Identification of Novel 1-O-Substituted Aporphine Analogues as Potent 5-HT2C Receptor Agonists

Article abstract of DOI:10.1021/acschemneuro.9b00563

The 5-HT_2C receptor has emerged as a promising target in the treatment of a variety of central nervous system disorders. We have first identified aporphines as a new class of 5-HT_2C receptor agonists. Structure-activity relationship

Full text of DOI:10.1021/acschemneuro.9b00563

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Article
Identification of Novel 1-O-substituted Aporphine
Analogues as Potent 5-HT2C Receptor Agonists
Qi Mao, Bingjie Zhang, Wanwan Li, Sheng Tian, Wenqing Shui, and Na Ye
ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.9b00563 • Publication Date (Web): 22 Jan 2020
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Identification of Novel 1-O-substituted Aporphine Analogues as
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Potent 5-HT2C Receptor Agonists
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Qi Mao,a,1 Bingjie Zhang,b,c,1 Wanwan Li,a Sheng Tian,a Wenjing Shui,b,c** and Na
Yea,*
aJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical
Sciences, Soochow University, Suzhou, Jiangsu 215123, China
biHuman Institute, ShanghaiTech University, Shanghai 201210, China
cSchool of Life Science and Technology, ShanghaiTech University, Shanghai, 201210,
China
1These authors contribute equally to this work.
Corresponding authors:
*Na Ye, PhD
Tel: +86-512-65881161
Email: yena@suda.edu.cn
**Wenjing Shui, PhD
Tel: +86-21-20685595
Email: shuiwq@shanghaitech.edu.cn
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Abstract
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The 5-HT2C receptor has emerged as a promising target in the treatment of a variety of
central nervous system disorders. We have first identified aporphines as a new class
of 5-HT2C receptor agonists. SAR results indicate that the aporphine core may be
required for 5-HT2C receptor activity, and substitutions on its C1 position are
important for 5-HT2C receptor activity. Our efforts to optimize our hit 15781 lead to
the identification of the highly potent and selective 5-HT2C agonist 18b (MQ02-439)
with an EC50 value of 104 nM, and weak antagonism at the 5-HT2A and 5-HT2B
receptor. The findings may serve as good starting points for the development of more
potent and selective 5-HT2C agonists as valuable pharmacological tools or potential
drug candidates.
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KEYWORDS: Serotonin, 5-HT2C receptor, 5-HT2B receptor, 5-HT2A receptor,
agonist, aporphine
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INTRODUCTION
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The 5-HT2C receptor belongs to 5-HT2 subfamily of serotonin
(5-hydroxytryptamine, 5-HT) receptors.1 The 5-HT2 receptors as G protein-coupled
receptors (GPCRs) couple preferentially to Gq/11 to increase the hydrolysis of inositol
phosphates and elevate cytosolic calcium concentrations to produce their
physiological activity. The 5-HT2C receptor has been explored for over 25 years in the
treatment of a variety of central nervous system (CNS) disorders including obesity,
depression, anxiety, obsessive-compulsive disorder, addictive disorders, and chronic
pain conditions,2-9 and there is an FDA approved CNS drug (lorcaserin) targeting this
receptor. Moreover, 5-HT2C receptor is almost exclusively expressed in the CNS,
which provides one of the many advantages of the 5-HT2C receptor as a CNS drug
target, and thus compounds selectively activating this receptor should have limited
peripheral effects.10 To date, a number of 5-HT2C receptor agonists have been
identified (Fig. 1),11-14 with the representative drug Lorcaserin as the first-in-class
antiobesity drug approved by FDA in 2012.15 However, it remains a challenge to
develop 5-HT2C receptor agonists with high potency and subtype selectivity since the
5-HT2C receptor exhibits 46–50% overall sequence identity with the other two 5-HT2
subtypes, 5-HT2A and 5-HT2B receptor, which may lead to hallucinogenic and lethal
valvulopathic side effect, respectively.12, 16, 17
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NH2
NH
NH2
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Cl
HO
N
O
NH
N
7
8
N
N
H
9
5-HT
Lorcaserin
WAY-163909
YM-348
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HN
N
O
N
NH
F
F
NH
NH2
Cl
N
NH
N
F
O
O
Bn
F
mCPP
O-Bn-THAZ
UIC
PF-4522654
Fig. 1. Structure of 5-HT and representative 5-HT2C selective agonists
Aporphines, a group of tetrahydroisoquinoline alkaloids, exhibit a wide range of
CNS pharmacological activities represented by antiparkinsonian drug apomorphine, a
dopamine D2 agonist.18-26 With regard to serotonin receptors, aporphines have mostly
been studied as ligands for 5-HT1A and 5-HT2A receptors.19, 21, 23, 27-30 However, they
are relatively unexplored as 5-HT2C receptor ligands. Recently, our team discovered
several aporphine derivatives as 5-HT2C hit ligands by using thermal stability assay to
screen a focused alkaloid library of over 300 chemical components isolated from
plants, e.g. (–)-crebanine (1, Fig. 2) as a 5-HT2C receptor antagonist with no
selectivity over 5-HT2A or 5-HT2B.31 Later, Sromek and coworkers32 identified a
series of fluorinated 11-O-aporphine derivatives as potent 5-HT2C receptor ligands but
with poor selectivity (e.g. the most potent compounds 2-3, Fig. 2). All these results
indicate that aporphines may serve as a viable source to develop novel ligands for
5-HT2C receptor.
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O
O
O
O
O
2
2
1
N
A
D
B
Me
F
N
N
H
R
H
6a
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C
7
O
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OCH3
OCH3
Crebanine
O
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11a
11b
15781
R = Me
R = Pr
5-HT2C: IC50 = 148 nM
5-HT2B: IC50 = 1693 nM
5-HT2A: IC50 = 564 nM
5-HT2C: Ki = 32 nM
5-HT2B: Ki = 102 nM
5-HT2A: Ki = 450 nM
5-HT2C: Ki = 24 nM
5-HT2B: Ki = 106 nM
5-HT2A: Ki = 414 nM
5-HT2C: EC50 = 678 nM
5-HT2B, 2A: NA
Fig. 2. Structure of aporphine analogs targeting 5-HT2 receptors
We have long been working on the structure-activity relationship (SAR) study of
aporphine analogues by structural modifications on the 10,11-dihydroxyl moiety of
apomorphine to generate new dopamine D2 receptor agonists with improved
metabolic stability.18-23 Recently, through screening natural herb extracts with the
affinity mass spectrometry approach,33, 34 we identified 1,2-dimethoxy-aporphine
15781 (3, Fig. 2) as a novel ligand for 5-HT2C receptor which showed submicromolar
agonist activity in the Gq-coupled calcium flux assay (EC50 = 678 nM). Interestingly,
this new agonist (to be disclosed in a separate publication in details) was highly
selective on 5-HT2c and had no effects toward 5-HT2A and 5-HT2B receptors (Figure
1). Of note, 15781 lacks the critical structural elements for dopaminergic and
adrenergic properties of aporphinoids, the N-alkyl substituent and
11-hydroxyphenethylamine component,24 and 7-hydroxy group,25 respectively,
indicating it may be inactive at these receptors. Inspired by these intriguing results
and aiming to develop leads with enhanced activity and selectivity on 5-HT2C
receptors, it is imperative to conduct SAR studies on aporphine derivatives by using
15781 as a chemical hit.
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RESULTS AND DISCUSSION
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Design and Synthesis. As shown in Fig.1, a number of 5-HT2C receptor agonists
have been identified with N “head” as a mimic of the primary amine in 5-HT, an
aromatic ring mimicking its indole core, and a linker between an aromatic ring and
the N “head”.16, 35 Aporphines share all these key structural features, but have two
aromatic rings in the tetracyclic skeleton, phenyl ring A and D. To confirm which
phenyl ring mimics the indole core of 5-HT, we initially simplify the compact
scaffold of aporphines by removal of phenyl ring C and D as in compounds 2a-b. To
analyze the linker between the desired phenyl ring and the N “head”, we then
investigate the effects of different linkers by opening phenyl ring C as in compounds
8, 9a and 13-14b. And we also explore the necessity of two methoxy groups on the
1,2-position of hit 15781 as in compounds 18a-k.
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Scheme 1a
O
O
O
NH2
O
O
NCO
a
b
c
O
O
NH
O
HN
O
O
n
1
4
d
2a
2b
n = 1
n = 2
O
MeO
Cl
OH
Cl
OH
Cl
OH
O
O
O
O
3
5
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O
O
O
O
O
O
O
O
N
NH
NH
H
g
NH
e
f
H
H
H
H
O
H
O
OH
Cl
O
O
O
Cl
Cl
Cl
9
(0 %)
8
9a
7
aReagents and conditions: (a) cycloketones, H3PO4, 90 °C, 24 - 48 h, 27%-34%. (b)
Cl(OCCl3)2, Et3N, DCM; 0 °C, 15 min, rt, 1 h, 32%. (c) SOCl2, MeOH, 0 °C, rt, 12 h,
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90%. (d) toluene, 110 °C, 12 h, 62%. e) i) DIBAL–H, - 78 °C, 1 h; ii) MeOH, - 20 °C,
10 min; iii) BF3·OEt2, rt, 1 h, 40% for three steps. (f) KOH, EtOH, H2O, THF,
100 °C, 7 h, 90%. (g) i) (Boc)2O, DCM, rt, 2 h, 90%; ii) DMP, DCM, rt, 1 h, 79%; iii)
conc. HCl : EtOAc = 1 : 2, rt, 1 h, 46%.
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As depicted in Scheme 1, tetrahydroisoquinoline compounds 2a-b were prepared
by the Pictet-Spengler cyclization reaction of 3,4-dimethoxyphenethylamine 1 and the
corresponding cycloketone under the treatment of phosphoric acid at 90 °C for 24-48
h in 27-34% yields.36 On the other hand, coupling of isocyanate 4 and alcohol 5
derived from material amine 1 and acid 3, respectively, generated the open carbamate
6 at 100 °C in toluene in 62% yield as shown in Scheme 1.37 Subsequent one-pot
reductive cyclization with sequential addition of DIBAL-H, methanol and BF3·OEt2
gave enantiomerically pure oxazolidinones 7 in 40% total yield.38 Hydrolysis of
precursor 7 gave 1-hydroxybenzyl substituted analogs 8. Subsequent oxidation of
electron-rich arene 8 with DMP directly generated benzoquinone 9a in 46% yield,
with no detection of desired 1-benzoyl substituted analogs 9.39
Scheme 2a
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R2
R1
R2
R1
N
Pr
N
7
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9
Br
14b
15a,b
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Br
c
d
O
R2
R1
Br
OH
H
N
R2
R1
NH
a
b
10
O
R2
R1
NH2
Br
11a-f
12a-f
13a-f
e
R2
R1
R2
R1
R2
R1
18a-b,g, j-k
for
from
NH
• HCl
N
N
17a-b, g, e-f
: g
COCF3
d
COCF3
18c-d
18e-f
17c-d
17e-f
: f,j,g
17b
: k,g
for
for
for
for
from
from
: h,j,g
Br
16a-f
18h
18i
from
from
18a-k
17b
: f,l,g
17a-g
18a, R1 = H, R2 = MeO
18b, R1 = MeO, R2 = H
18c, R1 = OPr, R2 = H
18d, R1 = OCH2cPr, R2 = H
18e, R1 = F, R2 = H
18f, R1 = Cl , R2 = H
18g, R1 = H, R2 = PrO
18h,R1 = MeO, R2 = Cl
18i,R1 = MeO, R2 = Br
18j,R1 = F, R2 =MeO
18k,R1 = Cl, R2 =MeO
11-16a
11-17b
11-17c
11-17d
11-17e
11-17f
17a
17g
, R1 = H, R2 = MeO
, R1 = MeO, R2 = H
, R1 = OPr, R2 = OBn
, R1 = OCH2cPr, R2 = OBn
, R1 = F, R2 = MeO
, R1 = Cl, R2 = MeO
, R1 = H, R2 = MeO
, R1 = H, R2 = PrO
f,c
aReagents and conditions: (a) EDCI, HOBt, DCM, rt, 24 h, 60%-90%. (b) i. Method
A: PCl5, DCM, reflux, 20 min, 35%-66%; Method B: POCl3, acetonitrile, reflux, 3 h,
43%-72%; Method C: P2O5, toluene, reflux, 3 h; ii. NaBH4, MeOH, 0°C-rt, 1 h, 70%.
(c) PrBr, K2CO3, KI, acetone, reflux, 4 h, 33%-71%. (d) Pd(OAc)2, PhDavePhos,
K2CO3, DMA, 130 °C, 4 h, 40%-83%. (e) TEA, TFAA, DCM, 0°C-rt, 1 h, 70%-80%.
(f) BBr3, DCM, -78°C-rt, 1 h, 80%-83%. (g) i. EtOH, NaBH4, N2, rt, 1.5 h; ii. HCl (1
M in EtOAc), rt, 4-6 h, 53%-72% for two steps. (h) H2, 10% Pd/C, DCM, MeOH, rt, 4
h, 85%-92%. (j) i. Tf2O, TEA, DCM, 0°C-rt, 0.5 h; ii. TEA, HCOOH, Pd(OAc)2,
DPPF, DMF, 60°C, 15 min, 40-64% for two steps. (k) NCS, ACN, 70°C, 2h, 60%. (l)
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i. Br2, HOAc, rt, 1h; ii. MeI, K2CO3, acetone, reflux, 4 h, 50% for two steps.
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The synthetic route of 1-benzyltetrahydroisoquinolines 13b and 14b is depicted
in Scheme 2. Condensation reaction of commercially available 2-bromophenylacetic
acid 10 with various phenylethylamine 11a-f,40, 41 gave amides 12a-f, followed by
Bischler–Napieralski cyclization with PCl5 / POCl3 / P2O5 and reduction with NaBH4,
furnished tetrahydroisoquinolines 13a-f. Subsequently, 13b was converted to its
N-n-propyl analog 14b by N-alkylation reaction with 1-bromopropane under the
condition of K2CO3 and KI at reflux. To construct the tetracyclic skeleton of
aporphines, 17a-b were initially intended to prepare directly by use unprotected
amines 13a-b via Pd-catalyzed intramolecular C-C coupling reaction. However, only
C-N coupling products 15a-b were yielded. Hence the trifluoroacetyl protected
amines 16a-f were prepared for oxidative cyclization to produce key aporphine
immediates 17a-f in the presence of Pd(OAc)2 and PhDavePhos in DMA at 130 °C.
17a was then converted to 17g by O-demethylation and subsequent O-propylation.
Removal of the trifluoroacetyl group of 17a-b, 17g and 17e-f using NaBH4 gave the
target compounds 18a-b, 18g and 18j-k while sequential hydrogenation of 17c-d or
demethylation of 17e-f, trifluoromethyl sulfonation, palladium-catalyzed
hydrogenolysis, and then detrifluoroacetylation yielded 18c-f. Chlorination of 17b
followed by detrifluoroacetylation obtained 18h, but 17b can’t be brominated for
synthesis of 18i in the same fashion. Finally, 18i was prepared sequentially by
demethoxylation of 17b, bromination, methylation, and detrifluoroacetylation.
Pharmacological Assays and Structure−Activity Relationship (SAR). All new
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compounds were screened employing recombinant, stably expressed human 5-HT2A,
5-HT2B, and 5-HT2C receptors in the Flp-In T-rex293 cell line, using a fluorescence
imaging plate reader (FLIPR) assay. Estimates of Emax and EC50 are found in Table 1.
Serotonin was used as a positive control, and its Emax values were normalized to 100%
for all receptors.
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As shown in Table 1, removal of ring C and D in hit 15781 leads to the
spiro-tetrahydroisoquinolines 2a-b with significant loss of activity on 5-HT2C
receptors, suggesting that it may be phenyl ring D mimicking the indole core of 5-HT
rather than ring A. And opening ring C also results in C-1 substituted
tetrahydroisoquinolines 8, 9a and 13-14b with no activity on 5-HT2C receptors even if
these tetrahydroisoquinolines keep pivotal structural characteristics of 5-HT2C
receptor agonists. It is noted that the linker of 8, 9a and 13-14b is flexible while the
linker in hit 15781 is restricted. However, C-N coupling byproducts 15a-b are also
inactive, suggesting that it is of great importance to keep the linker between the
phenyl ring D and the N “head” in an appropriate configuration. As we expected,
cyclization of 13b to aporphines 18b lead to regain 5-HT2C receptor activity. All these
above results suggest that the aporphine core may be required for 5-HT2C receptor
activity.
We later focused on investigating the effect of the monosubstituent on the 1- or
2-position of our hit 15781. Although ring A is not the desired aromatic ring
mimicking the indole core of 5-HT, its substitutions such as two methoxy groups on
the 1,2-position of hit 15781 play an important role in 5-HT2C effects. All the tested
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new compounds 18b-f with various substitutions on C1 position show potent agonism
of the 5-HT2C receptor, while compounds 18a and 18g with alkyloxy groups on C2
position completely lost activity (Fig. 3). The most potent compound 18b
(MQ02-439) with C1 methoxy group is 6-fold more potent than hit 15781 on 5-HT2C
activity (EC50 103 vs 678 nM), and also shows great selectivity with no effect on the
5-HT2A and 5-HT2B receptors (Fig. 4). Increasing the size of the C1-methoxy group of
18b as in compounds 18c-d results in decreased potency on 5-HT2C receptors, and
poor selectivity against 5-HT2A and 5-HT2B receptors. Replacement of the
C1-methoxy group of 18b with halogen as in compounds 18e-f also decreases potency
on 5-HT2C receptors, and selectivity against the 5-HT2B receptors. And compound 18f
with a chloro group is almost 3-fold potent than 18e with a fluoro group, and displays
higher efficacy on 5-HT2C (EC50 205 vs 568 nM; Emax 98% vs 51%) and 5-HT2B
receptors (EC50 222 vs 598 nM; Emax 72% vs 48%). Taken together, C1 position of
aporphine core may prefer small lipophilic and electro-donating groups for the
5-HT2C receptor activity. And it is noted that 18e-f are inactive at the 5-HT2A
receptors while 18c-d display moderate potency, indicating C1 position may be
tolerant of bulky lipophilic and electro-donating groups for 5-HT2A receptor activity.
Further halogenated 18b at 2-position as in compounds 18h-i, dramatically decreased
activities. However, fluorinated 18a (as in 18j) at 1-position was still no active while
chlorinated 18a (as in 18k) gained weak 5-HT2C agonist activity. All the SAR studies
indicates that C1 position on the aporphine core may be a key position to modify for
increasing agonist activity for 5-HT2C receptors, and appropriate groups on C2
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position may modulate the agonist activity.
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Table 1. Pharmacological Profiling of Aporphine Derivatives at 5-HT2 Receptors in
Calcium Flux Assay
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5HT2C
5HT2B
Emax
5HT2A
NO
Structure
EC50
Emax
(%)
EC50
(nM)
EC50
Emax
(%)
(nM)
(%)
(nM)
NH2
HO
0.12 ±
0.01
1.19 ±
0.09
0.23 ±
0.04
5-HT
100 ± 0.6
100 ± 0.9
100 ± 0.2
N
H
H3CO
NH
H
653 ±
0.51
65.61 ±
3.1
H3CO
15781
NA
-
NA
-
O
O
NH
2a
2b
NA
NA
NA
NA
-
-
-
-
-
-
-
-
O
O
NH
O
O
H
NH
OH
8
NA
NA
-
-
-
-
H
Cl
O
O
O
NH
6755 ±
0.125
67.28 ±
1.45
6412 ±
0.83
46.58 ±
5.01
9a
NA
NA
H
O
O
Cl
NH
O
13b
NA
NA
Br
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N
O
14b
15a
15b
18a
18b
18c
18d
18e
18f
NA
NA
NA
NA
NA
NA
NA
NA
-
-
-
-
-
-
-
-
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Br
O
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N
O
N
O
NH
• HCl
-
-
-
-
NH
• HCl
103.1 ±
0.04
95.91 ±
1.06
O
NA
NA
NA
NA
NH
• HCl
461 ±
0.50
211.2 ±
0.85
71.85 ±
3.53
372.0 ±
0.69
85.26 ±
3.73
O
O
96 ± 2.64
NH
• HCl
855.7 ±
0.66
89.53 ±
2.82
1920 ±
0.92
3566 ±
0.09
73.20 ±
0.47
85 ± 5.83
NH
• HCl
568.4 ±
0.54
51.44 ±
1.62
598.6 ±
1.27
48.47 ±
13.44
F
NA
NA
-
NA
NA
-
NH
• HCl
205.2 ±
0.23
98.50 ±
3.20
222 ±
0..79
Cl
72 ± 1.12
O
NH
• HCl
18g
NA
NA
-
-
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NH
• HCl
1643 ±
0.08
82.81 ±
1.31
O
18h
18i
14600
121.48
NA
NA
-
NA
NA
-
Br
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NH
• HCl
1680 ±
0.14
82.27 ±
2.46
3935 ±
0.25
85.28 ±
6.13
O
O
F
NH
• HCl
18j
18k
NA
NA
-
-
-
-
O
NH
• HCl
1163 ±
0.23
53.28 ±
4.62
Cl
-
-
aPharmacological data were acquired with recombinant, stably expressed human
5-HT2C, 5-HT2B, and 5-HT2A receptors in the Flp-In T-rex293 cell line, using a
fluorescence imaging plate reader (FLIPR) assay. EC50 and Emax values are shown as
the mean ± SEM (n ≥ 2). “NA” indicates no activity up to 10 μM. “−” indicates the
activity are not tested. Data were obtained from two independent experiments
performed in triplicate.
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Fig. 3. Representative intracellular calcium release response of Aporphine derivatives
at human 5-HT2C receptors compared with 15781 and 5-HT. Emax and EC50 values of
these compounds are listed in Table 1.
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Fig. 4. Representative intracellular calcium release responses of 18b at human 5-HT2A,
5-HT2B, and 5-HT2C receptors. Emax and EC50 values of these compounds are listed in
Table 1.
Synthesis and Pharmacological Effects of (+)-Enantiomers and
(-)-Enantiomers of Compound 18b in Calcium Flux Assay. From the results above,
aporlogue 18b stood out as the most potent 5-HT2C agonist identified in this report.
Since the compound was recemate, (+)-18b and (-)-18b were prepared using the
synthetic route depicted in Scheme 3 based on the asymmetric hydrogenation of
1-benzyl-3,4-dihydroisoquinoline intermediates 19b. As shown in Scheme 3,
Bischler–Napieralski cyclisation of 12b using phosphorus pentoxide in refluxing
toluene, followed by catalytic asymmetric hydrogenation of the resulting imines 19b,
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gave 1-benzyltetrahydroisoquinoline enantiomers (R)-13b with an e.e. value of 90%
(Table 2, entry 1) by using previously reported Noyori's ruthenium-based catalyst,
RuCl[S,S)-TsDPEN](p-cymene).42 After optimization of the reaction conditions
(Table 2), the e.e. value was improved to 95.5% (entry 5; see Supporting Information,
Fig. S2). Subsequently, (S)-13b was also synthesized under the optimal reaction
condition using RuCl[R,R)-TsDPEN](p-cymene) as the catalyst with identical e.e.
value (95.4%) as (R)-13b (Fig. S3). Finally, the desired products (R)-18b and (S)-18b
were accomplished from (R)-13b and (S)-13b respectively with remaining steps in the
same fashion as those described for the synthesis of 18b. (R)-18b and (S)-18b were
determined by chiral IC column with e.e. value of 96% and 94%, respectively with
n-hexane/ethyl alcohol/diethylamine as the mobile phase (Fig. S5-S6).
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Scheme 3a
NH
NH
• HCl
O
O
d-f
b
H
H
Br
13b
HN
O
N
O
O
18b
(R)-
(R)-
a
Br
Br
NH
NH
• HCl
H
12b
19b
O
d-f
O
c
H
Br
13b
18b
(S)-
(S)-
aReagents and conditions: (a) P2O5, toluene, reflux, 3 h, 70%. (b) TEA, HCOOH,
RuCl[S,S)-TsDPEN](p-cymene), DMF, 0°C-rt, 12 h, 57%. (c) TEA, HCOOH,
RuCl[R,R)-TsDPEN](p-cymene), DMF, 0°C-rt, 12 h, 57%. (d) TEA, TFAA, DCM,
0°C - rt, 1 h, 80%-85%; (e) Pd(OAc)2, PhDavePhos, K2CO3, DMA, 130 °C, 4 h,
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60%-70%. (f) i) EtOH, NaBH4, N2, rt, 1.5 h; ii) HCl (1 M in EtOAc), rt, 4-6 h, 60%
for two steps.
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Table 2. Optimization conditions for enantiomeric asymmetric synthesisa
N
NH
O
O
H
Br
Br
13b
19b
(R)-
Entry
S/Cb
50
50
50
50
30
25
30
30
F/Tc
Time
12h
12h
12h
12h
12h
12h
12h
4h
e.e.d
90%
1e
0.5 mL
0.5 mL
1.0 mL
1.0 mL
1.0 mL
1.0 mL
0.5 mL
1.0 mL
2
90.7%
92%
3e
4
91%
5
95.4%
92.5%
91.5%
94%
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7
8
aReaction conditions: 19b (1.0 mmol), RuCl[S,S)-TsDPEN](p-cymene), HCOOH,
b
c
TEA, DMF (2 mL); 0℃-rt. S/C = Substrate/Catalyst (molar ratio). F/T = HCOOH /
d
TEA (molar ratio = 5:2). Determined by HPLC equipped with a chiral IC column.
eunder N2 atmosphere.
From the results in Table 3, racemate 18b and its enantiomers are all selective
5-HT2C receptor agonist with no effect on 5-HT2A and 5-HT2B receptor, whereas both
of the enantiomers show weaker potency at the 5-HT2C receptor than its racemate (Fig.
5 and 6). Although (S)-18b (MQ02-592) showed slightly less potency than racemate
18b (139.3 vs 103.1 nM), it exhibited 12-fold more potency than (R)-18b at the
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5-HT2C receptor (139.3 vs 1658 nM). The significant effect of C6a-stereochemistry in
aporphine skeleton on the 5-HT2C receptor functionality assay was first observed in
our studies. It is of note that R-(-)-enantiomer aporphines typically are more potent
DA agonists while S-(+)-antipode aporphines usually have DA antagonist effects in
various assays,43, 44 e.g. R-(-)-apomorphine as a DA agonist and S-(+)-apomorphine as
weak agonist, partial-agonist, or antagonist effects at DA receptors.24
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Table 3. Effects of (+)- and (-)-enantiomers of the most potent compound 18b in
Calcium Flux Assay
5HT2C
5HT2B
5HT2A
No
e.e.
0
[] 2D5
EC50（nM） Emax（%） EC50（nM） Emax（%） EC50（nM） Emax（%）
103.1 ±
0.04
96.0 ±
1.06
18b
-
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
139.3 ±
0.15
81.8 ±
2.27
(S)-18b 96.1 +92.9
(R)-18b 94.0 -92.0
1658 ±
0.10
70.3 ±
1.93
EC50 and Emax values are shown as the mean ± SEM (n ≥ 2). “NA” indicates no
activity up to 10 μM. Data were obtained from two independent experiments
performed in triplicate.
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Fig. 5. Representative intracellular calcium release responses of 18b and its isomers
(S)-18b and (R)-18b at human 5-HT2C receptors compared with 15781. Emax and EC50
values of these compounds are listed in Table 2.
Fig. 6. Representative intracellular calcium release responses of (S)-18b (MQ02-592)
at human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Emax and EC50 values of these
compounds are listed in Table 2.
Functional profiles of Compound 18b and its Enantiomers at 5-HT2A and
5-HT2B receptors. To further determine the functional profiles of 18b and its
enantiomers, (S)-18b and (R)-18b, at 5-HT2A and 5-HT2B receptors, these three highly
potent 5-HT2C agonists were evaluated in an antagonist mode. As shown in Fig. 7, all
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of them acted as weak antagonists, and they were more potent in inhibiting the
calcium flux activated by 5-HT at 5-HT2B receptors than 5-HT2A receptors. Moreover,
(S)-18b was similarly more potent than (R)-18b in inhibiting the calcium flux at both
5-HT2A (IC50: 4.5 vs 111.5 µM) and 5-HT2B receptors (IC50: 1.4 vs 90.5 µM). Thus,
18b and its enantiomers are potent 5-HT2C receptor agonists, and weak 5-HT2A and
5-HT2B antagonists. Compared with nonselective 5-HT2 antagonist (–)-crebanine (1,
Fig. 2), it indicates the substitutions on aporphine scaffolds may result in their
function difference at 5-HT2 subfamily members.
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Fig. 7. Functional profiles of 18b, (S)-18b, and (R)-18b at human 5-HT2A and 5-HT2B
receptors.
Molecular docking studies. In order to examine the interaction pattern between
the most potent and selective agonist, compound (S)-18b and 5-HT2C, the compound
(S)-18b was selected and docked into the binding pocket of ergotamine-5-HT2C
crystal complex (PDB ID: 6BQG)45 using extra precision (XP) scoring function of
Glide docking. The binding pose and interaction pattern between compound (S)-18b
and 5-HT2c were shown in Fig. 8. As can be seen in Fig. 8, the molecular docking
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prediction results demonstrated that the most important key residue for compound
(S)-18b binding was V135. The arene-H interaction can be explicitly observed
between compound (S)-18b and V135 in the binding site of 6BQG. As described in
the previous study,46 the most important favorable residue for ergotamine binding
with 5-HT2C was D134. A strong salt bridge interaction can be found between
ergotamine and D134. Considering the inherent nature of GPCR targets, different
chemical scaffolds or even minor modifications for same chemical scaffold may
generate different interaction patterns in the binding site of 5-HT2c. This finding may
provide some clues to develop more promising 5-HT2c agonists with novel scaffold
architectures by employing rational-drug-design approaches.
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Fig. 8. The predicted binding pose (a) and interaction pattern (b) between compound
(S)-18b and 5-HT2c (PDB ID: 6BQG).
Summary. Aporphines were first identified as a new class of 5-HT2C receptor
agonists. SAR results indicate that the aporphine core may be required for 5-HT2C
receptor activity, and C1 position may be a key position to modify in order to improve
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agonist activity for 5-HT2C receptors. Our efforts to optimize our hit 15781 led to the
identification of the highly potent and selective 5-HT2C agonist 18b (MQ02-439)
possessing an EC50 of 104 nM, and weak antagonism at the 5-HT2A and 5-HT2B
receptor. Further profiling of the biological effects in animal models of behavior and
systematic optimizations based upon identified lead 18b toward high potency and
selectivity are under way, and the findings will be reported in due course.
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MATERIALS AND METHODS
Cell Lines and Cell Culture. The calcium flux assays were performed with
Flp-In T-rex 293 cells stably expressed 5-HT2A/2B/2C receptors.47 The stable cell lines
were cultured in DMEM containing 10% fetal bovine serum (FBS), 0.5%
Penicillin/Streptomycin and contained selection antibotics, 10 µg/mL Blasticidin and
100 µg/mL Hygromycin B in a humidified atmosphere at 37°C and 5% CO2.
Intracellular Calcium Flux Assay. Intracellular calcium (Cai+2) release was
monitored using the Fluo-4 Direct Calcium Assay Kit (Invitrogen) according to
previously published protocols with minor modifications.31 Cells were plated at
15000 cells/well in black-sided, clear bottomed 384-well tissue culture plates and
allowed to adhere overnight. Medium was removed and replaced with Fluo-4 Direct
dye reconstituted in FLIPR buffer (1× HBSS, 2.5 mM probenecid and 20 mM
HEPES, pH 7.4) Plates were incubated for 60 min at 37 °C followed by 30 min at
room temperature in the dark. Drug dilutions were prepared at 3× final concentration
in FLIPR buffer and aliquotted into 384-well source plate. The cell plate and the
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source plate were placed to the FLIPRTETRA. The fluidics module and plate reader of
the FLIPRTETRA were programmed to read baseline fluorescence prior to reading drug
dilutions (1 read/s per well). For the antagonist mode, 5-HT (3 nM) was used to
activate the receptor.
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Data Analysis. The response in each well was normalized to the average of the
baseline fluorescence. Then, the fold was determined by the maximum response over
the baseline fluorescence. The folds were plotted as a function of drug concentration,
normalized to the percent of 5-HT with 100% as the 5-HT Emax and 0% as the
baseline, and the EC50 was determined using log (agonist) vs. response (4-parameter)
or log (antagonist) vs response in GraphPad Prism 7.0. Data represent means ± SEM
of two independent experiments performed in triplicate.
Molecular Docking Procedure. First of all, the crystal structure of 5-HT2C
interacting with agonist, ergotamine was retrieved from the RCSB Protein Data Bank
(PDB ID; 6BQG).45 The Receptor Grid Generation mode in Glide of Schrödinger
9.048 was used to generate binding pocket for molecular docking. The binding site
with the size of 10 Å × 10 Å × 10 Å and centered on the centroid of the ergotamine of
6BQG. Then, the most potent 5-HT2C agonist, compound (S)-18b was preprocessed
using the LigPrep module in Glide. The ionized states and tautomers were generated
at pH = 7.0 ± 2.0 and the different combinations of chiralities were also generated by
setting the maximum number of stereoisomers to 32 by using Epik. Finally, the all
tautomers of compound (S)-18b were docked into the binding site of 6BQG and
scored by applying Glide docking.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acschemneuro.xxxx.xx.xxx.
Procedure for synthesis of new compounds; optimization of asymmetric
1
13
hydrogenation reaction conditions; H and C NMR and HPLC files of synthetic
intermediates and final products.
AUTHOR INFORMATION
Corresponding Author
Tel: +86-512-65881161; E-mail, yena@suda.edu.cn. (N. Ye).
Tel:+86-21-20685595; E-mail, shuiwq@shanghaitech.edu.cn. (W. Shui).
Author Contributions
1Q.M. and B.Z. contributed equally to this work. N.Y. conceived the project, and
oversaw and designed the chemistry. Q.M. and W.L. performed synthetic chemistry
work. B.Z. performed the pharmacology experiments, and W.S. interpreted the data.
S. T. performed molecular docking. N. Y., W.S., Q.M., B.Z., S.T. and W.L. wrote the
paper.
Funding
This work was supported by the National Natural Science Foundation of China
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(81703330, 31971362), the Natural Science Foundation of Jiangsu Province
(BK20170347), the Priority Academic Program Development of the Jiangsu Higher
Education Institutes (PAPD), and the Jiangsu Key Laboratory of Neuropsychiatric
Diseases (BM2013003). We very much thank Prof. Bryan Roth from UNC for kindly
providing us with the cell lines expressing 5-HT2 receptors and sharing their protocol.
We are grateful to Prof. Youyong Li in the Institute of Functional Nano & Soft
Materials (FUNSOM) at Soochow University for providing Schrödinger software for
molecular docking.
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Notes
The authors declare no competing financial interest.
ABBREVIATIONS
CNS, central nervous system; SAR, structure-activity relationship; HPLC,
high-performance liquid chromatography; DCM, dichloromethane; EtOAc, ethyl
acetate; e.e., enantionmeric excesses; CDI, N,N'-Carbonyldiimidazole; DMSO,
dimethyl sulfoxide; EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HOBt,
1-hydroxybenzotriazole; DMA, dimethylacetamide; TEA, triethylamine; TFAA,
trifluoroacetic anhydride; Tf2O, trifluoromethanesulfonic anhydride; PhDavePhos,
2-diphenylphosphino-2'-(N,N-dimethylamino)biphenyl; THF, tetrahydrofuran; DMF,
N,N-dimethylformamide; DPPF, 1,1'-bis(diphenylphosphino)ferrocene; LAH, lithium
aluminum hydride; Et2O, diethyl ether; RuCl[R,R)-TsDPEN](p-cymene),
Chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene
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)ruthenium(II); (Boc)2O, di-tert-butyl dicarbonate; RuCl[S,S)-TsDPEN](p-cymene),
Chloro{[(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)
ruthenium(II); BF3·OEt2; boron trifluoride etherate; DIBAL–H, diisobutylaluminium
hydride; DMP, Dess-Martin Periodinane. e.e., enantionmeric excesses; NCS,
N-chlorosuccinimide; ACN, acetonitrile.
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