Synthesis and antidepressant-like activity of novel alkoxy-piperidine derivatives targeting SSRI/5-HT1A/5-HT7

Article abstract of DOI:10.1016/j.bmcl.2019.126769

A series of novel alkoxy-piperidine derivatives were synthesized and evaluated for their serotonin reuptake inhibitory and binding affinities for 5-HT_1A/5-HT₇ receptors. In vivo antidepressant activities of the selective compounds were explored using the forced swimming test (FST) and tail suspension test (TST) in mice. The results showed that compounds 7a (reuptake inhibition (RUI), IC₅₀ = 177 nM; 5-HT_1A, K_i = 12 nM; 5-HT₇, K_i = 25 nM) and 15g (RUI, IC₅₀ = 85 nM; 5-HT_1A, K_i = 17 nM; 5-HT₇, K_i = 35 nM) were potential antidepressant agents in animal behavioral models with high 5-HT_1A/5-HT₇ receptor affinities and moderate serotonin reuptake inhibition, and good metabolic stability in vitro.

Full text of DOI:10.1016/j.bmcl.2019.126769

Journal Pre-proofs
Synthesis and antidepressant-like activity of novel alkoxy-piperidine derivatives
targeting SSRI/5-HT1A/5-HT7
Wen-Tao Wang, Hao Qian, Jian-Wei Wu, Xiao-Wen Chen, Jian-Qi Li
PII:
S0960-894X(19)30734-6
DOI:
https://doi.org/10.1016/j.bmcl.2019.126769
BMCL 126769
Reference:
Bioorganic & Medicinal Chemistry Letters
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Accepted Date:
8 September 2019
8 October 2019
16 October 2019
Please cite this article as: Wang, W-T., Qian, H., Wu, J-W., Chen, X-W., Li, J-Q., Synthesis and antidepressant-
like activity of novel alkoxy-piperidine derivatives targeting SSRI/5-HT1A/5-HT7, Bioorganic & Medicinal
Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.126769
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Synthesis and antidepressant-like activity of
novel alkoxy-piperidine derivatives targeting
SSRI/5-HT1A/5-HT7
Wen-Tao Wang a, b, Hao Qian a, Jian-Wei Wu a, Xiao-Wen Chen a, Jian-Qi Li a, *
a Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry,
285 Gebaini Road, Shanghai 201203, P.R. China
b
School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing
211198, P.R. China
*Corresponding author: Tel.: +86-021-20572128. E-mail: lijianqb@126.com; wentaowang95@163.com
Abstract
A series of novel alkoxy-piperidine derivatives were synthesized and evaluated for
their serotonin reuptake inhibitory and binding affinities for 5-HT1A/5-HT7 receptors.
In vivo antidepressant activities of the selective compounds were explored using the
forced swimming test (FST) and tail suspension test (TST) in mice. The results
showed that compounds 7a (reuptake inhibition (RUI), IC50 = 177 nM; 5-HT1A, Ki =
12 nM; 5-HT7, Ki = 25 nM) and 15g (RUI, IC50 = 85 nM; 5-HT1A, Ki = 17 nM; 5-HT7,
Ki = 35 nM) were potential antidepressant agents in animal behavioral models with
high 5-HT1A/5-HT7 receptor affinities and moderate serotonin reuptake inhibition, and
good metabolic stability in vitro.
Keywords
Antidepressant, alkoxy-piperidine derivatives, serotonin reuptake inhibition, 5-HT1A
receptor, 5-HT7 receptor
1

Depression is a chronic and progressive mental disorder with heterogeneous
etiology and symptoms and one of the major risk factors for suicide.1 It is estimated
that depression will become the second-largest global health burden and the main
cause of disability among all diseases by 2030.2,3 Although the treatment of
depression has been advanced by traditional antidepressants, these drugs still highly
unmet the clinical demands with limited efficacy including a long onset of action,
moderate patient response, and numerous adverse effects such as weight gain,
insomnia and sexual dysfunction.4-7
It was suggested that one of the most valuable approaches to enhance the
therapeutic efficacy of antidepressants was a combination of SSRIs (selective
serotonin reuptake inhibitors) with multiple actions on various 5-HT receptor
subtypes.8,9 SSRIs are believed to act by inhibiting serotonin reuptake into the
presynaptic nerve terminals, thereby enhancing the synaptic concentration of
serotonin (5-HT) and promoting neurotransmission. The effect of increasing
neurotransmission and elevating 5-HT synaptic levels relieved depressive
symptoms.10 Furthermore, the agonism of 5-HT1A receptor has been shown to
accelerate or enhance the clinical efficacy of antidepressants represented by
vilazodone.11 The agonistic action of the post-synaptic 5-HT1A receptor also enhances
serotonergic neurotransmission, which facilitates the rapid onset of
antidepressants.12,13 Moreover, the 5-HT7 receptor might be a significant target for the
treatment of depression.14 The blockade of 5-HT7 receptor has been shown to be
effective in the mouse forced swimming test, which has great predictive value for
antidepressant-like activity.15 The combined administration of an SSRI and 5-HT7
receptor antagonist (SB-269970) also represents antidepressant-like responses in
animal behavioral models.16 The recently approved antidepressant vortioxetine
exhibits potent serotonin reuptake inhibition and high 5-HT1A/5-HT7 receptor
affinities associated with long-term safety and tolerability.17,18 Therefore, compounds
targeting on SSRI/5-HT1A/5-HT7 may act as novel potential antidepressants.
2

Results from earlier studies by Serafinowska et al. demonstrated that the central
piperazine segment in derivative Ⅰ could be replaced by the 2-ethoxypiperdine linker
in derivative Ⅱ to maintain or enhance serotonin transporter (SERT) blockade and
high affinity for 5-HT1A receptor.19 Zajde et al. disclosed that arylsulfonamide
derivatives of aryloxyethyl-piperidine Ⅲ bearing 2-ethoxypiperdine linker exhibited
high affinity and moderate to good selectivity for the 5-HT7 receptor (Chart.1).20 In
our previous studies on SSRI/5-HT1A/5-HT7, we reported a series of arylalkanol and
aralkyl piperazine compounds (Chart.1, compound Ⅳ) with strong serotonin reuptake
inhibition and nanomolar 5-HT1A/5-HT7 receptor affinities.21 Since then we have been
extending our research to alternatives by using the alkoxyl-piperdine segments as
linker replacement (Chart.2).
H
O
N
O
N
N
H
N
N
O
N
O
N
O
I
II
Ki(SERT) = 6.3 nM
Ki(SERT) = 6.3 nM
Ki(5-HT1A) = 0.6 nM
Ki(5-HT1A) = 0.3 nM
F
O
N
N
O
S
O
N
F
N
H
N
H
F
III
IV
Ki(5-HT1A) = 62 nM
Ki(5-HT7) = 12 nM
IC50(RUI) = 31 nM
Ki(5-HT1A) = 436 nM
Ki(5-HT7) = 0.3 nM
Chart 1. Structures of SSRI/5-HT1A agents and 5-HT1A/5-HT7 agent
Herein we reported the synthesis and pharmaceutical evaluation of a series of
alkoxy-piperidine derivatives (Chart.2). Compounds were evaluated for binding
affinities for 5-HT1A/5-HT7 receptors and serotonin reuptake inhibition in vitro. The
selected compounds were tested for microsomal stabilities in vitro and
antidepressant-like activities in vivo. Preliminary results indicated that the target
compounds exhibited high affinities for 5-HT1A/5-HT7 receptors coupled with
moderate serotonin reuptake inhibition and marked antidepressant-like effect in vivo.
3

F
F
N
O
N
m
N
F
n
F
2
N
N
Ar
3
H
H
V
IV
Chart 2. The design of alkoxy-piperidine derivatives
The synthetic routes of all target compounds were outlined in Scheme 1-5. In
Scheme 1, a series of 3-(piperidin-4-yl)-1H-indole derivatives 7 were prepared.
Intermediate 3 was obtained by addition of 5-fluoro-1H-indole 1 to tert-butyl
4-oxopiperidine-1-carboxylate 2 under basic conditions. Then 3 was hydrogenated to
provide intermediate 4. The deprotection of the Boc group of intermediate 4 with 4N
HCl/MeOH solution gave intermediate 5. Then
5
was treated with
([1,1'-biphenyl]-2-yloxy)alkyl 4-methylbenzenesulfonate 6 via SN2 mechanism to
yield target compounds 7a-b.
Shown
in
Scheme
2
was
the
preparation
of
the
3-(piperidin-4-ylmethyl)-1H-indole derivatives 12a-b. Reaction of 5-fluoro-1H-indole
1 with 4-pyridinecarboxaldehyde 8 afforded intermediate 9. Then 9 was reduced
under triethylsilane and trifluoroacetic acid conditions to yield intermediate 10. The
target compounds 12a-b were prepared by the followed hydrogenation and
substitution steps.
The synthesis of compounds 15a-g was carried out by a procedure according to
Scheme 3. Substitution of 5-fluoro-3-(piperidin-4-yl)-1H-indole
5
with
2-bromo-1-(2-bromoethoxy)-4-fluorobenzene 13 provided intermediate 14. Suzuki
cross-coupling reaction of 14 with arylboronic acid obtained the target compounds
15a-g.
Scheme 4 showed the preparation of compound 19. Intermediate 17 was obtained
by reaction of 5-fluoro-1H-indole 1 with 4-vinylpyridine 16 under refluxing acetic
acid conditions. Then hydrogenation of 17 using platinum oxide as a catalyst provided
4

intermediate 18. The target compound 19 was obtained by substitution via SN2
mechanism. Alternatively, the substitution of intermediate 5 with 20 provided the
target compound 21 (Scheme 5).
Boc
Boc
N
Boc
N
N
H
N
O
F
2
b
c
F
N
F
F
a
H
N
N
N
H
H
H
1
3
4
5
TsO
O
n
F
F
F
O
6
n
N
d
HN
7a-b
7a.
7b.
n=0, R=H
n=1, R=H
Scheme 1. Reagents and conditions: (a) KOH, CH3OH, 70 °C; (b)10% Pd/C, H2, MeOH/THF
(1:1), r.t.; (c) 4N HCl/MeOH, MeOH, r.t.; (d) K2CO3, KI, CH3CN, 80 °C.
CHO
HO
N
N
NH
N
8
F
b
c
F
F
F
a
N
H
N
N
H
N
H
H
1
9
10
11
TsO
O
n
F
F
O
6
N
F
n
N
d
H
12a-b
12a.
12b.
n=0
n=1
Scheme 2. Reagents and conditions: (a) 50% NaOH, CH3OH, 0 °C→r.t.; (b) HSiEt3, TFA, DCM,
r.t.; (c) PtO2, H2, AcOH, r.t.; (d) K2CO3, CH3CN, 80 °C.
5

O
F
H
F
Br
N
Br
F
N
N
R-B(OH)2
b
O
13
O
F
HN
HN
a
Br
N
F
H
F
R
5
14
15a-g
15a.
15b
.R=4-F
R=4-Cl
15c.
15e.
15g.
15d.
15f.
R=4-CH3
R=4-OCH3
R=3-F
R=4-CN
R=2-F
Scheme 3. Reagents and conditions: (a) K2CO3, KI, CH3CN, 80 °C; (b) Pd(dppf)Cl2, Na2CO3,
Dioxane/H2O (3:1), 80 °C.
H
O
N
N
TsO
F
N
16
F
F
b
6a
F
N
a
c
H
N
N
H
H
1
17
18
O
F
N
F
N
H
19
Scheme 4. Reagents and conditions: (a) AcOH, 120 °C; (b) PtO2, H2, AcOH, r.t.; (c) K2CO3,
CH3CN, 80 °C.
O
TsO
F
F
H
N
N
O
20
HN
F
a
F
N
H
5
21
Scheme 5. Reagents and conditions: (a) K2CO3, CH3CN, 80 °C.
All synthesized compounds were tested for their inhibition of serotonin reuptake
6

and binding affinities for 5-HT1A/5-HT7 receptors. The binding affinity for 5-HT1A
receptor was determined by investigating the displacement of [3H]-8-OH-DPAT to
HEK-293 cell membrane homogenates22, and the affinity for the 5-HT7 receptor was
determined by displacement binding to CHO cell membrane homogenates using
[3H]-LSD to previous procedures reported.23 The inhibition of [3H]-5-HT
incorporation into rat brain synaptosomes through the serotonin uptake transporter
was also evaluated24. All compounds were initially screened at 1μM concentration,
and potent compounds, which inhibition of serotonin reuptake and binding affinities
at 5-HT1A/5-HT7 receptors all over 90%, were then assayed to obtain their IC50 and Ki
values. The results were summarized in Table 1-2. The metabolic stability of the test
compounds was measured in vitro using liver microsomes, a system widely used to
evaluate the susceptibility to first-pass oxidative metabolism (Table 3)25.
Firstly, we investigated the effects of linker lengths on serotonin reuptake
inhibitory and binding affinities for 5-HT1A/5-HT7 receptors. The length of the chain
linking the indole ring to the piperidine was first explored.
5-fluoro-3-(piperidin-4-yl)-1H-indole analog 7a displayed more than 90% inhibition
for serotonin reuptake and 5-HT1A/5-HT7 receptor at a concentration of 1μM, whereas
12a and 19 exhibited selective inhibition for serotonin reuptake and 5-HT7 receptor
(inhibition ratio > 90%). The result indicated that the indole ring directly linking to
piperidine ring was beneficial to increase the affinity for 5-HT1A receptor. The
influence of the chain linking the of piperidine ring to the 2-alkoxy-1,1'-biphenyl
moiety was also explored. The three-carbon chain analog compound 7b displayed
selective inhibition for the 5-HT1A receptor (7b vs 7a). Similarly, compound 12b
exhibited potential high inhibition for 5-HT7 receptor (inhibition ratio > 85%) merely
(12b vs 12a). These results suggested that the length of the linker had a great
influence on the affinities for 5-HT1A/5-HT7 receptors.
Next, we focused on the substitution position of the phenyl group at the
4-fluorophenoxyl fragment. Interestingly, compound 21 showed over 90% inhibition
for 5-HT1A receptor and potential moderate serotonin reuptake and 5-HT7 receptor
7

inhibition (Inhibition ratio > 50%) after moving the phenyl group with one position,
whereas 2-ethoxy-5-fluoro-1,1'-biphenyl derivative 7a exhibited moderate inhibition
for serotonin reuptake (IC50 = 177 nM) and high affinities for the 5-HT1A/5-HT7
receptors (5-HT1A, Ki = 12 nM; 5-HT7, Ki = 25 nM) as shown in Table 1 and Table 2.
Finally, the effect of different aromatic ring substituents at the C2 position was
explored. We first introduced various R substitutes into the para-position of the
phenyl group in 15. Compounds 15a, 15c-15e all showed selective inhibition for
5-HT1A receptors (inhibition ratio > 90%) but expressed less than 90% inhibition for
dual serotonin reuptake and 5-HT7 receptor at a concentration of 1μM. Interestingly,
the 4-fluorophenyl derivative 15b exhibited high inhibition for dual serotonin
reuptake and 5-HT1A receptor and potential high inhibition for 5-HT7 receptor
(inhibition ratio > 85%). These results indicated that the introduction of fluorophenyl
group substituent led to maintain or enhance the multiple actions on
SSRI/5-HT1A/5-HT7 possibly. Then we introduced a fluorophenyl into the ortho-,
meta-position of the phenyl group subsequently. The 2-fluorophenyl derivative 15f
also showed high inhibition for dual serotonin reuptake and 5-HT1A receptor and
potential high inhibition for 5-HT7 receptor (inhibition ratio > 85%). Especially, the
3-fluorophenyl derivative 15g displayed excellent inhibition for the 5-HT1A/5-HT7
receptors (5-HT1A, Ki = 17 nM; 5-HT7, Ki = 35 nM) and exhibited higher inhibition
for serotonin reuptake inhibitory (RUI, IC50 = 85 nM).
With the above information in hand, compounds 7a and 15g were selected for
metabolic stability evaluation in vitro. The results indicated that the two compounds
displayed a suitable half-life (t1/2 values were 34.5 min and 22.9 min, respectively),
which was better than vortioxetine in rat liver microsomal stability assay (t1/2 value
was 9.0 min). Additionally, 7a and 15g were also tested for human liver metabolic
stability and showed acceptable profiles (t1/2 values were 61.5 min and 61.4 min,
respectively) (Table 3).
On the basis of in vitro studies, compounds 7a and 15g were further
characterized in the mouse forced swimming test (FST)26. 7a and 15g were tested at
8

the dose range of 10, 20 and 40 mg/kg/day (PO) by repeated administration in male
mice for 7 days, respectively. As shown in Fig.1-2, 7a and 15g both produced a
reduction effect at different doses in the FST and values were statistically significant
at 40 mg/kg (PO). The effect of positive control, vortioxetine, was also statistically
significant at 40 mg/kg (PO).
Compounds 7a and 15g were also selected for further evaluation in the mouse
tail suspension test (TST)27. The results are shown in Fig.3-4. The compounds were
dosed at 10, 20 and 40 mg/kg/day (PO) by repeated administration in male mice for 7
days. 7a and 15g both produced a reduction effect at different doses in the TST.
Especially, compared with vehicle, 7a reduced immobility time in the TST
statistically significant at 40 mg/kg (PO).
In summary, a series of novel alkoxy-piperidine derivatives were synthesized as
our continuing effort to identify potential antidepressant agents targeting
SSRI/5-HT1A/5-HT7. The in vitro studies revealed that the length of linker had an
important effect on the affinities for 5-HT1A/5-HT7 receptors. Several compounds
displayed outstanding binding affinities for 5-HT1A/5-HT7 receptors and strong
inhibition of serotonin reuptake. Notably, compounds 7a and 15g exhibited marked
antidepressant-like activity in animal behavioral models. Further studies are ongoing
to fully appreciate the therapeutic potential of novel alkoxy-piperidine as potent
multi-model antidepressant agents.
Table 1
5-HT1A and 5-HT7 Receptor Binding and 5-HT Reuptake Inhibition of target compounds.a
Compd.
RUI (Inhibition ratio)
5-HT1A (Inhibition
ratio)
5-HT7 (Inhibition
ratio)
7a
96.3%
87.0%
100.9%
101.5%
27.3%
90.6%
38.9%
63.0%
12.3%
94.2%
90.4%
7b
97.7%
76.1%
12a
12b
15a
15b
15c
15d
15e
72.3%
97.2%
81.9%
86.4%
95.0%
80.3%
97.4%
86.5%
94.5%
86.2%
97.5%
95.8%
98.7%
95.9%
9

15f
97.1%
94.3%
99.8%
66.6%
101.1%
97.8%
95.9%
54.3%
96.9%
95.1%
88.7%
91.0%
94.3%
54.2%
92.5%
15g
19
21
Vortioxetine
a Percent inhibition measured at a concentration of 1μM.
Table 2
5-HT1A and 5-HT7 Receptor Binding and 5-HT Reuptake Inhibition of selected compounds.a
Compd.
7a
RUI (IC50, nM)
5-HT1A (Ki, nM)
5-HT7 (Ki, nM)
177
85
12
17
25
35
26
15g
Vortioxetine
2.9
9.5
a IC50 and Ki values were obtained from 8 concentrations of the compound, each in duplicate.
(Binding assays were conducted by Eurofins Cerep SA, Celle L'Evescault, France).
Table 3
Microsomal Metabolic Stability Assay
Compd.
7a
Species
t1/2 (min)
34.5
22.9
9.0
CL (μL/min/mg)
40.2
15g
60.4
Rat
153.2
Vortioxetine
Omeprazole
7a
8.5
162.6
61.5
61.4
22.5
22.6
6.5
15g
Human
214.3
44.7
Vortioxetine
Dextromethorphan
31.0
10

Fig. 1. Effect of treatment of mice with compound 7a at graded doses on the immobility time in
the forced swim test. Results are represented as mean ± SEM. with n = 10 in each group. Values
are significant at *P < 0.05, **P < 0.01 when compared with vehicle group.
Fig. 2. Effect of treatment of mice with compound 15g at graded doses on the immobility time in
the forced swim test. Results are represented as mean ± SEM. with n = 10 in each group. Values
are significant at *P < 0.05, **P < 0.01 when compared with vehicle group.
Fig. 3. Effect of treatment of mice with compound 7a at graded doses on the immobility time in
the tail suspension test. Results are represented as mean ± SEM. with n = 10 in each group. Values
are significant at *P < 0.05, **P < 0.01 when compared with vehicle group.
11

Fig. 4. Effect of treatment of mice with compound 15g at graded doses on the immobility time in
the tail suspension test. Results are represented as mean ± SEM. with n = 10 in each group. Values
are significant at *P < 0.05, **P < 0.01 when compared with vehicle group.
Acknowledgments
The authors gratefully acknowledge the financial support from the National
Science and Technology Major Project (Grant No. 2018ZX09711002-002-009), the
National Natural Science Foundation of China (Grant No. 81703358), Shanghai
Science and Technology Committee (Grant No. 18QB1404200). We thank Dr.
Zheng-song Gu for helpful discussions and Prof. Feng-hua Gu (Department of
pharmacology, Shanghai Institute of Pharmaceutical Industry, China) for in vivo
studies.
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6. Liu S, Molino BF, Annu Rep Med Chem. 2007; 42: 13-26.
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Synthesis and antidepressant-like activity of
novel alkoxy-piperidine derivatives targeting
SSRI/5-HT1A/5-HT7
13

Wen-Tao Wang a, b, Hao Qian a, Jian-Wei Wu a, Xiao-Wen Chen a, Jian-Qi Li a, *
a Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry,
285 Gebaini Road, Shanghai 201203, P.R. China
b
School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing
211198, P.R. China
*Corresponding author: Tel.: +86-021-20572128. E-mail: lijianqb@126.com; wentaowang95@163.com
Graphical abstract
F
F
N
O
N
m
N
F
n
F
N
N
Ar
H
H
IV
Lead Compound
V
Target Compound
Highlights
 A series of novel alkoxy-piperidine derivatives have been synthesized.
 All compounds were evaluated for SSRI/5-HT1A/5-HT7 activities in vitro.
 The potent compounds were screened using the forced swimming test and the tail
suspension test in vivo.
 Compounds 7a and 15g were potential antidepressant agents in animal behavioral
models, and good metabolic stability in vitro.
14