Synthesis and biological investigation of triazolopyridinone derivatives as potential multireceptor atypical antipsychotics

Article abstract of DOI:10.1016/j.bmcl.2020.127027

A series of triazolopyridinone derivatives originating from the antidepressant trazodone was designed and pharmacologically evaluated. Most of the compounds with a multireceptor functional profile exhibited high potency at the D₂, 5-HT_1A, and 5-HT_2A receptors. Compounds S1, S3, S9 and S12 were selected for further evaluation of druggable potential. Among these compounds, S1, as a D₂ receptor partial agonist, demonstrated very potent inhibition of quipazine-induced head-twitch response, which validated its 5-HT_2A receptor antagonistic efficacy in vivo. S1 also demonstrated a dose-dependent effect on PCP-induced hyperactivity when administered orally. Thus, S1 endowed with a triazolopyridinone scaffold represents a valuable lead for the development of novel atypical antipsychotics.

Full text of DOI:10.1016/j.bmcl.2020.127027

Journal Pre-proofs
Synthesis and biological investigation of triazolopyridinone derivatives as po-
tential multireceptor atypical antipsychotics
Wenqiang Shi, Yu Wang, Chunhui Wu, Feipu Yang, Wei Zheng, Song Wu,
Yongjian Liu, Zhen Wang, Yang He, Jingshan Shen
PII:
S0960-894X(20)30097-4
DOI:
https://doi.org/10.1016/j.bmcl.2020.127027
BMCL 127027
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 December 2019
4 February 2020
11 February 2020
Please cite this article as: Shi, W., Wang, Y., Wu, C., Yang, F., Zheng, W., Wu, S., Liu, Y., Wang, Z., He, Y., Shen,
J., Synthesis and biological investigation of triazolopyridinone derivatives as potential multireceptor atypical
antipsychotics, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127027
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Synthesis and Biological Investigation of
Triazolopyridinone Derivatives as Potential
Multireceptor Atypical Antipsychotics
Wenqiang Shi, Yu Wang, Chunhui Wu, Feipu Yang, Wei Zheng, Song Wu, Yongjian Liu, Zhen Wang, Yang
He, Jingshan Shen
D2R IC50 = 4485 nM
Cl
N
N
5-HT1AR EC50 = 785 nM
5-HT2AR IC50 = 243 nM
N
N
N
O
SAR optimization
N
N
O
D2R IC50 = 12.4 nM
N
N
N
5-HT1AR EC50 = 1.7 nM
5-HT2AR IC50 = 34.2 nM
S

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Synthesis and biological investigation of triazolopyridinone derivatives as
potential multireceptor atypical antipsychotics
Wenqiang Shia,b, Yu Wanga, Chunhui Wuc, Feipu Yanga, Wei Zhenga,b, Song Wuc, Yongjian Liuc, Zhen
Wang a,, Yang Hea,b,, Jingshan Shena,b
aCAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203,
China
bUniversity of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
cTopharman Shanghai Co., Ltd, 388 Jialilue Road, Shanghai 201203, China
———
ARTICLE INFO
ABSTRACT
 Corresponding author. E-mail: heyang@simm.ac.cn
 Corresponding author. E-mail: wangzhen@simm.ac.cn
Article history:
Received
A series of triazolopyridinone derivatives originating from the antidepressant trazodone was
designed and pharmacologically evaluated. Most of the compounds with a multireceptor
functional profile exhibited high potency at the D2, 5-HT1A, and 5-HT2A receptors. Compounds
S1, S3, S9 and S12 were selected for further evaluation of druggable potential. Among these
compounds, S1, as a D2 receptor partial agonist, demonstrated very potent inhibition of
quipazine-induced head-twitch response, which validated its 5-HT2A receptor antagonistic
efficacy in vivo. S1 also demonstrated a dose-dependent effect on PCP-induced hyperactivity
when administered orally. Thus, S1 endowed with a triazolopyridinone scaffold represents a
valuable lead for the development of novel atypical antipsychotics.
Revised
Accepted
Available online
Keywords:
Triazolopyridinone
Antipsychotic
Multireceptor
5-HT1A receptor
2019 Elsevier Ltd. All rights reserved.
Schizophrenia is a common psychiatric disorder that is
characterized by three main features, including positive, negative,
and cognitive symptoms, which appear to originate from the
disruption of brain development because of genetic or
environmental factors[1-3]. People with schizophrenia often have
additional mental health problems such as anxiety, depression,
or substance-use disorders[4]. It has become a major public health
conundrum that seriously threatens human health.
cognitive impairments, and cause a lower incidence of EPS
compared to FGAs[11, 12]. On the other hand, chronic treatment
with SGAs was usually accompanied by side effects related to
off-target effects, such as weight gain, hyperglycemia,
hyperlipidemia, and QT interval prolongation[13, 14]
.
Despite pharmacologic advances, negative symptoms and
cognitive deficits are difficulties in the long-term therapy of
schizophrenia[15,16]
.
Atypical
antipsychotics
with
dual
Current drugs to treat this disorder mainly include typical and
atypical antipsychotics. Schizophrenia is associated with a
dysregulation of dopaminergic circuits (hyperdopaminergic tone
in the mesolimbic pathway and hypodopaminergic signaling in
the mesocortical pathway), which supports the theory that
antagonism toward the D2 receptor in the mesolimbic pathway
reduces psychotic symptoms[5, 6]. Typical antipsychotics (first-
generation antipsychotics, FGAs) act primarily via the
mechanism of antagonism at the D2 receptor, whose
representative agents are chlorpromazine, haloperidol,
chlorprothixene, etc.[7]. However, FGAs have gradually been
withdrawn from first-line medication due to high rates of
extrapyramidal side effects (EPS), tardive dyskinesia,
hyperprolactinemia, and other adverse effects[8]. Atypical
antipsychotics (second-generation antipsychotics, SGAs), which
show enhanced potency at the 5-HT receptors, especially the 5-
HT2A receptor, are preferred by patients and clinicians[9, 10]. On
one hand, SGAs were claimed to have a broad efficacy spectrum,
which included improved efficacy in negative symptoms or
antagonistic properties at the D2 and 5-HT2A receptors have
limited efficacy in ameliorating negative symptoms and cognitive
deficits[17-19]. Several new antipsychotics, such as aripiprazole
and brexpiprazole, could reduce the severity of negative
symptoms and produce milder extrapyramidal symptoms, which
is partly attributed to their activation at the 5-HT1A receptor. The
5-HT1A receptor is highly expressed in limbic brain areas, such as
the hippocampus, lateral septum and the cortex, which is proven
to be associated with learning, memory, anxiety, depression,
neuropathic pain, and temperature regulation[20-22]
. 5-HT1A
receptor agonists have been explored for the treatment of various
neuropsychiatric disorders (depression, anxiety, ADHD, epilepsy,
etc) and non-neuropsychiatric diseases such as levodopa-induced
dyskinesia[23, 24]. In recent years, more attention has been brought
to the 5-HT1A receptor because of its potential for enhancing
cognition based on preclinical and clinical evidence[25, 26]. For
example, the anxiolytics tandospirone and buspirone, possessing
agonistic potency at the 5-HT1A receptor, were administered
orally to patients who were already treated with other
1

antipsychotics, and the results of clinical trials elicited an
improved effect in cognitive function[27]. In a word, an agonistic
effect at the 5-HT1A receptor is beneficial for the amelioration of
current antipsychotic therapy.
Our previous publications have described the synthesis and
biological activity studies of a series of N-substituted cyclic
imide derivatives. Some of these derivatives such as compound
1 demonstrated high activity at the D2, 5-HT1A, and 5-HT2A
receptors (Figure 1). Trazodone is mainly used to treat major
depressive disorder and anxiety disorders, which might be
attributed to serotonin reuptake inhibition, 5-HT2 receptor
N
N
O
S1
S2
12.4
26.3
1.7
0.1
34.2
46.3
N
N
S
N
O
N
N
F
N
N
S
antagonism and 5-HT1A receptor partial agonism[28, 29]
.
N
Our work aims to continue the search for new compounds
with antipsychotic potential. The present study focused on the
synthesis and pharmacological evaluation of a new class of
antipsychotic agents with a triazolopyridinone system linked to
the arylpiperazine (piperidine) group and characterized by high
activities for the D2, 5-HT1A, and 5-HT2A receptors. We designed
O
N
N
these
triazolopyridinone
derivatives
using
molecular
N
S3
S4
S5
S6
S7
S8
S9
30.2
62.8
135
94.7
406
105
12.4
1.8
1.2
9.5
12.1
0.1
7.0
2.0
35.5
27.0
144
368
652
131
13.0
N
S
N
hybridization methods (Figure 1). Their structure−activity
relationships (SARs) for dopamine and serotonin receptors were
associated with variation in the arylpiperazine (piperidine)
moieties and the substituents on the triazolopyridinone ring.
Among these compounds, we selected S1 as a potential candidate
for further development due to its potent antipsychotic effect in
behavioral tests.
F
O
N
N
F
N
N
S
N
F
N
N
O
Cl
N
N
.
S
HCl
N
N
N
O
N
N
S
Cl
N
N
O
Cl
N
N
S
N
Cl
N
N
N
O
N
S
N
Br
OCH3
N
N
N
O
N
N
S
S
N
N
O
N
N
S10
S11
102
2.2
85.2
104
N
OCH3
CN
N
N
O
Figure 1. Design of novel triazolopyridinone derivatives
42.6
20.2
N
N
S
N
The syntheses of the novel triazolopyridinone derivatives were
performed according to the reaction pathways illustrated in
Scheme 1. Substituted or unsubstituted triazolopyridinone Ⅰ-1
was alkylated with 1,4-dibromobutane or 1-bromo-4-
chlorobutane to provide intermediates Ⅰ-2, which was then
coupled with various arylpiperazine moieties under mild basic
conditions to produce S1–S18 with the General Formula Ⅰ.
N
N
O
CN
N
N
S12
S
1.03
146
9.7
5.9
11.0
726
N
N
N
O
N
N
S
S13
S14
N
CN
Scheme 1. Reagents and conditions: (i) 1-bromo-4-chlorobutane or 1,4-
dibromobutane, K2CO3, DMF, rt, overnight; (ii) K2CO3, KI, CH3CN, reflux,
12 h.
N
N
O
N
N
1.5
1.4
155
243
S
N
CN
Trazo
done
Table 1. Functional activities of compounds S1–S14 on D2, 5-HT1A, and 5-
HT2A receptors
/
4485
785
D2R
IC50
5-HT1AR
EC50
5-HT2AR
IC50
Cmpd
Structure
(nM)
(nM)
(nM)
2

The synthesized S1–S14 were assayed for their inhibitory
activity against the D2 and 5-HT2A receptors as well as their
agonistic activity at the 5-HT1A receptor using HTRF cAMP and
FLIPR calcium assays. The results were summarized in Table 1.
Generally, most of the compounds manifested obviously
improved potency compared to trazodone at the D2 and 5-HT1A
receptors. Compound S1 possessing a triazolopyridinone scaffold
was a substantially active molecule. Then, various substituent
groups were introduced to the [1,2,4]triazolo[4,3-a]pyridin-
3(2H)-one ring at positions 5–8 to explore the influence on
functional activities of the D2, 5-HT1A, and 5-HT2A receptors. We
first investigated the effect of introducing halogen atoms to the
[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one moiety (compounds S2–
S8). The 6-fluoro substituted derivative S2, 8-fluoro substituted
derivative S3, and 6,8-difluoro substituted derivative S4 all
showed decreased activity at the D2 receptor, whereas they
remained active at the 5-HT2A receptor. Compared to S1, S2 was
16-fold more potent at the 5-HT1A receptor. However, 6-chloro
substituted derivative S5, 8-chloro substituted derivative S6 and
6,8-dichloro substituted derivative S7 all showed a substantially
reduced potency at the D2 and 5-HT2A receptors. Notably,
compound S7 exhibited the same potency as S2 at the 5-HT1A
receptor. Additionally, when a bromo atom was introduced to the
[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one moiety at the C8
position, reduced activities of compound S8 were observed for all
three receptors. In short, the introduction of F, Cl or Br at the C6
or C8 position of the [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
moiety appeared to be detrimental to the functional activities of
these derivatives at the D2 and 5-HT2A receptors.
Figure 2.The binding modes of compounds S1 (A), risperidone (B), S10 (C),
and S14 (D) with D2 receptor. Key residues of the receptor were shown as
sticks. Hydrogen bonding interactions were marked as yellow dashed lines.
The figure depicting the binding modes was generated with PyMOL.
Table 2. Functional activities of S15–S18 at the D2, 5-HT1A, and 5-HT2A
receptors
D2R
5-HT1AR
5-HT2AR
Cmpd
S1
Structure
IC50
(nM)
EC50
(nM)
IC50
(nM)
N
N
O
N
12.4
117
40.5
7.0
1.8
2.8
34.2
2730
15.2
77.8
1070
N
S
N
Compounds S9–S14 with methoxy and cyano substituted at
different positions of the [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
moiety were designed to investigate the effect of substituent
positions and electrical factors. The 5-methoxy substituted
derivative S9 demonstrated comparable D2 and 5-HT1A receptor
potencies to S1 and its potency at the 5-HT2A receptor increased
to some extent. The 8-methoxy substituted derivative S10
exhibited weaker activities at the D2 and 5-HT2A receptors than
S1 while retaining similar agonistic activity at the 5-HT1A
receptor. 5-cyano substitution (S11) or 7-cyano substitution (S13)
led to a decrease in the activity, especially in the case of S13 at
the 5-HT2A receptor. To our surprise, the 6-cyano substituted
compound (S12) and the 8-cyano substituted compound (S14)
showed very potent antagonistic activity at the D2 receptor with
12-fold and 8-fold more potency than S1, respectively.
N
N
O
S15
S16
S17
S18
N
N
S
N
N
F
N
N
O
>10000
0.1
N
N
O
S
N
N
N
N
O
N
N
N
N
F
F
N
O
N
N
S
11.1
1.53
N
F
The next SAR focus was on the base moiety after summarizing
the previous study. As depicted in Table 2, compounds S15–S18
exhibited moderate to good antagonistic activity at the D2
receptor, but their efficacy at the 5-HT1A and 5-HT2A receptors
varied considerably. Although thiazole is one of the common
pharmacophores and has been widely used as a bioisostere of the
thiophene moiety, such replacement led to a sharp decline at the
D2 and 5-HT2A receptor antagonistic activities with little change
on 5-HT1A receptor activity (S15 vs S1). Compared with S15, its
8-fluoro substituted derivative S17 displayed ameliorated
activities for all three receptors, which may be due to the
formation of the potential H-F hydrogen bond. Compound S16,
bearing (6-fluorobenzo-[d]isoxazol-3-yl)piperidine as base
moiety, was devoid of 5-HT1A receptor agonistic activity,
although it showed strong antagonistic activities for the D2 and 5-
HT2A receptors. Maybe the arylpiperazine moiety is vital for
these derivatives to keep agonistic activity at the 5-HT1A receptor
instead of arylpiperidine. The introduction of a fluorine atom at
the 2-position of the benzothiophene ring resulted in an
appreciably decreased potency at the 5-HT2A receptor while D2
receptor potency increased slightly (S18 vs S3). Furthermore,
To explore the molecular basis of the antagonistic potency of
these new compounds at the D2 receptor, we selected compounds
S1, S10, and S14 to perform molecular docking studies.
Compared to risperidone, compound S1 shared a similar
interaction with the D2 receptor. The carbonyl oxygen of the
[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one moiety had an interaction
with residue (His393) via a water molecule. In addition, the
nitrogen atom of piperazine or piperidine could form a hydrogen
bond with the OH group of Asp114. The benzothiophene moiety
of compounds S1, S10 and S14 could also form hydrophobic
interactions with the binding pocket. The docking results of
compounds S10 and S14 with the D2 receptor indicated that the
H-bond established between the OH group of Asn396 and the
cyano nitrogen of S14, but not the methoxy oxygen of S10, may
explain why S14 showed more potent activity than S10 at the D2
receptor (Figure 2).
3

high potency at the 5-HT1A receptor was retained for S18
compared to S1.
S3
S9
S12
303.8
203.0
341.6
Aripiprazole
Citalopram
21% inhibition @ 400nM
13.41
Many adverse effects of atypical antipsychotics are associated
with off-target effects. In particular, the inhibition of the 1A, H1,
and 5-HT2C receptors and hERG is closely related to side effects
such as weight gain, hyperglycemia, dyslipidemia, and
cardiovascular diseases. Therefore, further characterization of the
pharmacological profiles of candidate compounds is essential.
Blockade of the 1-adrenoceptor (especially the peripheral
α1A-adrenoceptor) can result in orthostatic hypotension, which is
an undesirable side effect accompanied by many antipsychotic
drugs. Compounds S1, S3, and S12 showed weaker antagonistic
activity than risperidone at the 1A-adrenoceptor, suggesting that
they may run a lower risk of causing orthostatic hypotension. The
H1 and 5-HT2C receptors are involved in the regulation of diet and
weight, so the inhibition of these two kinds of receptors might be
responsible for atypical antipsychotics-induced weight gain.
Although all the tested compounds showed stronger and
moderate inhibitory potency at the H1 receptor compared to
risperidone, they all exhibited a substantially reduced activity at
the 5-HT2C receptor, which indicates low liability to lead to
weight gain. The pancreatic M3 cholinergic receptor is related to
acetylcholine-dependent insulin release, inhibition of the M3
receptor may cause hyperglycemia and diabetes. Clozapine and
olanzapine, which have a strong inhibitory effect on the M3
receptor, have a high risk of inducing diabetes in clinical
practice. All tested compounds hardly have antagonistic activity
at the M3 receptor, indicating that they have little possibility to
cause hyperglycemia.
Figure 3. Summary of the SAR studies on various regions of the
triazolopyridinone derivatives.
We selected compounds S1, S3, S9, and S12 for further in
vitro and in vivo bioassays for two main reasons. One is that
these four compounds had higher potency at the D2, 5-HT1A, and
5-HT2A receptors (IC50 or EC50 value < 40 nM). An additional
factor is that the potency ratio between any two of the three
receptors should be no greater than 20 to achieve a relatively
balanced receptor activity profile. We also evaluated if these
selected compounds could act as partial agonists at the D2
receptor, which is claimed to result in a unique clinical profile
related to efficacy against schizophrenia and improved
tolerability (low EPS liability, low propensity to induce weight
gain and a low risk to elevate prolactin). As shown in Table 3,
Compound S3 was devoid of D2 receptor agonistic activity,
indicating that it was a full antagonist at the D2 receptor. Both
compounds S1 and S12 showed slightly lower agonistic potency
than brexpiprazole at the D2 receptor in terms of EC50 values.
Additionally, as hERG potassium channel blockade is a
crucial indicator of potential pro-arrhythmic tendency,
investigation of the hERG channel blockade has become an
important step in the process of drug discovery. It is less likely
for all the tested compounds to elicit treatment-induced QT
interval prolongation because of their weak potency at the hERG
channel.
Table 3. Agonistic activities of selected compounds at the D2 receptor
D2 receptor
Compound
EC50(nM)
Emax(%)
S1
S3
S9
13.6
—
/
19
<20
/
Table 5. Functional activities at the 1A, H1, and 5-HT2C receptors and hERG
of compounds S1, S3, S9 and S12.
S12
27.3
—
—
41
risperidone
trazodone
brexpiprazole
<20
<20
29
IC50/nM
Compound
6.3
α1A
15.1
17.4
/
H1
88.5
30.9
/
5-HT2C
>10000
2100
/
M3
hERG
3010
2200
/
S1
S3
S9
>10000
>10000
/
/: not tested; —: not active. Emax, expressed as percentage of the effect of
10μM dopamine.
The serotonin transporter (SERT) is the target of many
antidepressant medications of the SSRI and tricyclic
antidepressant classes, and its dysfunction is associated with
many psychiatric disorders. We used a fluorescence-based high-
throughput assay to measure the SERT inhibitory activity of
selected compounds, and citalopram was used as the control.
Modification on the [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one ring
had no appreciable influence on 5-HT reuptake activities. As
shown in Table 4, all the tested compounds showed similar,
moderate antagonistic activities at the SERT and displayed
stronger potency compared to aripiprazole. This pharmacological
characteristic may contribute to the amelioration of the comorbid
depressive symptoms in schizophrenia.
S12
Risperidone
/: not tested
87.8
10.9
76.6
454
3290
1.81
>10000
>10000
1050
1330
The quipazine-induced head-twitch response (HTR) is a rapid
side-to-side head movement that occurs in mice and rats after the
5-HT2A receptor is activated. The HTR is used as a behavioral
model to assess the in vivo efficacy of 5-HT2A receptor
antagonists. Preliminary results indicated that S1 exhibited dose-
dependent high potency at inhibiting head twitches, which is
nicely in accordance with their in vitro high potency at the 5-
HT2A receptor (See Supplemental Figure S1). Then, we
compared the inhibitory action of the four promising compounds
on the HTR at the same dose. As depicted in Figure 2,
compound S9 shows a slight inhibition of HTR in mice, whereas
compounds S1 and S3 greatly inhibit HTR, which is superior to
aripiprazole at a low dose (0.3 mg/kg). Next, we selected
Table 4. Effects of selected compounds on inhibitory activity of SERT
Compound
SERT(IC50, nM)
536.9
S1
4

compound S1 for further investigation of PCP-induced
hyperlocomotion in vivo after analyzing and summarizing
previous results.
As seen in Table 6, the latent hepatotoxicity and
nephrotoxicity of compound S1 were also investigated.
Compound S1 displayed a weaker inhibitory activity at the
HEK293 cells and Chang liver cells compared to brexpiprazole,
but it showed a stronger inhibitory potency compared to that of
risperidone. In a word, compound S1 has a good safety profile.
Figure 4. Effect of selected compounds on ICR mice model of Quipazine-
induced head-twitch response. Mice were orally provided selected
compounds or vehicle after intraperitoneal administration of quipazine in a
single dose. Data represent the number of head twitches(mean ± SEM)
Table 6. Cell viability of compound S1 and reference antipsychotics
Hepatotoxicity
IC50(μg/ml)
62.2
Nephrotoxicity
IC50(μg/ml)
108.1
Compound
S1
Risperidone
Brexpiprazole
238.8
44.2
>600
19.1
In summary, a series of novel triazolopyridinone derivatives
with a multireceptor functional profile was designed and
pharmacologically evaluated. Compound S1 showed remarkable
potency at the D2, 5-HT1A and 5-HT2A receptors, which is in
accordance with its in vivo profile in behavioral models.
Additionally, compound S1 had a good safety profile due to its
weak inhibitory effect at the 1A, H1, and 5-HT2C receptors and
hERG. Specifically, S1 may preferentially activate the 5-HT1A
receptor and barely occupy other receptors in vivo at a low
dosage and could have advantages in treating several
neuropsychiatric disorders in which the 5-HT1A receptor was
deeply involved. Accordingly, compound S1 represents a
potential candidate for further preclinical investigation.
during the 15min test with n=5 in each group. *P<0.05, **P<0.01,
***P<0.001 compared with the quipazine-treated group.
Phencyclidine (PCP) with a noncompetitive antagonism
property at the N-methyl-D-aspartate (NMDA) receptor has been
widely used in experimental animal models to study the
underlying neurobiology of schizophrenia. Acute administration
of PCP could lead to an increase in locomotion, which is used as
a model to evaluate the antipsychotic-like efficacy of agents by
attenuating locomotion. In this test, compound S1 produced
substantial dose-dependent responses, which was consistent with
the potent D2 receptor antagonistic activity in vitro (Figure 3).
Moreover, the spontaneous locomotor activity of mice could be
influenced after administration of S1 at 3 or 10 mg/kg, but not at
0.3 mg/kg (See Supplemental Figure S2–S3), suggesting that S1
was devoid of the unpleasant side effect of sedation at the
effective dose of 0.3 mg/kg.
Acknowledgments
This work was supported by Special Foundation of Chinese
Academy of Sciences for strategic pilot technology (Grant No.
XDA12040105, XDA12040331), Youth Program of National
Natural Science Foundation of China (Grant No.81703338),
National Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program”, China (Grant No.
2018ZX09711002), and Science and Technology Commission of
Shanghai Municipality (18431907100).
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[2] Kelly S, Guimond S, Lyall A, et al. Neural correlates of
cognitive deficits across developmental phases of schizophrenia
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[3] Zhang J C H Y, Jiang X R, et al. Nature brings new avenues
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Figure 5. Mice were orally administrated compounds S1 and risperidone
(0.1mg/kg) after intraperitoneal administration of PCP in a single dose
(7mg/kg). Data are reported as the mean ± SEM (n=8). Statistical evaluation
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