Synthesis and Biological Evaluation of Five-Atom-Linker-Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile

Article abstract of DOI:10.1002/cmdc.201900439

Herein we describe a focused set of new arylpiperazine derivatives as potential broad-spectrum antipsychotics. The general structure contains a quinolinone-like moiety, an arylpiperazine moiety, and a five-atom linker. Among them, 7-(5-(4-(benzo[d]isothiazol-4-yl)piperazin-1-yl)pentyl)quinolin-2(1H)-one (S6) shows a promising preclinical profile. Compound S6, characterized by partial D₂R agonism, 5-HT_1AR agonism, 5-HT_2AR antagonism, and blockade of SERT activities, was found to decrease psychosis- and depressive-like symptoms in rodents. The polypharmacological profile of S6 could provide opportunities for the treatment of various other central nervous system disorders such as anxiety, depression, and psychoses associated with dementia. Furthermore, S6 demonstrated acceptable safety, toxicology, and pharmacokinetic profiles, and has been selected as a preclinical candidate for further evaluation in schizophrenia.

Full text of DOI:10.1002/cmdc.201900439

Full Papers
DOI: 10.1002/cmdc.201900439
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Synthesis and Biological Evaluation of Five-Atom-Linker-
Based Arylpiperazine Derivatives with an Atypical
Antipsychotic Profile
Chunhui Wu,[a, c] Yu Wang,[a, b] Feipu Yang,[b] Wenqiang Shi,[b] Zhen Wang,[b] Ling He,*[a]
Yang He,*[b] and Jingshan Shen[b]
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Herein we describe a focused set of new arylpiperazine
derivatives as potential broad-spectrum antipsychotics. The
to decrease psychosis- and depressive-like symptoms in
rodents. The polypharmacological profile of S6 could provide
opportunities for the treatment of various other central nervous
system disorders such as anxiety, depression, and psychoses
associated with dementia. Furthermore, S6 demonstrated
acceptable safety, toxicology, and pharmacokinetic profiles, and
has been selected as a preclinical candidate for further
evaluation in schizophrenia.
general structure contains
a quinolinone-like moiety, an
arylpiperazine moiety, and a five-atom linker. Among them, 7-
(5-(4-(benzo[d]isothiazol-4-yl)piperazin-1-yl)pentyl)quinolin-
2(1H)-one (S6) shows a promising preclinical profile. Compound
S6, characterized by partial D2R agonism, 5-HT1AR agonism, 5-
HT2AR antagonism, and blockade of SERT activities, was found
Introduction
neously modulates several specific targets to get better safety
and efficacy for the treatment of schizophrenia.[6–8] From the
target‘s perspective, treatment with D2 receptor partial agonists
represented by Aripiprazole and Brexpiprazole is regarded as
the best approach to modulate dopaminergic function because
of their excellent effectiveness and tolerability.[9–11] Besides
dopamine D2 receptors, various serotonin receptors are also
important targets for schizophrenia. A wealth of preclinical and
clinical evidence strongly supports the relevance of 5-HT1A
receptor activation and 5-HT2A receptor inhibition for the
Schizophrenia is a complex psychological disorder of unclear
etiology characterized by the coexistence of positive, negative
and cognitive symptoms.[1,2] Although the emergence of
antipsychotics brought enormous progress to the treatment of
schizophrenia, there are still huge unmet clinical needs that
exist owing to its complicated pathophysiology.[3,4]
In the field of drug discovery, the “one-target, one-drug”
paradigm has been the mainstream over the past years.
However, this strategy seems to be unsuitable for complex
psychiatric diseases such as schizophrenia. In clinical practice,
atypical antipsychotics are often used together with antidepres-
sants for schizophrenia to get maximum efficacy.[5] Patients
often take several single drugs with different bioavailability,
pharmacokinetics, and metabolism profiles. This therapeutic
regimen often leads to drug-drug interactions, particularly in
patients with psychiatric comorbidity. Literature data suggest
that the above drawbacks could be avoided by designing a
molecule with a “selective” multireceptor profile which simulta-
treatment of schizophrenia.[12–14] Furthermore, designing
a
molecule with serotonin (5-HT) transporter (SERT) inhibition
function is beneficial to the treatment of schizophrenia and
both the efficacy and safety of selective serotonin reuptake
inhibitors (SSRIs) as augmentation therapy for schizophrenia
have been proven clinically.[15] Although the antipsychotic drug
ziprasidone, introduced in 2000, possessed 5-HT2AR antagonism,
5-HT1AR agonism, and SERT blockade activities, however, it is a
full antagonist for D2R. Thus, our work aimed to search for
versatile molecules that combine D2 receptor partial agonism
and serotonin reuptake inhibition with functional action on
various 5-HT receptors, especially 5-HT1A receptors. We expected
that compounds with such a multifunctional profile would be
more effective and better tolerated than currently-used anti-
psychotics.
In this paper, we described a series of five-atom-linker-
based multireceptor acting compounds that possess antipsy-
chotic-like activity. The design concept of new compounds was
shown in Figure 1. The general structure contains a quinoli-
none-like moiety, an arylpiperazine moiety, and a five-atom
linker. We select the dihydroquinolinone fragment of Aripipra-
zole and Brexpiprazole or its bioisostere on the basis of their
weak to moderate serotonin reuptake inhibition activities.[16,17]
The choice of arylpiperazines originates from potent fragments
reported by literature as well as our own experience.[18,19] As our
[a] Dr. C. Wu, Dr. Y. Wang, Prof. L. He
Department of Pharmacology
China Pharmaceutical University
Nanjing 210009 (China)
E-mail :
E-mail: heling92@hotmail.com
[b] Dr. Y. Wang, Dr. F. Yang, Dr. W. Shi, Prof. Z. Wang, Dr. Y. He, Prof. J. Shen
CAS Key Laboratory of Receptor Research
Drug Discovery and Design Center
Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS)
Shanghai 201203 (China)
E-mail: heyang@simm.ac.cn
[c] Dr. C. Wu
Department of Druggability Evaluation
Topharman Shanghai Co. Ltd.
Shanghai 201203 (China)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cmdc.201900439
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Results and Discussion
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Synthesis of these new arylpiperazine derivatives was per-
formed as exemplified in Schemes 1–3. Pentyl methanesulfo-
nates substituted with quinolinone-like moieties were coupled
with various arylpiperazine moieties to produce S1–S13. Target
compounds S14–S16 were synthesized via N-alkylation of the
appropriate chloride intermediates with corresponding arylpi-
perazine moieties as outlined in Scheme 2. Treatment of S14–
S16 with a 4% H2SO4 solution in the presence of HgSO4 to
affect the hydration of the alkyne functionality to afford aryl
ketone derivatives S17–S19. The reduction of the carbonyl
groups of S17 and S18 with NaBH4 in the DCM/MeOH system
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gave alcohol derivatives S20 and S21 respectively in
a
Figure 1. Design of new five-atom-linker-based arylpiperazine derivatives.
quantitative yield. Alcohol S21 was dehydrated under acidic
conditions to give compound S22. The synthesis of benzyl ether
derivatives S23–S24 was shown in Scheme 3. Firstly, intermedi-
ate mesylates S23b–S24b was obtained through initial alkyla-
tion of corresponding arylpiperazine moieties with 3-bromo-1-
propanol to alcohols S23a–S24a followed by reaction with
methanesulfonyl chloride. Then S23b–S24b were condensed
with 7-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one in the
presence of NaH to give S23–S24.
Taking Aripiprazole and Brexpiprazole as lead compounds,
our work started from the synthesis of S1–S13. As shown in
Table 1, compound S1 behaved like a low potency ligand for all
three receptors, especially for 5-HT1AR and 5-HT2AR. Compounds
S2 and S3 owning a 1-(benzo[d]isothiazole-3-yl)piperazine frag-
ment exhibited good activities for all the three receptors. In
light of the crucial role of 5-HT2AR in the action of antipsychotics
such as the alleviation of the negative symptoms of
schizophrenia,[20] we emphasized the antipsychotic potential
displayed by compound S3 with high potency at the 5-HT2AR
(IC50 =61.2 nM), greater than that displayed for reference drug
Brexpiprazole. Compounds S4 and S5 possessing a 1-(benzo[b]
thiophen-4-yl)piperazine fragment displayed similar strong
activities for all the three receptors, which is consistent with S2
and S3. This result points out that changing the 3,4-dihydroqui-
nolin-2(1H)-one moiety with quinolin-2(1H)-one moiety made
little difference in receptor function profiles. Furthermore, the
3-(piperazin-1-yl)benzo[d]isothiazole moiety seemed to be
superior to the 1-(benzo[b]thiophen-4-yl)piperazine moiety in
terms of 5-HT2AR potency (S2 vs S4, S3 vs S5). Replacement of
the 1-(benzo[b]thiophen-4-yl)piperazine moiety of S5 with its
bioisostere 1-(benzo[d]isothiazole-4-yl)piperazine had almost no
previous SAR studies on antipsychotic drugs indicated that an
appropriate linker is of great importance for desired multi-
receptor activity, we also explored the influence of linker
flexibility of the new derivatives on receptor function profiles.[18]
Among the derivatives prepared, compound S6 manifested a
unique polypharmacological antipsychotic profile. It displayed
much higher potency for the desired targets (D2, 5-HT1A, 5-HT2A,
and SERT) than other off-target receptors (α1A, H1, 5-HT2C, M3,
hERG). Thus, compound S6 was developed as an atypical
antipsychotic candidate to treat schizophrenia based on the
D2R, 5-HT1AR, 5-HT2AR and SERT multi-target profile.
Scheme 1. Reagents and conditions: (i) K2CO3, CH3CN, reflux, 7 h.
Scheme 2. Reagents and conditions: (i) NaI, K2CO3, CH3CN, reflux, 24 h; (ii)
°
S14 to S17 or S15 to S18 or S16 to S19, 4% H2SO4, HgSO4, MeOH, 50 C,
Scheme 3. Reagents and conditions: (i) K2CO3, 3-bromo-1-propanol, CH3CN,
reflux, 5 h; (ii) MsCl, Et3N, DCM, rt, 0.5 h; (iii) 7-(hydroxymethyl)-3,4-
dihydroquinolin-2(1H)-one, NaH, THF, reflux, 8 h.
40 h; (iii) S17 to S20 or S18 to S21, NaBH4, DCM/MeOH, rt, 0.5 h; (iv) S21 to
S22, 6 N HCl, MeOH, reflux, 12 h.
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5-HT2AR (S8 and S9 vs S5). In contrast, compound S10 with a
fluorine atom at 6-position of benzothiophene part showed
increased potency for D2R but the effect on 5-HT1AR and 5-
HT2AR was significantly decreased (S10 vs S5). These outcomes
suggested that the substitution of electron-withdrawing groups
on benzothiophene or benzo[d]isothiazole ring was detrimental
for 5-HT2AR potency. Compounds S11 and S12 were bioisosteric
analogs of compound S5 and both of them exhibited lower
activities for D2 and 5-HT1A receptors than S5. Additionally, the
introduction of a methyl group to the quinazolin-4(3H)-one
moiety of compound S11 was harmful to 5-HT2AR potency
whereas beneficial for D2 and 5-HT1AR potency (S12 vs S11).
Compound S13 as a bioisosteric analog of compound S6
displayed comparable potency for D2 receptor while reduced
potency for 5-HT1AR and 5-HT2AR (S13 vs S6). These data
supported the contention that the quinolin-2(1H)-one moiety is
superior to the quinazolin-4(3H)-one moiety.
To examine the effects of the central linker on functional
activities, we also designed the compounds outlined in Table 2,
which contain substituted or conformationally constrained five-
atom linkers. The alkynyl containing compound S14 showed
enhanced activities for D2 and 5-HT2AR compared with S1 while
retained medium activity for 5-HT1AR. In contrast, the alkynyl
containing compound S15 displayed reduced activities for D2
and 5-HT1AR compared with S4 while comparable activity for 5-
HT2AR. With respected to S16, it exhibited reduced activities for
D2, 5-HT1AR, and 5-HT2AR compared with S5. Substituent
modification on the pentyl linker seems to be beneficial for
functional activities at D2R and 5-HT2AR. Replacement of the
Table 1. Functional activities of S1–S13 on main targets.
1
2
3
4
5
6
7
8
9
Compd
S1
Structure
D2R
IC50 [nM]
5-HT1A
EC50 [nM]
R
5-HT2AR
IC50 [nM]
83.0
1260
8070
S2
S3
6.8
12.2
14.6
157
10
11
12
13
14
15
16
17
18
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44
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51
52
53
54
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57
10.1
61.2
S4
S5
10.1
10.2
9.9
9.2
203
209
S6
S7
S8
8.5
9.9
358
36.8
4.8
>10000
21.8
394
1020
S9
22.3
1.5
13.0
2980
974
methylene adjacent to quinolin-2(1H)-one moiety with
a
carbonyl group resulted in improved potency for all three
receptors (S17 vs S1). Similarly, compound S18 as well as S19
retained high potency for D2R, and 5-HT2AR while their effect on
5-HT1AR was slightly reduced (S18 vs S4, S19 vs S5). Introducing
a hydroxy group to the pentyl linker at the carbon atom
adjacent to quinolin-2(1H)-one moiety elicited considerably
enhanced activities for the main targets (S20 vs S1). Notably,
S20 with the privileged structure of Aripiprazole had the
strongest activity for the D2 receptor (IC50 =1.3 nM), even higher
than that of Brexpiprazole. Unlike S20, S21 with a hydroxy
substitution on the pentyl linker is more potent at D2R and 5-
HT2AR but slightly less potent at 5-HT1AR than S4. Interestingly,
the alkenyl-containing compound S22 retained high potency
for D2R but the effect on 5-HT1AR and 5-HT2AR was weakened
(S22 vs S4). The benzyl ethers S23 and S24 manifested
moderate to weak activities for D2R, 5-HT1AR, and 5-HT2AR, which
suggested the significance of the presence of O atom in the
linker in modulating dopaminergic and serotonergic function
(S24 vs S4). Furthermore, compared with the pentyl linker, the
less lipophilic nature of the propyloxymethyl linker will decrease
lipid solubility of compounds (See Supplemental Table S1), thus
reducing the blood–brain barrier penetration of the molecular
which will result in insufficient drug concentration to achieve
efficacy. We can see that unlike 1-(benzo[b]thiophen-4-yl)
piperazine and 1-(benzo[d]isothiazole-3-yl)piperazine moieties,
1-(2,3-dichlorophenyl)piperazine fragment makes compounds
lack appreciable activity for 5-HT2AR (S14, S17, S20), which was
S10
S11
>10000
54.0
324
201
S12
50.7
25.9
781
S13
4.9
4.8
26.5
66.8
630
320
BRE[a]
–
[a] Brexpiprazole.
effect on the D2R and 5-HT1AR activities, however, this could
slightly decrease the 5-HT2AR antagonistic activity (S6 vs S5). It
is worth to note that compounds S2–S6 presented a favorable
balance between functional activities at D2 and 5-HT1A receptors
(0.5<IC50 (D2R):EC50 (5-HT1AR)<2). Introduction of a chlorine
atom at 6-position of benzo[d]isothiazole fragment brought
about remarkably reduced activities for the main targets (S7 vs
S3). Specifically, S7 was completely devoid of agonistic activity
for 5-HT1AR. For the 2-position of benzothiophene part, the
introduction of a fluorine or chlorine atom induced comparable
activities for D2R and 5-HT1AR while sharply reduced potency for
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Table 2. Functional activities of S14–S24 on main targets.
1
2
3
4
5
6
Compd Structure
D2R
5-HT1A
R
5-HT2AR
IC50 [nM] EC50 [nM] IC50 [nM]
7
8
9
S14
S15
S16
30.6
51.9
22.8
1265
22.6
47.6
2214
210
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Figure 2. Summary of the SAR studies on different regions of the five-atom-
linker-based arylpiperazine derivatives.
782
the D2 receptor further. Our design assumptions prompt us to
select compounds with D2 partial activity. For D2R partial
agonists, too high or low D2 intrinsic activity is unsuitable, as
high D2 intrinsic activity will not produce robust antipsychotic
activity while low D2 intrinsic activity will result in elevated
prolactin secretion and risk of EPS.[21] As shown in Table 3,
compounds S2–S4 and S21 were devoid of D2 receptor
agonistic activity, indicating that they were full antagonists at
the D2 receptor. Both S3 and S6 displayed significant partial
agonistic activity at D2 receptor, comparable to that of
Brexpiprazole in terms of Emax value. Furthermore, S6 is a more
potent D2 receptor agonist than S5 and Brexpiprazole in terms
of EC50 value. Compound S6 possesses a relatively low D2
intrinsic activity and high 5-HT1A/2A receptors activity, which will
lead to minimal side effects and produce beneficial antipsy-
chotic effects.[22,23]
SERT is closely involved in psychiatric diseases. We used a
fluorescence-based assay to measure the SERT uptake activity
of S6.[24] As shown in Table 4, compound S6 showed potency
stronger than that of Brexpiprazole while slightly weaker than
that of Citalopram at SERT. This pharmacological characteristic
may contribute to the alleviation of the comorbid depressive
symptoms in schizophrenia.
S17
3.0
380
3840
S18
S19
6.2
3.8
31.1
19.8
285
138
S20
S21
S22
S23
1.3
238
15.7
97.5
121
754
108
502
1390
4.5
9.0
76.7
S24
121
4.8
44.7
66.8
525
320
Table 3. Agonistic activities of selected compounds on D2R.
D2R
BRE[a]
[a] Brexpiprazole.
–
EC50 [nM][a]
E
max [%][b]
Compd
S2
S3
S4
S5
N.A.
N.A.
N.A.
2.0
<20
<20
<20
23
S6
S21
Brexpiprazole
0.3
N.A.
6.3
27
<20
29
consistent with SAR of compounds discussed in our previous
study.[19] These relationships are summarized in Figure 2.
In our examination of novel five-atom-linker-based arylpi-
perazine derivatives as potential antipsychotic agents, we have
attempted to balance the D2R and 5-HT1AR potency ratio on the
hypothesis that the desired ratio might be a key to drug’s
atypical nature. For further characterization, we set two
compounds selection criteria: (a) IC50 (D2R), EC50 (5-HT1AR)
<30 nM, IC50 (5-HT2AR) <500 nM; (b) the potency ratio between
D2R and 5-HT1AR should be no greater than 5. Then compounds
S2–S6 and S21 were chosen to test their intrinsic activities for
[a] N.A.: not active. [b] Expressed as percentage of the effect of 10 μM
dopamine.
Table 4. SERT uptake activity of S6 and reference drugs.
Compd
SERT IC50 [nM]
S6
39.7
176.3
8.3
Brexpiprazole
Citalopram
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The atypical antipsychotics can trigger many adverse events
and several off-target receptors are reported to contribute to
these side effects.[25–27] Therefore, further in vitro pharmacolog-
ical characterization of S6 is essential. Schizophrenia patients
treated with antipsychotic medication often suffer from ortho-
static hypotension, due to the blockade of the α1A-adrenocep-
tor.[28,29] Unlike Risperidone, compounds S6 and Brexpiprazole
showed moderate α1A adrenoreceptor antagonistic activity, this
means that they will not elicit orthostatic hypotension (Table 5).
Antagonism of histamine H1 receptor and serotonin 5-HT2C
receptor has been identified as the main cause of antipsychotic-
induced weight gain.[30–33] Concerning H1R, all tested com-
pounds displayed mild-to-moderate potency. Furthermore,
compound S6 was devoid of 5-HT2C receptor antagonistic
activity. Based on the above results, compound S6 exhibited a
low propensity to cause drug-induced weight gain. Pancreatic
M3 cholinergic receptor is involved in antipsychotics-induced
hyperglycemia and type II diabetes mellitus.[34] Potent M3
receptor antagonists olanzapine and clozapine caused a higher
incidence of diabetes than other antipsychotics in clinical
practice. Like Risperidone and Brexpiprazole, S6 had no
antagonistic activity against the M3 receptor, suggesting it will
not cause hyperglycemia. Moreover, S6, as well as Risperidone
and Brexpiprazole, may have a low ability to cause QT interval
prolongation due to their weak potency on hERG.[35]
The possible drug-induced hepatotoxicity, as well as
nephrotoxicity of compound S6, was examined and the results
were shown in Table 6. S6 exhibited lower cell toxicities against
Chang Liver cells than Risperidone and Brexpiprazole. Besides,
both compound S6 and Risperidone displayed low cell toxicities
against HEK 293 cells (>600 μgmLÀ 1). These results indicated
that compound S6 was almost nontoxic and suitable for further
in vivo exploration.
The hyperactivity induced by NMDA receptor antagonists
such as MK-801, Phencyclidine (PCP) or ketamine is often used
as a rodent model of psychoses.[36] Thus agents normalizing
hyperactivity demonstrate antipsychotic-like properties.[37] In
this model, compound S6 reversed the PCP-induced hyper-
activity dose-dependently (ED50 =3.08 mgkgÀ 1, Figure 3), which
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Figure 3. Effect of all doses of compound S6 (po, 1 mgkgÀ 1, 3 mgkgÀ 1 and
10 mgkgÀ 1) and Aripiprazole (ARI, 3 mgkgÀ 1) on ICR mouse model (PCP-
induced hyperactivity; PCP: 7 mgkgÀ 1, ip). Data are presented as mean-
s�SEM with N=8 in each group. The one-way ANOVA followed by
Dunnett’s post-hoc test was performed. ***p<0.001 versus vehicle treat-
ment; #p<0.05, ##p<0.01 and ###p<0.001 versus PCP treatment.
is in line with its strong activity for D2R in vitro. Besides, it is
worth to note that Aripiprazole produced less potent efficacy
than S6 at 3 mgkgÀ 1.
The head twitch responses (HTR) in rodents elicited by
Quipazine, a serotonin receptor agonist, is a specific behavior
relative to the activation of 5-HT2AR.[38] Consistent with its strong
activity for 5-HT2AR in vitro, S6 inhibited head twitches dose-
dependently (Table 7). Furthermore, S6 expressed a potent
inhibitory action on the HTR comparable to that of Brexpipra-
zole at 1 mgkgÀ 1. Additionally, Aripiprazole had a much higher
occupancy at D2R than at 5-HT2AR,[16] whereas compound S6
may have comparable occupancy at D2R and 5-HT2AR at the
same dosage. This characteristic of S6 may bring clinical
benefits. The high potency of S6 for 5-HT2AR in vitro is
supported by in vivo data displaying strong inhibition of
Quipazine-induced HTR in mice. 5-HT2AR antagonism may be
the main mechanism involved in the drug-induced reduction of
HTR, but 5-HT1AR agonists are also inhibitory.[39] Therefore, the
Table 5. Functional activities of compound S6 and reference antipsy-
chotics on several off-target receptors.
Compd
IC50 [nM]
α1A
H1
5-HT2C
M3
hERG
Table 7. Effect of S6 on ICR mice model of quipazine-induced head
twitches response.
S6
391
10
202
194
454
349
>10000
7
69.5
>10000
>10000
>10000
1020
1330
1260
RIS[a]
BRE[b]
Treatment
Dose
Head twitches
[number of episode-
s][a]
HTR reduction
[%]
[mgkgÀ 1
]
[a] Risperidone. [b] Brexpiprazole.
Vehicle
S6
0
1
3
1
3
14.8�1.07
6.4�0.75***
3.2�1.24***
3.8�0.86***
5.0�1.38***
56.76
78.38
74.32
66.21
Table 6. Cell viability of compound S6 and reference antipsychotics.
Compd
Hepatotoxicity
Nephrotoxicity
Brexpiprazole
Aripiprazole
IC50 [μgmLÀ 1
]
IC50 [μgmLÀ 1
]
S6
>600
238.8
44.2
>600
>600
19.1
[a] Data are presented as means�SEM with N=5 in each group. The one-
way ANOVA followed by Dunnett’s post-hoc test was performed. *** p<
0.001 versus Quipazine-treated group.
Risperidone
Brexpiprazole
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detailed mechanism involved in the effect of S6 is unclear and
further research is needed.
the muscle relaxation test in mice as it did not elicit muscle
relaxation at the maximum dosage of 30 mg kg–1.
1
2
The antidepressant potential of compound S6 was inves-
tigated in the forced swim test (FST) in mice. Neither
Aripiprazole nor Brexpiprazole, only compound S6 was effective
at the dose of 0.1 mgkgÀ 1 (Figure 4), which is in line with its
strong inhibition on SERT. At 0.3 mgkgÀ 1, the partial agonist S6
may behave as an antagonist for D2R in vivo and would
influence the motor function of mice, which led to the
ineffectiveness of S6 in the FST at this dosage.[40] Besides,
Fluoxetine at the dose of 10 mgkgÀ 1 caused a statistically
significant decrease in immobility time. Aripiprazole lacks
Compound S6 with excellent in vivo activity drew our
attention. Then we evaluated the in vivo pharmacokinetic
profile of S6 in rats. S6 reached maximum blood concentration
at 0.83h post oral administration (AUC (0–24h) =1485.58 ng×
hmLÀ 1). Other pharmacokinetic parameters were shown in
Table 9. The acceptable bioavailability of S6 (F=35.5%) recom-
mends further drug development of these novel antipsychotic
agents.
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antidepressant-like activity in FST (data not shown), which is Conclusions
consistent with results reported by Bourin et al.[41] Moreover, as
the spontaneous locomotor activity of mice after administration
of S6 or Fluoxetine at effective doses was not influenced (data
not shown), their antidepressant-like effects should be specific.
Catalepsy in rodents is a model predictive of EPS in
humans.[42] As shown in Table 8, S6 displayed a low probability
for inducing catalepsy (CAT/PCP=19.59), better than that of
Risperidone and Aripiprazole. The high threshold for catalepsy
of S6 might translate into low clinical EPS liability. As 5-HT1A
agonists could alleviate antipsychotic-induced extrapyramidal
symptoms (EPS), the good performance of S6 in the catalepsy
test may be partly attributed to its high potency for 5-
HT1AR.[43,44] Additionally, S6 also has excellent performance in
Our endeavor in the synthesis and biological investigation of
novel five-atom-linker-based arylpiperazine derivatives have
facilitated the discovery of compound S6 with excellent
antipsychotic profile, combining partial agonistic activity for
D2R, agonistic activity for 5-HT1AR as well as antagonistic activity
for 5-HT2AR and SERT. The polypharmacology profile of S6
makes it have opportunities to treat diverse CNS diseases.
Besides, S6 demonstrated no appreciable action on targets
associated with side effects. In rodents, S6 displayed antipsy-
chotic and antidepressant potential with a high threshold for
inducing catalepsy or muscle relaxation. Finally, S6 manifested
an acceptable pharmacokinetic profile in rats. Based on the
pleasing preclinical findings, we suggest that S6 for the
treatment of schizophrenia deserves further development.
Experimental Section
General Procedures
Reaction solvents were purchased and used without further
purification. Nuclear magnetic resonance (NMR) spectra were
1
recorded on Varian Mercury Plus-300 (300 MHz for H NMR), Bruker
AVANCE III 400 (400 MHz for 1H NMR, 101 MHz for 13C NMR) or
Bruker AVANCE III 500 (500 MHz for 1H NMR) spectrometer with
TMS in DMSO-d6 or CDCl3 solution as an internal standard. Chemical
shifts were given in d values (ppm) and coupling constants (J) were
given in Hz. Signal multiplicities were characterized as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet) and br (broad). ESIMS
were performed on a Finnigan MAT95 mass spectrometer.
Procedures for the Synthesis of Compounds S1–S24
Figure 4. Effect of compounds Flux (Fluoxetine, 10 mgkgÀ 1) and S6 adminis-
tered ip in the forced swim test in C57 mice. Data are presented as means
�SEM with N=8 in each group. The one-way ANOVA followed by Dunnett’s
post-hoc test was performed. *p<0.05 and **p<0.01 versus vehicle treat-
ment.
7-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pentyl)quinolin-2(1H)-
one (S1). 5-(2-oxo-1,2-dihydroquinolin-7-yl)pentyl methanesulfo-
nate
(220 mg,
0.71 mmol),
1-(2,3-dichlorophenyl)piperazine
Table 9. Sprague–Dawley rat PK profile of S6.
Table 8. Pharmacological profile of S6 in vivo.
PCP[a]
CAT[b]
CAT/PCP
Parameters
max [ng mL–1]
po [10 mgkgÀ 1
]
iv [5 mgkgÀ 1
]
Compd
C
170.20
0.83
4.54
1485.58
1535.55
35.5
1646.71
0.083
5.72
2091.58
2115.48
–
S6
3.08
60.33
19.59
2.43[45]
10[45]
2.93[45]
0.03[45]
7.13[45]
0.30[45]
Tmax [h]
Aripiprazole
Risperidone
t
1/2 [h]
AUC0–24h [ng×hmLÀ 1
]
[a] PCP: phencyclidine-induced hyperactivity (ED50, mgkgÀ 1, po). [b] CAT:
catalepsy (ED50, mgkgÀ 1, po).
AUC0–inf [ng×hmLÀ 1
]
F [%]
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hydrochloride (200 mg, 0.75 mmol) and potassium carbonate
(258 mg, 1.87 mmol) were added to acetonitrile (3 ml) under a
nitrogen atmosphere and the mixture was stirred at reflux for 7 h.
The reaction mixture was concentrated, washed three times with
brine, dried, subjected to column chromatography using
DCM:MeOH (60:1) as eluent to give a crude product. The crude
residue was slurried in acetonitrile, filtered, and dried to give S1 as
a white solid (190 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ 11.65(s,
1H), 7.85 (d, J=9.5 Hz, 1H), 7.55(d, J=8.0 Hz, 1H), 7.29 (m, 2H),
7.12(m, 2H), 7.03(d, J=8.0 Hz, 1H), 6.42 (d, J=9.5 Hz, 1H), 2.95 (br,
4H), 2.64 (t, J=7.5 Hz, 2H), 2.50 (br, 4H), 2.31(t, J=7.2 Hz, 2H), 1.62
(m, 2H), 1.48 (m, 2H), 1.32(m, 2H). ESI-MS m/z 445.90 [M+H]+.
2H), 1.62 (m, 2H), 1.50 (m, 2H), 1.33 (m, 2H). 13C NMR (100 MHz,
CHCl3) δ 162.55, 154.11, 153.63, 148.28, 145.34, 140.48, 139.52,
130.16, 129.47, 128.28, 122.97, 121.38, 117.78, 114.90, 114.81,
113.14, 55.79, 51.46, 49.17, 35.45, 30.58, 26.11, 23.29. ESI-MS m/z
433.2 [M+H]+.
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7
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7-(5-(4-(6-chlorobenzo[d]isothiazol-3-yl)piperazin-1-yl)pentyl)qui-
nolin-2(1H)-one (S7). The title compound was prepared in 55%
yield from 5-(2-oxo-1,2-dihydroquinolin-7-yl)pentyl methanesulfo-
nate
and
1-(6-chloro-benzo[d]isothiazole-3-yl)piperazine
hydrochloride following the procedure described for synthesis of
1
S1. H NMR (300 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.23(d, J=1.5 Hz,
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1H), 8.03(d, J=8.8 Hz, 1H), 7.83(d, J=9.4 Hz, 1H), 7.54 (d, J=8.0 Hz,
1H), 7.43 (dd, J=8.7, 1.9 Hz, 1H), 7.10 (s, 1H), 7.03 (dd, J=8.0,
1.5 Hz, 1H), 6.40(d, J=9.6 Hz, 1H), 3.40(br, 4H), 2.64(t, J=7.5 Hz, 2H),
2.54(br, 4H), 2.32(t, J=7.2 Hz, 2H), 1.62(m, 2H), 1.48(m, 2H), 1.32(m,
2H). ESI-MS m/z 467.027 [M+H]+.
7-(5-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)pentyl)-3,4-dihy-
droquinolin-2(1H)-one (S2). The title compound was prepared in
53% yield from 5-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)pentyl
methanesulfonate
and
1-(benzo[d]isothiazole-3-yl)piperazine
hydrochloride following the procedure described for synthesis of
7-(5-(4-(2-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)pentyl)qui-
nolin-2(1H)-one hydrochloride (S8). The title compound was
prepared in 63% yield from 5-(2-oxo-1,2-dihydroquinolin-7-yl)
pentyl methanesulfonate and 1-(2-fluorobenzo[b]thiophen-4-yl)pi-
1
S1. H NMR (300 MHz, DMSO-d6) δ 9.98(s, 1H), 8.03(m, 2H), 7.55(t,
J=7.8 Hz, 1H), 7.42(t, J=7.8 Hz, 1H), 7.04(d, J=7.6 Hz, 1H), 6.73(d,
J=7.8 Hz, 1H), 6.66(s, 1H), 2.80(t, J=7.5 Hz, 2H), 2.57(br, 4H),
2.42(m, 4H), 2.33(t, J=7.5 Hz, 2H), 1.51(m, 4H), 1.30(m, 2H). ESI-MS
m/z 435.48 [M+H]+.
1
perazine following the procedure described for synthesis of S1. H
NMR (300 MHz, DMSO-d6) δ 11.70(s, 1H), 10.67(br s, 1H), 7.85(d, J=
9.4 Hz, 1H), 7.61(d, J=8.0 Hz, 1H), 7.57(d, J=8.0 Hz, 1H), 7.31(t, J=
7.9 Hz, 1H), 7.13(m, 2H), 7.05(d, J=8.2 Hz, 1H), 7.01(d, J=7.7 Hz,
1H), 6.42(d, J=9.4 Hz, 1H), 3.55(d, J=10.4 Hz, 2H), 3.44(d, J=
11.6 Hz, 2H), 3.05–3.29(m, 6H), 2.67(t, J=7.5 Hz, 2H), 1.77(m, 2H),
1.64(m, 2H), 1.35(m, 2H). ESI-MS m/z 450.2 [M+H]+.
7-(5-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)pentyl)quinolin-
2(1H)-one (S3). The title compound was prepared in 58% yield
from 5-(2-oxo-1,2-dihydroquinolin-7-yl)pentyl methanesulfonate
and 1-(benzo[d]isothiazole-3-yl)piperazine hydrochloride following
the procedure described for synthesis of S1. 1H NMR (300 MHz,
DMSO-d6) δ 11.64(s, 1H), 8.05(d, J=5.1 Hz, 1H), 8.02(d, J=5.1 Hz,
1H), 7.83(d, J=9.5 Hz, 1H), 7.55(m, 2H), 7.42(t, J=7.6 Hz, 1H), 7.10(s,
1H), 7.03(d, J=8.1 Hz, 1H), 6.40(d, J=9.5 Hz, 1H), 3.41(br, 4H), 2.64(t,
J=7.6 Hz, 2H), 2.56(br, 4H), 2.33(t, J=7.3 Hz, 2H), 1.61(m, 2H),
1.49(m, 2H), 1.32(m, 2H). ESI-MS m/z 433.31 [M+H]+.
7-(5-(4-(2-chlorobenzo[b]thiophen-4-yl)piperazin-1-yl)pentyl)qui-
nolin-2(1H)-one (S9). The title compound was prepared in 65%
yield from 5-(2-oxo-1,2-dihydroquinolin-7-yl)pentyl methanesulfo-
nate and 1-(2-chlorobenzo[b]thiophen-4-yl)piperazine following the
1
procedure described for synthesis of S1. H NMR (500 MHz, DMSO-
7-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)pentyl)-3,4-dihydro-
quinolin-2(1H)-one (S4). The title compound was prepared in 65%
yield from 5-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)pentyl methane-
sulfonate and 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride
following the procedure described for synthesis of S1. 1H NMR
(300 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.68(d, J=5.6 Hz, 1H), 7.60(d, J=
8.0 Hz, 1H), 7.38(d, J=5.6 Hz, 1H), 7.26(t, J=7.9 Hz, 1H), 7.04(d, J=
7.6 Hz, 1H), 6.88(d, J=7.7 Hz, 1H), 6.74(d, J=7.6 Hz, 1H), 6.67(s, 1H),
3.04(br, 4H), 2.80(t, J=7.5 Hz, 2H), 2.57(br, 4H), 2.49(m, 2H), 2.40(t,
J=7.6 Hz, 2H), 2.34(t, J=7.3 Hz, 2H), 1.51(m, 4H), 1.30(m, 2H). ESI-
MS m/z 434.30 [M+H]+.
d6) δ 11.66(br s, 1H), 7.84(d, J=9.5 Hz, 1H), 7.55(m, 2H), 7.36(s, 1H),
7.29(t, J=7.9 Hz, 1H), 7.10(s, 1H), 7.03(d, J=8.0 Hz, 1H), 6.91(d, J=
7.7 Hz, 1H), 6.41(d, J=9.4 Hz, 1H), 3.00(br, 4H), 2.64(t, J=7.4 Hz, 2H),
2.56(br, 4H), 2.33(t, J=7.0 Hz, 2H), 1.61(m, 2H), 1.49(m, 2H), 1.32(m,
2H). ESI-MS m/z 466.26 [M+H]+.
7-(5-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)pentyl)qui-
nolin-2(1H)-one (S10). The title compound was prepared in 74%
yield as off-white solid from 5-(2-oxo-1,2-dihydroquinolin-7-yl)
pentyl methanesulfonate and 1-(6-fluorobenzo[b]thiophen-4-yl)pi-
1
perazine following the procedure described for synthesis of S1. H
NMR (300 MHz, DMSO-d6) δ 11.65(s, 1H), 7.84(d, J=9.5 Hz, 1H),
7.65(d, J=5.5 Hz, 1H), 7.55(d, J=7.9 Hz, 1H), 7.49(dd, J=8.4, 1.2 Hz,
1H), 7.35(d, J=5.6 Hz, 1H), 7.10(s, 1H), 7.03(d, J=8.1 Hz, 1H),
6.73(dd, J=11.7, 1.9 Hz, 1H), 6.41(d, J=9.6 Hz, 1H), 3.06(br, 4H),
2.64(t, J=7.6 Hz, 2H), 2.57(br, 4H), 2.35(t, J=7.1 Hz, 2H), 1.62(m,
2H), 1.49(m, 2H), 1.33(m, 2H). ESI-MS m/z 449.90 [M+H]+.
7-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)pentyl)quinolin-
2(1H)-one (S5). The title compound was prepared in 72% yield
from 5-(2-oxo-1,2-dihydroquinolin-7-yl)pentyl methanesulfonate
and 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride following
the procedure described for synthesis of S1. 1H NMR (300 MHz,
DMSO-d6) δ 11.65(s, 1H), 7.84(d, J=9.5 Hz, 1H), 7.68(d, J=5.5 Hz,
1H), 7.60(d, J=8.0 Hz, 1H), 7.55(d, J=8.0 Hz, 1H), 7.38(d, J=5.6 Hz,
1H), 7.26(t, J=7.9 Hz, 1H), 7.11(s, 1H), 7.03(dd, J=8.0, 1.4 Hz, 1H),
6.87(d, J=7.7 Hz, 1H), 6.41(d, J=9.5 Hz, 1H), 3.03(br, 4H), 2.65(t, J=
7.5 Hz, 2H), 2.57(br, 4H), 2.34(t, J=7.2 Hz, 2H), 1.62(m, 2H), 1.49(m,
2H), 1.33(m, 2H). ESI-MS m/z 432.30 [M+H]+.
6-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)pentyl)quinazolin-
4(3H)-one (S11). The title compound was prepared in 57% yield as
off-white solid from 5-(4-oxo-3,4-dihydroquinazolin-6-yl)pentyl
methanesulfonate
and
1-(benzo[b]thiophen-4-yl)piperazine
hydrochloride following the procedure described for synthesis of
1
S1. H-NMR(500 Hz, DMSO-d6) δ 12.15(br s, 1H), 8.03(s, 1H), 7.93(d,
7-(5-(4-(benzo[d]isothiazol-4-yl)piperazin-1-yl)pentyl)quinolin-
2(1H)-one (S6). The title compound was prepared in 71% yield
from 5-(2-oxo-1,2-dihydroquinolin-7-yl)pentyl methanesulfonate
and 1-(benzo[d]isothiazole-4-yl)piperazine following the procedure
J=1.7 Hz, 1H), 7.68(d, J=5.6 Hz, 1H), 7.66(d, J=1.9 Hz, 1H), 7.61(d,
J=4.1 Hz, 1H), 7.58(d, J=4.3 Hz, 1H), 7.38(d, J=5.6 Hz, 1H), 7.27(t,
J=7.8 Hz, 1H), 6.87(d, J=7.6 Hz, 1H), 3.03(br, 4H), 2.74(t, J=7.5 Hz,
2H), 2.58(br, 4H), 2.35(t, J=7.2 Hz, 2H), 1.65(m, 2H), 1.51(m, 2H),
1.33(m, 2H). ESI-MS m/z 433.42 [M+H]+.
1
described for synthesis of S1. H NMR (300 MHz, DMSO-d6) δ 11.64
(s, 1H), 9.06 (s, 1H), 7.84 (d, J=9.5 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H),
7.55 (d, J=8.0 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.10 (s, 1H), 7.03 (dd,
J=8.0, 1.4 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.40 (d, J=9.5 Hz, 1H),
3.16 (br, 4H), 2.66 (t, J=7.6 Hz, 2H), 2.60 (br, 4H), 2.35 (t, J=7.2 Hz,
6-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)pentyl)-2-meth-
ylquinazolin-4(3H)-one (S12). The title compound was prepared in
37% yield as off-white solid from 6-(5-chloropentyl)-2-meth-
ylquinazolin-4(3H)-one and 1-(benzo[b]thiophen-4-yl)piperazine
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hydrochloride following the procedure described for synthesis of
S1. 1H-NMR (300 Hz, CDCl3) δ 10.84(br s, 1H), 8.05(s, 1H), 7.51–
7.63(m, 3H), 7.38(m, 2H), 7.27(t, J=8.7 Hz, 1H), 6.91(d, J=7.5 Hz,
1H), 3.27(br, 4H), 2.83(br, 4H), 2.77(t, J=7.5 Hz, 2H), 2.57(m, 2H),
(m, 2H), 7.10 (m, 1H), 6.62 (d, J=9.5 Hz, 1H), 3.08 (t, J=7.1 Hz, 2H),
2.95 (br, 4H), 2.51 (br, 4H), 2.37 (t, J=6.9 Hz, 2H), 1.68 (m, 2H), 1.53
(m, 2H). ESI-MS m/z 458.31 [M+H]+.
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3
4
5
6
7
8
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7-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)pentanoyl)-3,4-di-
hydroquinolin-2(1H)-one (S18). The title compound was prepared
in 70% yield as off-white solid from 7-(5-(4-(benzo[b]thiophen-4-yl)
2.54(s, 3H), 1.72(m, 4H), 1.41(m, 2H). ESI-MS m/z 447.32 [M+H]+
.
6-(5-(4-(benzo[d]isothiazol-4-yl)piperazin-1-yl)pentyl)-2-meth-
ylquinazoli-n-4(3H)-one (S13). The title compound was prepared in
51% yield as off-white solid from 6-(5-chloropentyl)-2-meth-
ylquinazolin-4(3H)-one and 1-(benzo[d]isothiazole-4-yl)piperazine
following the procedure described for synthesis of S1. 1H NMR
(400 MHz, CDCl3) δ 11.75 (br, 1H), 8.94 (s, 1H), 8.05 (s, 1H), 7.56 (m,
3H), 7.40 (t, J=7.8 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 3.34 (br, 4H), 2.84
(br, 4H), 2.77 (t, J=7.6 Hz, 2H), 2.58 (m, 5H), 1.71 (m, 4H), 1.41 (m,
2H). ESI-MS m/z 448.30 [M+H]+. 13C NMR (100 MHz, CHCl3) δ
163.99, 153.72, 153.05, 152.53, 147.72, 141.07, 135.65, 130.49,
128.74, 127.00, 125.00, 120.16, 113.44, 112.28, 58.40, 53.24, 51.90,
45.87, 35.55, 31.07, 26.98, 20.02.
piperazin-1-yl)pent-1-yn-1-yl)-3,4-dihydroquinolin-2(1H)-one
S15
following the procedure described for synthesis of S17. 1H NMR
(300 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.68 (d, J=5.5 Hz, 1H), 7.60 (d,
J=8.0 Hz, 1H), 7.57 (dd, J=8.1, 1.5 Hz, 1H), 7.43 (d, J=1.4 Hz, 1H),
7.38 (d, J=5.5 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H),
6.87 (d, J=7.6 Hz, 1H), 3.04 (br, 4H), 2.96 (m, 4H), 2.59 (br, 4H), 2.42
(m, 4H), 1.65 (m, 2H), 1.52 (m, 2H). ESI-MS m/z 448.30 [M+H]+.
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12
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16
17
18
19
20
21
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23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
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7-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)pentanoyl)quinolin-
2(1H)-one (S19). The title compound was prepared in 62% yield as
off-white solid from 7-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)
pent-1-yn-1-yl)quinolin-2(1H)-one S16 following the procedure
described for synthesis of S17. 1H NMR (300 MHz, DMSO-d6) δ 11.89
(s, 1H), 7.97 (d, J=9.6 Hz, 1H), 7.88 (s, 1H), 7.77 (m, 2H), 7.68 (d, J=
5.5 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.38 (d, J=5.5 Hz, 1H), 7.25 (t,
J=7.9 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 6.62 (d, J=9.5 Hz, 1H), 3.08 (t,
J=7.0 Hz, 2H), 3.03 (br, 4H), 2.59 (br, 4H), 2.41 (t, J=7.0 Hz, 2H),
1.68 (m, 2H), 1.54 (m, 2H). ESI-MS m/z 446.26 [M+H]+.
7-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pent-1-yn-1-yl)quino-
lin-2(1H)-one (S14). 7-(5-chloropent-1-yn-1-yl)quinolin-2(1H)-one
(150 mg,
0.61 mmol),
1-(2,3-dichlorophenyl)piperazine
hydrochloride (171 mg, 0.64 mmol), potassium carbonate (126 mg,
0.92 mmol) and sodium iodide (3 mg, 0.02 mmol) were added to
acetonitrile (3 ml) under a nitrogen atmosphere and the mixture
was stirred at reflux for 24 h. The reaction mixture was poured into
ice water to precipitate a pale yellow solid. The resulting solid was
filtered, washed three times with ice water, then slurried in
acetonitrile, filtered, and dried to give S14 as a pale yellow solid
7-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)-1-hydroxypentyl)qui-
nolin-2(1H)-one (S20). Compound S17 (100 mg, 0.22 mmol) was
dissolved in DCM/MeOH (1 mL/1 mL) system, NaBH4 (33 mg,
0.87 mmol) was added and the mixture was stirred at room
temperature for 0.5 h. The reaction mixture was extracted with
dichloromethane, washed with brine, dried, subjected to column
chromatography to give S20 as a white solid (65 mg, 65%). 1H NMR
(300 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.85 (d, J=9.5 Hz, 1H), 7.57 (d,
J=8.2 Hz, 1H), 7.28 (m, 3H), 7.10 (m, 2H), 6.42 (d, J=9.5 Hz, 1H),
5.31 (d, J=4.1 Hz, 1H), 4.57 (m, 1H), 2.93 (br, 4H), 2.48 (br, 4H), 2.28
(t, J=6.4 Hz, 2H), 1.60 (m, 2H), 1.20–1.49 (m, 4H). ESI-MS m/z 461.40
[M+H]+.
1
(170 mg, yield: 63%). H NMR (300 MHz, DMSO-d6) δ 11.74 (s, 1H),
7.89 (d, J=9.5 Hz, 1H), 7.62 (d, J=8.1 Hz,1H), 7.30 (m, 3H), 7.15 (m,
2H), 6.49 (d, J=9.5 Hz, 1H), 3.00 (br, 4H), 2.57 (br, 4H), 2.49 (m, 4H),
1.75 (m, 2H). ESI-MS m/z 440.3 [M+H]+.
7-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)pent-1-yn-1-yl)-3,4-
dihydro-quinolin-2(1H)-one (S15). The title compound was pre-
pared in 82% yield as off-white solid from 7-(5-chloropent-1-yn-1-
yl)-3,4-dihydroquinolin-2(1H)-one and 1-(benzo[b]thiophen-4-yl)pi-
perazine hydrochloride following the procedure described for
7-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)-1-hydroxypentyl)-
3,4-dihydroquinolin-2(1H)-one (S21). The title compound was
prepared in 70% yield as off-white solid from S18 following the
procedure described for synthesis of S20. 1H NMR (300 MHz, DMSO-
d6) δ 10.02 (s, 1H), 7.67 (d, J=5.5 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H),
7.37 (dd, J=5.6, 0.7 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.07 (d, J=
8.3 Hz, 1H), 6.85 (m, 3H), 5.09 (d, J=4.1 Hz, 1H), 4.42 (m, 1H), 3.04
(br, 4H), 2.82 (t, J=7.5 Hz, 2H), 2.56 (br, 4H), 2.41 (t, J=7.5 Hz, 2H),
2.32 (t, J=7.1 Hz, 2H), 1.44 (m, 6H). ESI-MS m/z 450.61 [M+H]+.
1
synthesis of S14. H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.69
(d, J=5.5 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.40 (d, J=5.5 Hz, 1H),
7.28 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.7 Hz, 1H), 6.93 (d, J=7.7, 1.3 Hz,
1H), 6.90 (d, J=7.6 Hz, 1H), 6.86 (d, J=1.3 Hz, 1H), 3.08 (br, 4H), 2.86
(t, 2H), 2.63 (br, 4H), 2.40–2.53 (m, 6H), 1.74 (m, 2H). ESI-MS m/z
430.41 [M+H]+.
7-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)pent-1-yn-1-yl)qui-
nolin-2(1H)-one (S16). The title compound was prepared in 86%
yield as off-white solid from 7-(5-chloropent-1-yn-1-yl)quinolin-
2(1H)-one and 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride
following the procedure described for synthesis of S14. 1H NMR
(300 MHz, DMSO-d6) δ 11.74 (s, 1H), 7.88 (d, J=9.5 Hz, 1H), 7.69 (d,
J=5.5 Hz, 1H), 7.61 (m, 2H), 7.40 (dd, J=5.5, 0.8 Hz, 1H), 7.27 (m,
2H), 7.15 (dd, J=8.1, 1.4 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.48 (d, J=
9.5 Hz, 1H), 3.08 (br, 4H), 2.64 (br, 4H), 2.51 (m, 4H), 1.77 (m, 2H).
ESI-MS m/z 428.34 [M+H]+.
(E)-7-(5-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)pent-1-en-1-yl)-
3,4-dihydroquinolin-2(1H)-one hydrochloride (S22). Compound
S21 (100 mg, 0.23 mmol) was dissolved in hydrochloric acid (6 N,
1 mL) and methanol (5 mL) and refluxed overnight. Methanol was
concentrated and the mixture was adjusted to pH=7 with aqueous
sodium hydroxide solution. The mixture was extracted twice with
dichloromethane. The combined organic phase was dried, concen-
trated and the residue was purified by column chromatography to
obtain S22 as a white solid (75 mg, 83%).1H NMR (300 MHz, DMSO-
d6) δ 10.93 (s, 1H), 10.06 (s, 1H), 7.74 (d, J=5.1 Hz, 1H), 7.68 (d, J=
7.9 Hz, 1H), 7.46 (d, J=5.4 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.09 (d,
J=8.4 Hz, 1H), 6.95 (m, 2H), 6.85 (s, 1H), 6.38 (d, J=16.1 Hz, 1H),
6.15 (m, 1H), 3.53 (m, 4H), 3.21 (m, 6H), 2.81 (t, J=7.3 Hz, 2H), 2.40
(t, J=7.3 Hz, 2H), 2.25 (m, 2H), 1.93 (m, 2H). ESI-MS m/z 432.26 [M+
H]+.
7-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pentanoyl)quinolin-
2(1H)-one (S17). Compound S14 (200 mg, 0.45 mmol) was sus-
pended in methanol, 4% sulfuric acid solution (2 mL) and mercury
sulfate (40 mg, 0.3 eq) were added and the mixture was stirred at
°
50 C for 40 h. The reaction mixture was adjusted to pH=7~8 with
sodium bicarbonate aqueous solution, extracted with DCM, washed
three times with brine, dried, subjected to column chromatography
using DCM : MeOH (30:1) as eluent to give a crude product. The
crude residue was slurried in acetonitrile, filtered, and dried to give
7-((3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propoxy)methyl)-3,4-
dihydroquinolin-2(1H)-one (S23). 3-(4-(2,3-dichlorophenyl)pipera-
zin-1-yl)propyl methanesulfonate (300 mg, 0.82 mmol), 7-
1
S17 as a white solid (155 mg, 75%). H NMR (400 MHz, DMSO-d6) δ
11.90 (s, 1H), 7.98 (d, J=9.5 Hz, 1H), 7.87 (s, 1H), 7.78 (m, 2H), 7.29
(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one
(122 mg,
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0.69 mmol), NaH (15 mg, 0.62 mmol) was added into dry THF
(5 mL). The reaction mixture was refluxed for 8 h, cooled to room
temperature, and then purified by column chromatography using
DCM : MeOH (60:1) as eluent to give S23 (80 mg, 26%) as a white
solid. 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 7.37 (m, 2H), 7.20
(m, 2H), 7.14 (s, 1H), 6.98 (d, J=7.5 Hz, 1H), 4.52 (s, 2H), 3.97 (t, J=
6.9 Hz, 2H), 3.58 (m, 2H), 3.43 (m, 2H), 3.19 (m, 6H), 2.87 (t, J=
7.1 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 2.04(m, 2H). ESI-MS m/z 448.00
[M+H]+.
corresponding concentration of DMSO. Then the diluted solution of
tested compounds and the vehicle control were treated with the
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°
cells for 24 h at 37 C in a 5% CO2 incubator. After that, removal of
the supernatant liquor, 100 μL of new media diluted CCK-8 solution
(10% CCK-8) was added to each well and the plates were incubated
for 1 h. The cell survival was evaluated by measuring the
absorbance at 450 nm and calculated by the formula (cell
viability=(ODpositiveÀ ODcontrol)/(ODnegtiveÀ ODcontrol)). All experiments
were carried out in triplicate. Calculate the IC50 value of the test
sample according to the inhibition rate using the Logit method.
7-((3-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)propoxy)methyl)-
3,4-dihydroquinolin-2(1H)-one (S24). The title compound was
prepared as an off-white solid in 37% yield from 7-(hydroxymeth-
yl)-3,4-dihydroquinolin-2(1H)-one and 3-(4-(benzo[b]thiophen-4-yl)
piperazin-1-yl)propyl methanesulfonate following the procedure
described for synthesis of S23. 1H NMR (400 MHz, DMSO-d6) δ
11.21(s, 1H), 7.80(d, J=5.5 Hz, 1H), 7.73(d, J=8.1 Hz, 1H), 7.52(d, J=
5.5 Hz, 1H), 7.34(t, J=7.9 Hz, 1H), 7.22(m, 2H), 7.01(d, J=8.0 Hz, 1H),
6.99(d, J=7.7 Hz, 1H), 4.55(s, 2H), 4.02(t, J=7.1 Hz, 2H), 3.62(m, 2H),
3.56(m, 2H), 3.31(m, 6H), 2.90(t, J=6.8 Hz, 2H), 2.58(t, J=6.8 Hz, 2H),
2.13(m, 2H). ESI-MS m/z 435.70 [M+H]+.
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Experimental Protocol for in vivo Biological Evaluation
PCP-Induced Hyperlocomotion
Male ICR mice (18~22 g, n=8) were individually placed into a
Plexiglas open field arena (40×40×45 cm) for 10 min. After intra-
gastric administration of vehicle, S6 (1, 3 and 10 mgkgÀ 1) or
aripiprazole (3 mgkgÀ 1) for 45 min, animals were treated with PCP
(7 mgkgÀ 1, i.p.), and placed back into the experimental apparatus.
The locomotor activity of each animal was recorded for 75 min.
Results are expressed as the means�SEM of distance traveled.
Statistical evaluation was performed by one-way ANOVA followed
by Dunnett’s post-hoc test. ***p <0.001 versus vehicle treatment;
#p<0.05 versus PCP treatment; ##p<0.01 versus PCP treatment;
###p<0.001 versus PCP treatment.
Experimental Protocol for in vitro Biological Evaluation
Functional Activity Assays
All the compounds were screened on 5-HT1A agonist, D2 agonist &
D2 antagonist mode assays using Ultra Lance. Several compounds
were screened on H1, Alpha1A, M3, 5-HT2A, 5-HT2C antagonist mode
assays using FLIPR. Ultra Lance cAMP assay and FLIPR assay were
conducted according to our previous literature.[1] Selected com-
pounds were tested for effect on hERG potassium channels by
automated patch clamp method (QPatchHTX, Sophion, Stockholm,
Sweden) at Shanghai ChemPartner Co. Ltd.
Induction of Head Twitches in ICR Mice
Quipazine (s.c., 5 mgkgÀ 1) was used to induce head twitches in ICR
mice. Antagonism of head twitches induced by Quipazine in mice
indicates anti-serotonergic activity. Vehicle, S6 or brexpiprazole was
given ig 30 min before Quipazine treatment. The mice were
returned to the test cages and then head twitches were assessed
for 15 min, starting 30 min after the Quipazine treatment. An
observer made all observations unaware of the specific drug
treatments. The results were shown as means�SEM and compared
with one-way analysis of variance, the inter-group significance or
post hoc comparison was analyzed using Dunnet’s t-test.
Assay Protocol for SERT
1) On the first day, HEK-hSERT cells were seeded into 384 wells
plate at 20000 cells per well in 20 μL. Then incubate cells in the
°
incubator at 37 C overnight.
2) On the second day, the reference compound was made 10
doses, 4-fold serial dilution in assay buffer containing 0.1% BSA
at the top concentration of 2 μM. The testing compounds were
made 10 doses, 4-fold serial dilution in assay buffer containing
0.1% BSA at the top concentration of 20 μM.
Forced Swimming Test
We use transparent Plexiglas cylindrical tanks (30 cm height×10 cm
diameters) for the forced swimming test in mice. The water level of
every test is 12 cm from the bottom of the tanks consistently and
3) Remove the cell plate from the incubator. Aspirate the medium
from the wells, and transfer 25 μL per well of the compound
into the plate. Note: For High control wells, a 25 μL assay buffer
containing BSA is added. For Low control wells, 25 μL of 2 μM
reference solution is added.
°
water temperature is maintained at 24�1 C. The swimming time
of mice is six minutes, from start to finish. The immobility time of
mice is recorded during the last 4 min of 6 min test. Movements
that are necessary to balance the body and keep the head above
the water belong to immobility behavior.
°
4) Incubate at 37 C for 30 minutes.
5) After incubation of the cells with compounds, add 25 μL of dye
°
Catalepsy Test
solution per well. Incubate at 37 C for 30 minutes.
6) Read plate on Flexstation 3 and analyze data using Prism.
ICR mice were orally dosed with vehicle or compounds. Assessment
of catalepsy was done by placing the forepaws of mice on a
horizontal bar 0.3 cm in diameter kept positioned 4.5 cm above the
platform with hind paws resting on the platform. The evaluation of
catalepsy was done by recording how long the mice retained their
forepaws on the horizontal bar during the observation periods of
3 min. A mean immobility score of 20 s was used as the criterion for
the presence of catalepsy.
Cell Viability Assay
Cell viability of all the tested compounds against Chang liver cells
and HEK-293 cells was determined using the CCK-8 assay. The cells
were plated in 96-well culture plates at a density of 10000 cells per
°
well and incubated for 24 h at 37 C in a 5% CO2 incubator. The
tested compounds were dissolved in DMSO and diluted with
culture medium (DMSO final concentration <0.4%). The vehicle
control was prepared by mixing the culture medium with a
ChemMedChem 2019, 14, 1–11
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Experimental Protocol for in vivo Pharmacokinetic Study
In Vivo Pharmacokinetics in Rats. Pharmacokinetic studies were
performed in male SD rats weighing 165~195 g (n=3). Pharmaco-
kinetic parameters were obtained by single intravenous (5 mgkgÀ 1
)
or oral administration of S6 (10 mgkgÀ 1), which was dissolved in a
mixed solution (DMSO/PEG400/NaCl (5:40:55, v/v/v)). Heparinized
samples of blood were collected at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h,
4 h, 8 h, and 24 h after dosing. Plasma was separated by
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centrifugation and stored frozen at À 20 C until subsequent
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Abbreviations
5-HT serotonin
NE
norepinephrine
DA dopamine
SERT serotonin transporter
hERG human ether-a go-go-related gene
PK
pharmacokinetics
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We gratefully acknowledge Topharman Shanghai Co., Ltd. for
providing intermediates. This work was supported by Special
Foundation of Chinese Academy of Sciences for strategic pilot
technology (Grant No. XDA12040105), Youth Program of National
Natural Science Foundation of China (Grant No. 81703338) and
National Science & Technology Major Project “Key New Drug
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Conflict of Interest
The authors declare no conflict of interest.
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Keywords: D2 · 5-HT1A · 5-HT2A · serotonin · SERT · PCP-induced
hyperactivity
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Manuscript received: July 23, 2019
Revised manuscript received: October 13, 2019
Version of record online: ■■■, ■■■■
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FULL PAPERS
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Toward new antipsychotics! We
report the design, synthesis, and bio-
logical evaluation of a series of five-
atom-linker-based arylpiperazine de-
rivatives with an atypical antipsy-
chotic profile. One of the derivatives,
S6, with high potency for all the
desired targets (D2, 5-HT1A, 5-HT2A,
and SERT) displayed a promising pre-
clinical profile, opening up new di-
rections for the development of
next-generation antipsychotic drugs.
Dr. C. Wu, Dr. Y. Wang, Dr. F. Yang,
Dr. W. Shi, Prof. Z. Wang, Prof. L. He*,
Dr. Y. He*, Prof. J. Shen
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Synthesis and Biological Evaluation
of Five-Atom-Linker-Based Arylpi-
perazine Derivatives with an
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Atypical Antipsychotic Profile