
memory decline at a dose of 1 mg kg−1 (i.p.).
like activity in the four-plate test in mice (1.25 mg kg−1) than
compound 7. Additionally these effects were similar to that
produced by active control SB-269970. Moreover, all the
selected compounds displayed pro-cognitive effect in the
novel object recognition task in rats (1 mg kg−1). Future
reports on this new class of 5-HT7R antagonists, which may
have advantages over available therapeutics, will focus on
their characterization in a variety of preclinical models of
depression and related mood disorders as well as learning
and memory disorders.
Funding sources
Finally, compound 7 from the previous study and newly
identified compound 10 with improved pharmacological
activities were also evaluated for their affinity for off-targets,
i.e. β1, H1 and M1Rs. These targets, followed with the adren-
ergic α1 receptors (Table 2), are considered as sources of
potential cardiovascular or CNS side effects.36 The com-
pounds did not bind to the β1 and M1 receptors (<10% at a
concentration 1 μM), and display weak activity for the H1
sites (<74% at a concentration of 1 μM). This may contribute
to low propensity of the evaluated compounds to produce
sedation. Moreover, the low affinity for the α1 receptors
seems important as blockade of adrenergic receptors may
decrease effectiveness of antidepressant drugs.
This study was supported by the National Science Center
Grant no. DEC-2012/05/B/NZ7/03076 and by the project
“ProKog,” UDAPOIG.01.03.01-12-063/09-00, co-financed by the
European Union from the European Fund of Regional Devel-
opment (EFRD).
Acknowledgements
The authors wish to thank Mr. A. Miodoński for his technical
assistance.
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