Discovery of novel potent and selective ligands for 5-HT2A receptor with quinazoline scaffold

Article abstract of DOI:10.1016/j.bmcl.2015.07.030

Abstract A series of compounds with quinazoline scaffold were designed, synthesized and evaluated as novel potent 5-HT_2A receptor ligands. N-(4-Chlorophenyl)-2-(piperazin-1-yl)quinazolin-4-amine (5o) has a K_i value of 14.04 ± 0.21 nM, with a selectivity more than 10,000 fold over 5-HT_1A receptors (D₁ and D₂-like receptors). The functional assay showed that this compound is an antagonist to 5-HT_2A receptor with an IC₅₀ value of 1.66 μM.

Full text of DOI:10.1016/j.bmcl.2015.07.030

Accepted Manuscript
Discovery of Novel Potent and Selective Ligands for 5-HT2A Receptor with
Quinazoline Scaffold
Xinxian Deng, Lin Guo, Lili Xu, Xuechu Zhen, Kunqian Yu, Weili Zhao, Wei
Fu
PII:
S0960-894X(15)00734-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.07.030
BMCL 22919
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
25 March 2015
15 June 2015
13 July 2015
Please cite this article as: Deng, X., Guo, L., Xu, L., Zhen, X., Yu, K., Zhao, W., Fu, W., Discovery of Novel Potent
and Selective Ligands for 5-HT2A Receptor with Quinazoline Scaffold, Bioorganic & Medicinal Chemistry
Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.07.030
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Discovery of Novel Potent and Selective
Ligands for 5-HT2A Receptor with
Quinazoline Scaffold
Xinxian Deng, Lin Guo, Lili Xu, Xuechu Zhen, Kunqian Yu, Weili Zhao, Wei Fu
1

Bioorganic & Medicinal Chemistry Letters
journal h omepage: www.els evier. com
Discovery of Novel Potent and Selective Ligands for 5-HT2A Receptor with
Quinazoline Scaffold
Xinxian Denga§, Lin Guoc§, Lili Xua§, Xuechu Zhenb*, Kunqian Yuc, Weili Zhaoa*, Wei Fua**
aDepartment of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University,
Shanghai 201203, China
bJiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-disorders & Department of Pharmacology, College of Pharmaceutical
Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu Province, China. 215123
cDrug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai 201203, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of compounds with quinazoline scaffold were designed, synthesized and evaluated as
novel
potent
5-HT2A
receptor
ligands.
Revised
Accepted
Available online
N-(4-chlorophenyl)-2-(piperazin-1-yl)quinazolin-4-amine (5o) has a Ki value of 14.04 ± 0.21
nM , with a selectivity more than 10000 fold over 5-HT1A receptors (D1 and D2-like receptors).
The functional assay showed that this compound is an antagonist to 5-HT2A receptor with an
IC50 value of 1.66 µM.
Keywords:
2009 Elsevier Ltd. All rights reserved.
5-HT2A receptor antagonist;
quinazoline derivatives;
Synthesis;
Molecular Docking
* Corresponding authors
Wei Fu, Prof./Ph.D. Department of Medicinal Chemistry, School of Pharmacy, Fudan University 826 Zhangheng Road, Shanghai 201203,
P.R. China; Fax: +86-21-51980010, Phone: +86-21-51980010; E-mail: wfu@fudan.edu.cn.
Xuechu Zhen, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-disorders & Department of Pharmacology,
College of Pharmaceutical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu Province, China. Email:
zhenxuechu@suda.edu.cn
Weili Zhao, Department of Medicinal Chemistry, School of Pharmacy, Fudan University; 826 Zhangheng Road, Shanghai 201203, China;
Email: zhaoweili@fudan.edu.cn.
§These authors contributed equally to this work.
2

5-HT2A receptor is a G protein-coupled receptor (GPCR)
coupling with Gq/G11 protein which generally mediates
excitatory neurotransmission1, 2. One of the most fundamental
biological functions of 5-HT2A receptor is the regulation of
dopamine release in three dopaminergic pathways3-5. 5-HT2A is
involved in a wide array of etiology processes including
schizophrenia, depression, anxiety, migraine, hallucinations,
insomnia and addiction. Nevertheless, 5-HT2A antagonists have
joined with D2 dopamine antagonists as the most used atypical
antipsychotic agents6. The importance of 5-HT2A antagonism
in atypical antipsychotic drug is believed to associate with
alleviating “negative symptom” of schizophrenia and reducing
extrapyramidal system (EPS). Great efforts in identifying
novel chemicals with 5-HT2A antagonistic activity have been
made, which are mainly based on tricycle scaffold and
long-chain arylpiperazine (LCAP), represented by clozapine
(Ki = 5.35 nM) and aripiprazole (Ki = 8.7 nM), respectively
(Figure 1). Limited novel scaffold has been reported. Herein,
the discovery of a structurally novel class of 5-HT2A inhibitors
exemplified by compound 5o which derived from
a
quinazoline scaffold, was described.
Figure 1 Structures of clozapine and aripiprazole.
Efforts directed toward the identification of 5-HT2A selective
inhibitors were initiated by pharmacophore-based virtual
screening of our in-house library against 5-HT2A receptor,
followed by biological assays. A number of potential
candidates were found suitable for lead optimization studies,
among them compound 5a was particularly attractive7. It
possessed medium activity to 5-HT2A receptor (Ki = 593 nM)
with extremely high selectivity over 5-HT1A, D1 and D2
dopamine receptors7. Besides, properites of 5a caclulated by
Schrӧdinger conformed to Lipinski’s rule and its extension. 5a
has a molecular weight below 500 KDa, a topological polar
surface area of 80 Å2, a predicted cLogP of 2, 7 rotable bonds,
3 hydrogen bond donors and 7 hydrogen bond acceptors. It is
NH group in aniline and the hydroxyl group in ethanol moiety
of 5a form hydrogen bond interactions with N7.36 and S3.36,
respectively. Our predicted binding mode is quite consistent
with available site-directed mutagenesis studies which have
13,
proved that D3.3210-12, Ser3.3610,
14, and Y7.4314-17 are
important to binding affinities of 5-HT2A ligands. It indicates
that the piperazinyl-ethanol arm is critical to the activity, as
these indispensable interactions determined the binding
orientation of the arm down into the hydrophilic binding
pocket (ArmBP) enclosed by D3.32, S3.36 and Y7.43, and the
tail up to a hydrophobic binding pocket (TailBP) comprised of
the extracellular segments of TM-II and VII. Careful
examination showed that the tail part of 5a did not form any
interaction with surrounding residues (Figure 2), suggesting
that 5a could be optimized by appending favorable groups in
aniline part (Table 1, 5b-5l). On the other hand, we consider
that the piperazinyl-ethanol arm has high flexibility and the
hydrogen bond formed by hydroxyl group of arm with S3.36
may not be conservative in all the quinazoline analogues.
Therefore, several different fragments were added in the arm
region to examine the effect of piperazinyl-ethanol on activity
(Table 2, 5m-5v). The synthesis of target compounds was
accomplished according to scheme 1. 2-amino-1-methyl
benzoate (1), as starting material, was coupled with KCNO in
acetic acid at ambient temperature. Cyclization of methyl
2-ureidobenzoate (6) was done at reflux in KOH methanol
worth
noting
that
5a
has
a
novel
N4-phenylquinazoline-2,4-diamine scaffold (Tabel 1) as
5-HT2A antagonist, and quinazoline is one of the most
developed skeletons as kinase inhibitors8, 9. They showed weak
antitumor activity and very narrow therapeutic window in
several cell lines including H2228, U87MG, LNCap and A549
(see supporting information, Table S3). Such skeleton has
rarely been reported to show affinity to 5-HT2A receptor. We
thus thought to further optimize it.
Compound 5a is composed by a quinazoline core, an arm
(piperazinyl-ethanol) and a tail (dimethoxy-aniline). To
rationalize the design of the derivatives, the structural model of
the complex 5a-5-HT2A was constructed by combining
molecular docking and all available experimental data (Figure
2). 5a is lying at the antagonistic crevice comprised of TM-III,
TM-VI and TM-VII10. And several important interactions were
identified. The protonated nitrogen atom (N1) of 5a is not only
involved in the conserved hydrogen bond with D3.32, but also
participates in an additional cation-π interaction with W3.28.
solution
(pH
=
10)18.
Chlorination
of
quinazoline-2,4(1H,3H)-dione (2) was achieved by refluxing
with POCl3 at the presence of tri-n-propylamine in toluene19.
Then the corresponding phenylamine derivatives were attached
to the 4-position of 2,4-dichloroquinazoline (3) through
nucleophilic addition under basic condition in THF at room
temperature20. The aniline analogs were added to the 2,
3

4-dichloroquinazoline THF solution in a dropwise way so that
less di-substituted side products were produced. The next step
was another nucleophilic addition where three different
published protocol22, 23. For the initial screening, the inhibition
percentages of the compounds 5a-5v at 10 μM were measured
and the values of Ki were given only when the inhibition rate
of compound was greater than 90%. The potent compound of
5-HT2A (+)Butaclamol was used as reference compound to test
the binding affinity. The results are summarized in Table 1 and
2, which illustrated that most of these compounds exhibited
moderately strong inhibitory activities.
secondary
amines
were
attached
to
2-chloro-N-phenylquinazolin-4-amine
derivatives
(4),
respectively21. Finally, intermediates 5 were treated with conc.
HCl to get the corresponding hydrochloride salt. The receptor
binding assays were conducted according to our previous
Scheme 1
(i) KCNO; AcOH; H2O; (ii) KOH; MeOH; H2O; (iii) POCl3; PhMe; tri-n-propylamine; (iv) corresponding phenylamine derivatives; TEA; THF; (v)
corresponding amine; TEA; acetonitrile; (vi) conc. HCl; THF
4

Figure 2 Predicted Binding mode of 5a, 5f, 5g and 5k with 5-HT2A receptor. Ligands were shown in yellow sticks and surrounding residues in green.
5-HT2A was shown in white ribbon. Hydrogen bond interactions were represented in dotted blue lines and cation-π interactions in orange.
As inspired by the binding mode of 5a with 5-HT2A, the effect
of substituent at o-, m- and p- positions of aniline was expected
to form favorable interaction with residues in the Tail BP. As a
result, 5f and 5g were obtained. o-OCH3 substituted compound
5g provided a delightful improvement in the binding affinity
(Ki = 145.64 nM), while p-OCH3 substituted 5f exhibited a
decreased affinity. It is worth noting that the activities of
compounds were sensitive to substituent’s properties and
position in tail part of compounds. Then what is the intrinsic
reason that causes such sensitivity? The comparison of binding
modes of 5a, 5f and 5g unmasks this veil (Figure 2). The
hydroxyl group and the protonated amino group in three
compounds form the hydrogen bonds with the S3.36 and
D3.32, respectively. While the o-OCH3 group in 5g forms the
hydrogen bond with the Y7.43, p-OCH3 in 5f does not form
any interaction with the surrounding residues; in 5a, the
p-OCH3 changes the orientation of o-OCH3 and blocks the
formation of this hydrogen bond. Instead, a new hydrogen
bond is formed by the amino group of 5a and N7.36 (Figure 2).
Therefore, 5g with substituent o-OCH3 shows the strongest
activity among three compounds. Unfortunately, the analogue
with m-OCH3 substituent was not obtained due to the difficulty
in getting the crude reagent, while the compound 5k with
m-OH substituent showed improved activity than 5a, 5f and 5g,
since the m-OH was located in a favorable position and forms
strong hydrogen bond interaction with Y7.43. The predicted
binding energies of compounds 5a, 5f, 5g, 5k, 5m and 5n with
5-HT2A receptor correlated well with their experimental
binding activities (Figure S1 in supporting information).
Compounds 5b-5e were next prepared to evaluate the
influence of different halogens at p-position of aniline on
binding affinity. The results indicated that all halogenated
derivatives displayed improved binding affinity and the
brominated compound performed better than other halogenated
ones (p-Br > p-Cl > p-F > p-I), demonstrating the important
role of halogens in 5-HT2A ligand design. The compound 5i
with o-F substituent on aniline was designed and synthesized
to further examine the effect of halogen’s position on binding
affinity. Similar to the case with -OCH3 substituent at aniline,
5i with o-F substituent showed 2-fold improvement (65 nM)
compared to 5b with p-F substituent in aniline (120 nM).
Above hints inspire us to design compounds with -Cl, -Br and
-I at o- and p-position of aniline in the future.
The effect of larger hydrophobic substituent at p-position of
aniline on the affinity was also examined by designing
compounds 5h (p-isopropyl) and 5l (Benzyl-amine). It turned
out that 5h showed 3-fold improved activity while 5l
maintained its activity.
Table 1 Binding affinities of compounds 5a-5l for 5-HT2A. (Ki or percentage displacement of radio-ligand at 10 μM)
Ki ± SD (nM)
Entry
R
5-HT2A [3H]-Ketanserin
5a*
o-OMe p-OMe
p-F
593.89 ± 34.10
120.13 ± 17.71
109.17 ± 1.05
92.05 ± 13.45
383.02 ± 7.79
1359.45 ± 51.69
145.64 ± 9.91
149.11 ± 19.01
65.78 ± 17.64
267.70 ± 11.25
83.38 ± 3.38
5b
5c
5d
5e
5f
5g
5h
5i
p-Cl
p-Br
p-I
p-OMe
o-OMe
p-isopropyl
o-F
o-Me, p-Me
m-OH
5j
5k
5l
Benzy-amine
519.60 ± 15.25
2.97 ± 0.60
(+)Butaclamol
5

* Lead compound; not synthetic.
Table 2. Binding affinities of compounds 5m-5v for 5-HT2A. (Ki or percentage displacement of radioligand at 10 μM).
Ki ± SD (nM)
Entry
5m
R1
R2
5-HT2A[3H]-Ketanserin
o-OMe
45.77 ± 8.67
o-F
p-Cl
69.99 ± 6.30
14.04 ± 0.21
5n
5o
5p
5q
5r
5s
p-I
496.24 ± 31.75
42.14 ± 1.43
234.77 ± 5.66
184.33 ± 28.22
p-isopropyl
p-F
o-F
p-Cl
45.27%
5.91%
5t
p-isopropyl
p-isopropyl
5u
75.11%
5v
2.97 ± 0.60
(+)Butaclamol
Note: Ki value for 5-HT2A were given only if compounds with inhibition ratio higher than 90%; percentage data represents inhibition ratio.
As depicted in Figure 2, the flexible group ethoxy tail in 5a, 5f
and 5g contributed to the binding affinity by forming a
hydrogen bond with S3.36. In order to quantitatively examine
the contribution of this flexible ethoxy tail on binding affinity,
compounds 5m-5q with eliminated flexible ethoxy group were
designed and synthesized. Surprisingly, these designed
compounds 5m-5q showed largely improved activity (10-100
nM). Especially, 5o displayed potent activity of 14.04 nM,
which is ca. 10 times higher than that of 5c with flexible
ethoxy tail (109.1 nM). This extraordinary event inspired us to
further investigate the binding mode of these new designed
compounds with 5-HT2A receptor. 5o (p-Cl, without ethoxy tail)
and 5c (p-Cl, with ethoxy tail) were overlaid in the binding site
of 5-HT2A receptor to uncover the essence of the diminished
activity in 5c (Figure 3). Specifically, in the case of 5o
(without ethoxyl), the piperazine ring forms hydrogen bond
and electrostatic interaction with D3.32 and cation-π
interaction with Y7.43. The addition of ethoxyl destroys the
hydrogen bond with Y7.43 by anchoring S3.36 through a new
hydrogen bond. In the meantime, this anchor action makes the
quinazoline core revolve toward helix VI, and this rotation
adjusts the aniline arm to stretch into the pocket formed by
TM-VII and TM-II from the pocket formed by TM-VI and
TM-V. It turns out that the amino group in aniline tail in 5o
forms hydrogen bond with N6.55 which might account for the
higher activity24.
6

Figure 3 The superimposition of 5g and 5m (up and left), 5c and 5o (down and left) in the binding pocket of 5-HT2A (shown as surface) and detailed binding
mode of 5m and 5o with 5-HT2A
.
The well-known consensus knowledge in A-class GPCR
inhibitory design is that a protonated N in ligand is required for
the binding activity because it can form the salt bridge
interaction with the conserved residue D3.3210 in the binding
site. There are few cases that the ligand without protonated N
shows activity toward A-class GPCR25. Therefore, 5r-5u were
designed to examine whether this new quinazoline scaffold for
GPCR can show activity toward 5-HT2A receptor when the
protonated N is eliminated. Interestingly, 5r and 5s with
morpholine fragment showed medium activity toward 5-HT2A
receptor (234.77 nM and 184.33 nM), while 5t and 5u did not
display activity. The molecular docking showed that the
hydrophilic morpholine could stay in the hydrophilic pocket
composed by the TM-III and TM-VII and atom O acted as
hydrogen bond acceptor that formed hydrogen bond with
D3.32, while the hydrophobic aniline substituent at this
position was unfavorable for the binding. Besides, this type of
compounds with quinazoline scaffold showed higher
selectivity over 5-HT1A receptor and dopamine D1, D2 and D3
receptors (supporting information, Table S1). Only four
compounds 5d, 5h, 5l and 5q exhibited weak activity toward
dopamine receptors.
[35S]GTPγS binding assays26 were employed to determine the
agonistic or antagonistic activities of compounds with Ki
values less than 130 nM (5b, 5c, 5d, 5i, 5k, 5o, 5m 5n), in
which olanzapine was used as reference compound. The potent
antagonist olanzapine of 5-HT2A was also used as reference
compound. As shown in Table 3, compound 5i and 5o
produced relatively strong antagonistic activity against 5-HT2A,
displaying IC50 values of 1.37 µM and 1.66 µM, respectively.
The result demonstrated that the compounds with quinazoline
scaffold are a novel type of high potent and selective
antagonist for 5-HT2A receptor.
Table 3. [35S]GTPγS binding assays of compounds 5b, 5c, 5d, 5i, 5k, 5o, 5m 5n for 5-HT2A receptor.
EC50 (µM)
IC50 (µM)
Compounds
21.26
7.43
27.72
1.37
9.12
ND
5b
5c
5d
5i
5k
5m
ND
5n
1.66
0.10
-
5o
-
Olanzapine
5-HT
0.13
ND: not determined
These compounds are antagonists, no EC50 value.
In summary, a new scaffold of compounds with the core
structure of quinazoline was identified as highly potent and
analogues can be highly potent and selective ligands for
5-HT2A receptor. Investigations of more potent and selective
quinazoline derivatives are required for their practical and
therapeutic applications in the future.
selective 5-HT2A ligands by combining
a
series of
computational approaches, synthetic chemistry and binding
assays. Compound 5o showed relatively high binding affinity
to 5-HT2A receptor (Ki =14.04 nM) and antagonist activity
(IC50 = 1.66 µM). Molecular docking disclosed the binding
sites of quinazoline analogues for 5-HT2A: ArmBP and TailBP.
The underlying mechanism of the increased activity by
eliminating flexible ethoxy tail was also explored. To our best
knowledge, this is the first time to find out that the quinazoline
Experimental Section
Experimental
procedures
for
medicinal
chemistry,
pharmacology and molecular modeling as well as
characterization of compounds are provided in the Supporting
Information.
7

Acknowledgments
This work was supported by the National Natural Science
Foundation of China (No. 81172919, 81130023, 31373382),
National Basic Research Plan (973) of the Ministry of Science
and Technology of China (2011CB5C4403), the State Key
Laboratory of Drug Research, and National Drug Innovative
Program (No.2009ZX09301-011). Support from Priority
Academic Program Development of Jiangsu Higher Education
Institutes (PAPD) is also appreciated.
Supplementary Material
Description of 1H NMR, 13C NMR, HRMS and melting point
of the target compounds. Description of 5-HT1A, 5-HT2A, D1,
D2 and D3 binding assays, [35S]-GTPγS assays and antitumor
assays. Description of molecular modeling. This information is
available via the Internet.
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