Further SAR study on 11-O-substituted aporphine analogues: Identification of highly potent dopamine D3 receptor ligands

Article abstract of DOI:10.1016/j.bmc.2011.01.053

A series of new aporphine analogues (aporlogues) were prepared from appropriate aporphine precursors and arylpiperazines using the Click reaction protocol. These compounds displayed good to high affinity at the D₃ receptor, low or no affinity at the D₁ and D₂ receptors. Compounds 7f and 11c stood out as the most potent at the D₃ receptor among our newly synthesized aporlogues with K_i values of 2.67 and 1.14 nM, respectively. Further assay at the 5-HT_1A receptor revealed that aporlogues 7f and 11c also showed high affinity at this receptor with K_i values of 9.68 and 7.59 nM, respectively. They were 3.6- and 6.6-fold more potent at the D₃ over 5-HT_1A receptors. Such D₃/5-HT_1A dual property of these compounds may be useful in the treatment of several brain disorders.

Full text of DOI:10.1016/j.bmc.2011.01.053

Bioorganic & Medicinal Chemistry 19 (2011) 1999–2008
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Further SAR study on 11-O-substituted aporphine analogues: Identification
of highly potent dopamine D3 receptor ligands
Na Ye a, , QianQian Wu b, , Liyuan Zhu b, Longtai Zheng c, Bo Gao c, Xuechu Zhen b,c, , Ao Zhang a,
⇑
⇑
a Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
b State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
c Department of Pharmacology, Soochow University of Pharmaceutical Science, Suzhou, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new aporphine analogues (aporlogues) were prepared from appropriate aporphine precursors
and arylpiperazines using the Click reaction protocol. These compounds displayed good to high affinity at
the D3 receptor, low or no affinity at the D1 and D2 receptors. Compounds 7f and 11c stood out as the
most potent at the D3 receptor among our newly synthesized aporlogues with Ki values of 2.67 and
1.14 nM, respectively. Further assay at the 5-HT1A receptor revealed that aporlogues 7f and 11c also
showed high affinity at this receptor with Ki values of 9.68 and 7.59 nM, respectively. They were 3.6-
and 6.6-fold more potent at the D3 over 5-HT1A receptors. Such D3/5-HT1A dual property of these com-
pounds may be useful in the treatment of several brain disorders.
Received 7 January 2011
Revised 22 January 2011
Accepted 25 January 2011
Available online 31 January 2011
Keywords:
Aporphine analogues
Dopamine D3 receptor
5-HT1A receptor
Arylpiperazine
Ó 2011 Elsevier Ltd. All rights reserved.
Click reaction
1. Introduction
possessing substantial potency for the D2 receptor.5 The major
obstacle to achieve highly D3-selective compounds is attributed
Dopamine (DA) D3 receptor belongs to the D2-like subfamily of
dopamine receptors, including D2, D3 and D4, functionally distinct
from the D1-like subfamily (D1 and D5). Compared to the D2 recep-
tor, D3 receptor is much less abundant and predominantly distrib-
uted in the brain limbic region known to be associated with
cognitive and emotional functions.1 The highest expression of the
D3 receptor in humans is in the ventral striatum and associated
striatum.2,3 Therefore, D3 receptor is implicated in a variety of
brain functions and proposed as a promising therapeutic target
for a number of neurological and psychiatric disorders, including
schizophrenia, depression, drug abuse, Parkinson’s disease and
restless leg syndrome.4–9 Although tremendous D3 receptor active
compounds have been invented and evaluated in vitro and
in vivo,10 truly selective D3 receptor agonists or antagonists (over
the D2 receptor) with good solubility and bioavailability are rare.
For example, the well-known anti-Parkinsonian drug pramipexole
(1) is a D3 receptor-preferring agonist but with limited selectivity
among the D2-like receptors.11,12 The representative D3 receptor
antagonist BP 897 (2) is indeed a D3 receptor partial agonist
to the nearly identity of the amino acid residues in the binding do-
mains of D2 and D3 receptors, as well as the high degree (>70%) of
sequence identity within their transmembrane helices.3,8 Fortu-
nately, several differences in the extracellular binding sites of the
two DA receptors were identified recently from the crystal struc-
ture of the human D3 receptor in complex with a small D2/D3-spe-
cific antagonist.13 Hopefully, this will provide new directions for
the development of D3 receptor selective agents. In addition, accu-
mulating evidences have indicated that alteration of serotonin 1A
(5-HT1A) receptor function is also associated with a number of neu-
ropsychological disorders, including anxiety and depression,14,15
pain,16 neuroprotection,17,18 schizophrenia,19,20 Parkinson’s dis-
ease,21–23 and Alzheimer’s disease.24 Therefore, new agents selec-
tively acting at the D3 or both D3 and 5-HT1A receptors are highly
needed to explore their therapeutic benefits.
During our SAR study on the aporphine analogues (apor-
logues),25 we recently found that replacing the catecholic hydroxyl
groups of the D2 receptor agonist apomorphine (3, Fig. 1) with a
alkyletheric moiety led to a series of metabolic stable aporlogues.
These compounds showed potent affinity at several receptor tar-
gets (D1, D3, 5-HT1A, 5-HT2A) other than the original D2 receptors.
Among these compounds, 11-prop-2-ynyloxy aporlogue 425b dis-
played moderate affinity at the D3 receptor with Ki value of
⇑
Corresponding authors. Fax: +86 21 50806750 (X.Z.); tel.: +86 21 50806035;
fax: +86 21 50806600 (A.Z.).
E-mail addresses: xzhen@mail.shcnc.ac.cn (Xuechu Zhen), aozhang@mail.shcnc.
ac.cn (A. Zhang).
2.4
lM, while completely lost activity at both D1 and D2 receptors.
In view of the readily functional transformation capacity of the
These two authors contributed equally to this work.
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.01.053

2000
N. Ye et al. / Bioorg. Med. Chem. 19 (2011) 1999–2008
2
1
N
S
O
N6
H
H2N
6a
NH
NH
N
N
HO
O
11
HO10
pramipexole (1)
BP 897 (2)
apomorphine (3)
N
H
Ar
N
H
Click reaction
N
N
O
n O
N
N
m
N
4
D1, D2 - inactive
D3, Ki = 2.4 µM
Our designed aporlogues
(J Med Chem 2010, 53, 1319)
Figure 1. Representative D3 receptor agents and proposed aporphine analogues (aporlogues).
acetylenyl group in compound 4, we decided to explore the poten-
tial of generating more potent D3 receptor agents. Therefore, a ser-
ies of novel triazole-containing aporlogues were synthesized based
on hit 4 through the widely used click reaction protocol26 (Fig. 1).
in 90–93% yields (Scheme 1). However, the same procedure was
not successful in the preparation of aporlogue 7f due to the low
yield in preparation of precursor 6f. In the process of preparation
of compound 6f, a b-elimination reaction was generally observed
from the substrate 1-(4-chlorobutyl)-4-(2-methoxyphenyl)pipera-
zine. Alternatively, compound 7f was prepared in 56% yield by
alkylation of triazole 8. The precursor 8 was obtained by Click
reaction of aporphine 4 and 1-azido-4-chlorobutane28 in 94%
yield.
As a comparison, aporlogues 11a–d were prepared by switching
the functional groups (azido and acetylenyl) between the two
‘Click’ reaction precursors. As described in Scheme 2, azide 9 was
prepared by alkylation of phenol 5 followed by azidization in
89% overall yield. Meanwhile, arylpiperazines 10a–d equipped
with the prop-2-ynyl function were obtained in 85–99% yields.
Click reaction of azide 9 with arylpiperazines 10a–d provided the
expected aporlogues 11a–d in 88–95% yields.
2. Chemistry
The key intermediate, 11-hydroxy-N-propylnoraporphine 5,
was prepared by total synthesis in eight steps from Reissert salt
and arylmethylbromide according to the reported procedures.27
Alkylation of phenol 5 with propargyl bromide provided 11-
prop-2-ynyloxy N-propylnoraporphine 4 in 97% yield (Scheme 1).
Alkylation of commercially available arylpiperazines with an
appropriate chloroalkyl bromide followed by axidization with
NaN3 gave corresponding azide precursors 6a–e in 52–75% overall
yields. Click reaction26 of aporphine 4 with azides 6a–e under CuI/
DIPEA yielded the corresponding triazole-derived aporlogues 7a–e
Cl
m
N
N
N
O
N
iv
n
o
i
t
c
a
e
r
k
c
i
8
(m = 4, 94%)
7f
l
C
N
N
for
v
i
HO
O
Ar
N
N
vi
Click
N
m
N
5
4
N
(97%)
O
reaction
N
N3
m
ii,iii
6a
Ar
N
NH
Br
+
Ar
N
N
Cl
m
7a
(Ar = 2-MeO-Ph, m = 3, 93%)
7b
7c
7d
7e
7f
(Ar = 2,3-di-Cl-Ph, m = 3, 91%)
(Ar = 2-MeO-Ph, m = 3, 71%)
(Ar = Ph, m = 3, 92%)
6b
6c
6d
6e
(Ar = 2,3-di-Cl-Ph, m = 3, 73%)
(Ar = Pym-2-yl, m = 3, 92%)
(Ar = 2-MeO-Ph, m = 2, 90%)
(Ar = 2-MeO-Ph, m = 4, 56%)
(Ar = Ph, m = 3, 75%)
(Ar = Pym-2-yl, m = 3, 75%)
(Ar = 2-MeO-Ph, m = 2, 52%)
6f
(Ar = 2-MeO-Ph, m = 4, un successful)
Scheme 1. Reagents and conditions: (i) allyl bromide, KOH, KI, acetone, rt; (ii) chloroalkyl bromide, K2CO3, MeCN, 50 °C; (iii) DMSO, NaN3, 100 °C; (iv) 1-azido-4-
chlorobutane, CuI, DIPEA, THF, rt; (v) for 7f: 1-(2-methoxyphenyl)piperazine, NaI, K2CO3, MeCN, reflux; (vi) CuI, DIPEA, THF, rt.

N. Ye et al. / Bioorg. Med. Chem. 19 (2011) 1999–2008
2001
N
N
O
i, ii
HO
N
N
O
3
N3
iv
5
9
(89%)
N
Click
m
reaction
N
O
O
N
N
O
iii
N
N
N
NH
3
TsO
+
m
m
10a
(m = 4, 99%)
11a
(m = 4, 95%)
10b
10c
10d
(m = 3, 85%)
(m = 2, 90%)
(m = 1, 89%)
11b
11c
11d
(m = 3, 88%)
(m = 2, 90%)
(m = 1, 91%)
Scheme 2. Reagents and conditions: (i) 1-bromo-3-chloropropane, 50% aq NaOH; TBAB, rt; (ii) DMSO, NaN3, 100 °C; (iii) K2CO3, acetone, 50 °C; (iv) CuI, DIPEA, THF, rt.
O
N
N
N
i
N
ii
HO
O
4
Cl
N
O
4
5
12
(82%)
15 (80%)
iii
N
N
iv
v
H
N
O
N
O
Cl
HO
14 (83%)
13
(92%)
O
N
N
N
Ms
N
Ms
N
O
ii
O
MsO
17 (80%)
16 (81%)
Scheme 3. Reagents and conditions: (i) 1-bromo-4-chlorobutane, TBAB, 50% aq NaOH, rt; (ii) 1-(2-methoxyphenyl)piperazine, NaI, K2CO3, MeCN, reflux; (iii) 1-bromo-3-
chloropropane, 50% aq NaOH, TBAB, rt; (iv) 3-aminopropan-1-ol, n-BuOH, reflux; (v) MsCI, Et3N, CH2Cl2, rt.
In addition, similar aporlogues without the triazole or arylpip-
erazine functions were also prepared (Scheme 3). Alkylation of
phenol 5 with 1-bromo-4-chlorobutane gave compound 12 in
82% yield. Compound 12 was then treated with an appropriate
arylpiperazine leading to aporlogue 15 in 80% yield. Similarly,
alkylation of phenol 5 with 1-bromo-3-chloropropane yielded
chloride 13 in 92% yield, which was then treated with 3-amino-
propanyl alcohol giving aporlogue 14 in 83% yield. Double mesyla-
tion of alcohol 14 provided compound 16 in 81% yield. Reaction of
mesylate 16 with 1-(2-methoxyphenyl)piperazine yielded apor-
logue 17 in 80% yield.
concentration to inhibit the binding of a tritiated radioligand to
the corresponding receptor was tested. Compounds with inhibited
binding by more than 80% were further assayed at six or more con-
centrations, ranging above and below IC50. The Ki SE was then de-
rived from the equation Ki = IC50/1+[C/Kd]. These procedures were
similar to those reported previously by us.25b–d,26 [3H]-SCH23390
(D1) and [3H]-Spiperone (D2, D3) were used as the standard radio-
ligands. The inhibition or Ki values of the newly synthetic apor-
phines were summarized in Table 1.
Since the phenolic hydroxyl group in apomorphine (3) is an
essential request10e,25a for binding to the D2 receptor, it is conceiv-
able that the newly synthetic aporlogues, as well as compound 4,
did not show appreciable affinity at this receptor. However, signif-
icant potency was observed at the D3 receptor. First, compounds
7a–d represented a small series of aporlogues bearing variant aryl-
piperazine functions. Compared to the initial ether 4, 4–10-fold
higher potency was observed in these compounds at the D3 recep-
tor. Aporlogues 7a and 7b with 2-methoxyphenyl- and 2,3-dichlo-
rophenyl as the N-4 aryl substituent in the piperazine component,
respectively, showed the highest D3 receptor affinity among this
3. Biological activity
3.1. DA D1, D2, and D3 receptor binding assays
All the newly synthetic aporlogues 7a–f, 11a–d and 14, 15, 17
were subjected to the competitive binding assays for the three
DA receptors, respectively, using membrane preparation obtained
from stable transfected HEK293 cells. First, the ability at 10 lM

2002
N. Ye et al. / Bioorg. Med. Chem. 19 (2011) 1999–2008
Table 1
In vitro binding assays of new aporlogues at D1, D2 and D3 receptors in HEK293 cellsa
Compound
Structure
Inhibition (%) or Kib (nM)
D1
—
D2
D3
N
4
28%
2400 75
O
O
N
N
7a
67%
1203 17
21 1.4
N
N
N
O
N
Cl
Cl
N
N
7b
2007 206
40.49%
35 4.9
N
N
N
O
N
N
N
N
N
7c
63%
6.0%
191 38
N
N
N
O
N
N
N
O
N
N
7d
32%
13%
539 71
N
O
N
N
N
7e
35%
19%
44 7.7
N
N
N
O
N
O
N
N
7f
2700 147
661 1.1
2.67 0.29
N
N
N
O
N

N. Ye et al. / Bioorg. Med. Chem. 19 (2011) 1999–2008
2003
Table 1 (continued)
Compound
Structure
Inhibition (%) or Kib (nM)
D1
D2
D3
O
N
N
11a
1900 53
206 11
8.14 0.79
N
N
N
O
N
O
N
N
11b
14%
18%
8.16 0.49
N
N
N
O
N
O
N
N
11c
64%
7384 1090
1.14 0.02
N
N
N
O
N
N
O
N
11d
42%
51%
281 36
N
N
N
O
N
N
H
14
15
44%
9%
4514 406
19.9 1.16
102 5.7
HO
N
O
O
N
N
735 40
88 8.0
N
O
O
N
N
Ms
N
17
910 122
399 12
O
N
a
Values are means of three to five experiments, and all compounds were tested in racemic form.
Only compounds with inhibition of radioligand binding higher than 80% was further tested for Ki values.
b

2004
N. Ye et al. / Bioorg. Med. Chem. 19 (2011) 1999–2008
small series. They exhibited Ki values of 21 and 35 nM, respec-
tively. Non-substituted phenylpiperazin-4-yl- (7c) and 1-hetero-
aryl (1,3-pyrimid-2-yl) substituted piperazin-4-yl- (7d) analogues
showed moderate affinity at this receptor. Shortening the alkyl lin-
ker between the arylpiperazine and triazole core led to compound
7e which retained good affinity at the D3 receptor (44 nM). Elonga-
tion of the alkyl linker gave compound 7f showing a significant
enhancement. This compound has a Ki value of 2.7 nM at the D3
receptor, 100-fold more potent than the initial aporphine 4. Inter-
estingly, compound 7f also displayed substantial affinity at the D2
receptor with a Ki value of 661 nM.
Compounds 11a–d represented another series of aporlogues
with the triazole fragment formed in a different manner. On
the basis of the optimizing results in aporlogues 7a–d, the
2-methoxyphenyl group was directly selected as the terminal
N-substituent in piperazine fragment. Compounds 11a and 11b
contained a four- and three-methylene unit as the linkage be-
tween the arylpiperazine and triazole moieties, respectively.
They displayed identical Ki values at the D3 receptor (8.1 nM).
It is quite intriguing that the former compound (11a) showed
moderate affinity at the D2 receptor as well. Further shortening
the linkage to a two-methylene unit led to aporlogue 11c, exhib-
iting very potent affinity with a Ki value of 1.14 nM. However,
compound 11d with a one-methylene linkage displayed remark-
ably reduced potency. It showed a Ki value of 281 nM that is
246-fold less potent than aporlogue 11c.
3.3. 5-HT1A and 5-HT2A receptor binding assays
During our previous report,25a,b we found that many aporlogues
with lipophilic substituents at either the C10 or C11 or both showed
substantial potency at the serotonin (5-HT) receptors, especially
5-HT1A and 5-HT2A subtypes. To confirm if this is also the case for
our newly synthetic D3 receptor ligands, we further evaluated the
binding profile of aporlogues 7f, 11c and 15 at the 5-HT1A and
5-HT2A receptors. [3H]8-OH-DPAT and [3H]ketanserin were used as
the standard radioligands, respectively, by following a procedure
we reported before.25a–d,26 As summarized in Table 3, these com-
pounds generally displayed good affinity at the 5-HT1A receptor,
and moderate or no affinity at the 5-HT2A receptor. The triazole-con-
taining aporlogues 7f and 11c showed Ki values of 9.68 and 7.59 nM
at the 5-HT1A receptor, respectively. There were 18- and 32-fold
selective over 5-HT2A receptor. Much lower affinity was observed
for compound 15 at the 5-HT1A and 5-HT2A receptors. This result
indicated that the H-bonding potential of the triazole moiety may
be contributed to the interaction of the new aporlogues with the
5-HT receptors. In spite of the significant potency at the 5-HT1A
receptor, compounds 7f and 11c were 3.6- and 6.6-fold selective
for the D3 over 5-HT1A receptors, respectively.
4. Conclusion
In summary, a series of new aporlogues were prepared from
appropriate aporphine precursors and arylpiperazines using the
Click reaction strategy. These compounds generally displayed good
to high affinity at the D3 receptor, whereas low or no affinity at the
D1 and D2 receptors. Among these new aporlogues, compounds 7f
and 11c were identified as the most potent at the D3 receptor. They
displayed Ki values of 2.67 and 1.14 nM, respectively, at this recep-
tor. Further assay at the 5-HT1A receptor revealed that aporlogues
7f and 11c also showed high affinity at this receptor with Ki values
of 9.68 and 7.59 nM, respectively. They were 3.6- and 6.6-fold
more potent at the D3 over 5-HT1A receptors. In view of the prom-
ising role of 5-HT1A receptor in a number of neuropsychological
disorders, such D3/5-HT1A dual action compounds may find use
in the treatment of these brain disorders. Further efforts will be fo-
cused on the functional assay of these compounds at the two
receptors.
To evaluate the contribution of arylpiperazine and triazole func-
tions to the binding affinity at the D3 receptor, aporlogues 14, 15
and 17 were investigated as a control. Compound 14 lacking both
arylpiperazine and triazole moieties displayed negligible potency
at the D3 receptor. However, compound 15 bearing an arylpiper-
azine moiety but lacking triazole function retained significant
affinity with a Ki value of 20 nM. Interestingly, this compound also
showed good affinity at the D2 and moderate affinity at the D1
receptors, with Ki values of 88 and 735 nM at the two receptors,
respectively. Similar receptor selectivity profile was observed for
compound 17, although it is much less potent at all the three DA
receptors. These results indicated that the good potency at the D3
receptor for these compounds may be irrelevant to the triazole
function, whereas the arylpiperazine moiety likely offered signifi-
cant contribution to the D3 receptor binding.
3.2. Binding profiles of the (+)- and (ꢀ)-enantiomers of
5. Experimental
compounds 7f, 11c and 15
1H NMR spectral data were recorded in CDCl3 on Varian Mer-
cury 300 NMR spectrometer and 13C NMR were recorded in CDCl3
on Varian Mercury 400 NMR spectrometer. Low-resolution mass
spectra (MS) and high-resolution mass spectra (HRMS) were re-
corded at an ionizing voltage of 70 eV on a Finnigan/MAT95 spec-
trometer. Column chromatography was carried out on silica gel
(200–300 mesh). All reactions were monitored using thin-layer
chromatography (TLC) on silica gel plates. Yields were of purified
compounds and were not optimized. Compounds 4,25b 527 were
prepared according to the literature procedures.27
From the results above, compounds 7f, 11c and 15 stood out
as the most potent D3 receptor aporlogues synthesized in this re-
port. Since these compounds were recemates, they were resolved
to their corresponding (+)- and (ꢀ)-enantiomers, respectively by
chiral AD column with ethyl alcohol/diethylamine as the mobile
phase (Table 2). From the results in Table 2, all the enantiomers
of these compounds did not show better affinity at the D3 recep-
tor than their corresponding racemates. (+)-7a and (ꢀ)-7a exhib-
ited almost identical affinity (8.0 vs 9.18 nM) and were threefold
less potent than racemic 7a. However, in the case of aporlogue
11c, the (ꢀ)-enantiomer (ꢀ)-11c displayed similar high potency
as the racemate with Ki values of 1.8 and 1.1 nM, respectively.
While the (+)-enantiomer, (+)-11c was fourfold less potent than
either the (ꢀ)-enantiomer or the racemate. Quite differently,
(+)-15 was equally potent to its racemate 15, whereas (-)-15
was 10-fold less potent than the racemate. Although the effect
of C6a-stereochemistry in aporphine skeleton on the D3 receptor
binding affinity was not universal, significant difference does ex-
ist in our study, especially in aporlogues 10c and 15. It is of note
that such significant difference was not observed at the D2
receptor.
5.1. General procedure for preparation of azides 6a–e
An appropriate arylpiperazines (1.0 equiv), chloroalkyl bromide
(10.0 equiv) and K2CO3 (2.0 equiv) were stirred at 50 °C for 2 h. The
reaction suspension was filtered and the filtrate was concentrated.
The crude material was chromatographed to give the correspond-
ing chloride derivatives that were used directly for the next step.
The mixture of the chloride obtained above (1.0 equiv) and
NaN3 (2.0 equiv) was dissolved in DMSO (5 mL) and stirred at
100 °C for 2 h. After cooling to rt, the reaction mixture was diluted

N. Ye et al. / Bioorg. Med. Chem. 19 (2011) 1999–2008
2005
Table 2
Binding profiles of (+)- and (ꢀ)-enantiomers of the most potent compounds
½ ꢁ
a 2D0
Compd
ee%
Inhibition (%) or Ki (nM)
D1
D2
D3
7f
0
—
2700 147
66%
1600 130
64%
68%
54%
735 40
1174 143
1307 236
661 1.1
293 17
616 38
7384 1090
600 4.6
770 156
88 8.0
174 4.45
141 0.88
2.67 0.29
8.0 1.19
9.18 1.26
1.14 0.02
1.82 0.09
7.70 1.74
19.9 1.16
189 13
(ꢀ)-7f
(+)-7f
11c
(ꢀ)-11c
(+)-11c
15
99.8
100
0
99.7
100
0
ꢀ32.7 (1.10, MeOH)
29.6 (1.25, MeOH)
—
ꢀ63.2 (0.90, MeOH)
66.2 (0.85, MeOH)
—
(ꢀ)-15
99.8
99.0
ꢀ36.8 (1.30, MeOH)
(+)-15
42.6 (1.25, MeOH)
23.4 4.98
Table 3
In vitro binding assays of new aporlogues at 5-HT1A and 5-HT2A receptors in CHO cells
27.9 Hz), 4.44 (t, 2H, J = 6.9 Hz), 3.85 (s, 3H), 3.36 (d, 1H,
J = 12.3 Hz), 3.12 (m, 7H), 3.02 (m, 1H), 2.83 (m, 1H), 2.54 (m,
9H), 2.09 (m, 2H), 1.58 (m, 2H), 0.96 (t, J = 7.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 155.1, 152.1, 144.3, 141.1, 138.4, 135.2,
132.9, 131.4, 128.0, 127.5, 126.2, 125.6, 123.5, 122.9, 121.4,
120.9, 118.1, 112.1, 111.1, 63.0, 59.5, 56.4, 55.3, 54.4, 53.2, 50.5,
48.8, 48.1, 35.1, 29.1, 27.2, 19.5, 12.0. MS (EI, [M+]) m/z 592; HR-
MS (EI) calcd for C36H44N6O2: 592.3544, found: 592.3526.
Compound
Ki (nM)
5-HT1A
5-HT2A
D3
7f
11c
15
9.68 2.11
7.59 0.13
58 5.3
174 20
245 41
100,000
2.67 0.29
1.14 0.02
19.9 1.16
with CHCl3, washed with water, brine, and then dried over anhy-
drous Na2SO4. The solvents were removed and the residue was
subjected to chromatograph giving the corresponding azides 6a–e.
5.2.2. 11-((1-(3-(4-(2,3-Dichlorophenyl)piperazin-1-yl)propyl)-
1H-1,2,3-triazol-4-yl)methoxy)-N-propylnoraporphine (7b)
Yield 91%; 1H NMR (300 MHz, CDCl3): d 8.09 (d, 1H, J = 7.5 Hz),
7.60 (s, 1H), 7.02 (m, 8H), 5.31 (dd, 2H, J = 12.0, 27.0 Hz), 4.44 (t,
2H, J = 6.9 Hz), 3.29 (d, 1H, J = 12.3 Hz), 3.12 (m, 8H), 2.73 (m, 1H),
5.1.1. 1-(3-Azidopropyl)-4-(2-methoxyphenyl)piperazine (6a)
Yield 71% (for two steps); 1H NMR (300 MHz, CDCl3): d 6.93 (m,
3H), 6.86 (m, 1H), 3.85 (s, 3H), 3.35 (t, 2H, J = 6.9 Hz), 3.09 (br s,
4H), 2.65 (br s, 4H), 2.49 (t, 2H, J = 6.9 Hz), 1.81 (m, 2H).
2.29 (m, 9H), 2.09 (m, 2H), 1.60 (m, 2H), 0.96 (t, 3H, J = 7.8 Hz). 13
C
NMR (100 MHz, CDCl3) d 155.0, 151.0, 144.3, 138.6, 135.5, 133.9,
133.1, 131.4, 127.9, 127.4, 127.3, 126.1, 125.5, 124.5, 123.6, 122.9,
121.4, 118.5, 112.0, 63.0, 59.5, 56.5, 54.3, 53.0, 51.1, 48.9, 48.0,
35.2, 29.3, 27.1, 19.6, 12.0. MS (EI, [M]+) m/z 630; HR-MS (EI) calcd
for C35H40N6OCl2: 630.2483, found: 630.2641.
5.1.2. 1-(3-Azidopropyl)-4-(2,3-dichlorophenyl)piperazine (6b)
Yield 73% (for two steps); 1H NMR (300 MHz, CDCl3): d 7.11 (m,
2H), 6.93 (m, 1H), 3.34 (t, 2H, J = 6.3 Hz, 6.9 Hz), 3.03 (br s, 4H),
2.60 (br s, 4H), 2.47 (dd, 2H, J = 6.3, 7.5 Hz), 1.78 (m, 2H).
5.2.3. 11-((1-(3-(4-Phenylpiperazin-1-yl)propyl)-1H-1,2,3-
triazol-4-yl)methoxy)-N-propylnoraporphine (7c)
5.1.3. 1-(3-Azidopropyl)-4-phenylpiperazine (6c)
Yield 92%; 1H NMR (300 MHz, CDCl3): d 8.10 (d, 1H, J = 8.1 Hz),
7.60 (s, 1H), 7.06 (m, 10H), 5.31 (dd, 2H, J = 12.3, 26.7 Hz), 4.44 (t,
2H, J = 6.9 Hz), 3.36 (dd, 1H J = 2.7, 10.8 Hz), 3.14 (m, 7H), 2.90 (m,
1H), 2.73 (m, 1H), 2.50 (m, 7H), 2.32 (t, 2H, J = 3.9 Hz), 2.10 (m, 2H),
1.60 (m, 2H), 0.98 (t, 3H, J = 7.8 Hz). 13C NMR (100 MHz, CDCl3) d
155.1, 151.1, 144.3, 138.6, 135.5, 133.0, 131.4, 129.0, 128.0,
127.5, 126.2, 125.6, 123.6, 122.9, 121.4, 119.7, 116.0, 112.1, 63.0,
59.5, 56.5, 54.3, 53.0, 49.1, 48.9, 48.1, 35.2, 29.3, 27.2, 19.6, 12.0.
MS (EI, [M+]) m/z 562; HR-MS (EI) calcd for C35H42N6O: 562.3447,
found: 562.3420.
Yield 75% (for two steps); 1H NMR (300 MHz, CDCl3): d 7.25 (m,
2H), 6.94 (m, 2H), 6.85 (m, 1H), 3.37 (dd, 2H, J = 6.6, 6.9 Hz), 3.20
(m, 4H), 2.61 (m, 4H), 2.49 (dd, 2H, J = 6.9, 7.5 Hz), 1.81 (m, 2H).
5.1.4. 2-(4-(3-Azidopropyl)piperazin-1-yl)pyrimidine (6d)
Yield 75% (for two steps); 1H NMR (300 MHz, CDCl3): d 8.23 (d,
2H, J = 4.5 Hz), 6.43 (t, 1H, J = 4.8 Hz), 3.79 (t, 4H, J = 4.8 Hz), 3.33 (t,
2H, J = 6.9 Hz), 2.43 (m, 6H), 1.75 (m, 2H).
5.1.5. 1-(2-azidoethyl)-4-(2-methoxyphenyl)piperazine (6e)
Yield 52% (for two steps); 1H NMR (300 MHz, CDCl3): d 6.87 (m,
4H), 3.85 (s, 3H), 3.39 (dd, 2H, J = 6.0, 6.3 Hz), 3.11 (br s, 4H), 2.69
(m, 6H).
5.2.4. 11-((1-(3-(4-Pyrimidinpiperazin-2-yl)propyl)-1H-1,2,3-
triazol-4-yl)methoxy)-N-propylnoraporphine (7d)
Yield 92%; 1H NMR (300 MHz, CDCl3): d 8.28 (d, 2H, J = 5.4 Hz),
8.07 (d, 1H, J = 7.5 Hz), 7.58 (s, 1H), 7.06 (m, 5H), 6.47 (t, 1H,
J = 4.5 Hz), 5.29 (dd, 2H. J = 12.6, 27.6 Hz), 4.44 (t, 2H, J = 6.9 Hz),
3.77 (m, 4H), 3.39 (d, 1H, J = 12.3 Hz), 3.14 (m, 3H), 2.90 (m, 1H),
2.73 (m, 1H), 2.35 (m, 9H), 2.09 (m, 2H),1.58 (m, 2H), 0.96 (t, 3H,
5.2. General procedure for preparation of aporlogues 7a–e by
Click reaction
A mixture of alkyne 4 (1.0 equiv), CuI (0.2 equiv), and an appro-
priate azide 6 (1.1 equiv) in THF (5 mL) was stirred for 5 min. N,N-
Diisopropylethylamine (DIPEA, 5.0 equiv) was added slowly. The
mixture was stirred at rt overnight. The solid was filtered off and
the filtrate was concentrated. The crude material was subjected
to chromatography to afford the desired cyclization products 7a–e.
J = 7.8 Hz). 13C NMR(100 MHz, CDCl3):
d 161.5, 157.6, 155.1,
144.4, 138.5, 135.3, 133.0, 131.4, 128.0, 127.5, 126.2, 125.6,
123.6, 122.8, 121.4, 112.1, 109.8, 63.0, 59.5, 56.4, 54.5, 52.9, 48.9,
48.1, 43.5, 35.1, 29.2, 27.2, 19.6, 12.0. MS (EI, [M+]) m/z 564; HR-
MS (EI) calcd for C33H40N8O: 564.3325, found: 564.3325.
5.2.5. 11-((1-(3-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-1H-
1,2,3-triazol-4-yl) methoxy)-N-propylnoraporphine (7e)
5.2.1. 11-((1-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)propyl)-
1H-1,2,3-triazol-4-yl)methoxy)-N-propylnoraporphine (7a)
Yield 93%; 1H NMR (300 MHz, CDCl3): d 8.10 (d, 1H, J = 8.4 Hz),
7.60 (s, 1H), 7.16 (m, 2H), 6.93 (m, 7H), 5.30 (dd, 2H, J = 12.6,
Yield 90%; 1H NMR (300 MHz, CDCl3):
d
8.10 (d, 1H,
J = 8.4 Hz), 7.75 (s, 1H), 7.05 (m, 9H), 5.30 (dd, 2H, J = 12.6,

2006
N. Ye et al. / Bioorg. Med. Chem. 19 (2011) 1999–2008
28.5 Hz), 4.48 (t, 2H, J = 6.9 Hz), 3.85 (s, 3H), 3.18 (d, 1H,
J = 7.8 Hz), 2.99 (m, 11H), 2.59 (m, 7H), 1.63 (m, 2H), 0.97 (t,
5.4.3. 1-(2-Methoxyphenyl)-4-(but-3-ynyl)piperazine (10c)
Yield 90%; 1H NMR (300 MHz, CDCl3): d 6.87 (m, 4H), 3.86 (s,
3H), 3.10 (br s, 4H), 2.68 (m, 6H), 2.42 (m, 2H), 1.99 (m, 1H).
3H, J = 7.8 Hz). 13C NMR (100 MHz, CDCl3):
d 155.1, 152.1,
144.3, 140.9, 138.5, 135.3, 132.9, 131.4, 128.0, 127.5, 126.2,
125.6, 123.6, 123.2, 123.0, 121.4, 120.9, 118.2, 112.2, 111.1,
63.0, 59.5, 57.5, 56.4, 55.3, 53.3, 50.5, 48.9, 47.6, 35.1, 29.2,
19.5, 12.0. MS (EI, [M+]) m/z 578; HR-MS (EI) calcd for
5.4.4. 1-(2-Methoxyphenyl)-4-(prop-2-ynyl)piperazine (10d)
Yield 91%; 1H NMR (300 MHz, CDCl3): d 6.91 (m, 4H), 3.86 (s,
3H), 3.36 (d, 2H, J = 2.7 Hz), 3.13 (br s, 4H), 2.78 (m, 4H), 2.72 (t,
1H, J = 2.4 Hz).
C35H42N6O2: 578.3373, found: 578.3369.
5.5. General procedure for synthesis of aporlogues 11a–d by
Click reaction
5.3. 11-((1-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl)-1H-
1,2,3-triazol-4-yl) methoxy)-N-propylnoraporphine (7f)
The procedure is same as that for preparation of aporlogues
7a–e.
A
mixture of alkyne 4 (32 mg, 0.10 mmol), CuI (4 mg,
0.02 mmol), and 1-azido-4-chlorobutane (16 mg, 0.12 mmol) in
THF (5 mL) was stirred for 5 min. N,N-Diisopropylethylamine (DI-
PEA, 0.09 mL, 0.5 mmol) was added slowly, and the mixture was
stirred at rt overnight. The reaction suspension was filtered and
then concentrated. The crude material was chromatographed to af-
ford cyclization product 8 (42 mg, 94%). 1H NMR (300 MHz, CDCl3):
d 8.08 (d, 1H, J = 7.5 Hz), 7.56 (s, 1H), 7.17 (m, 2H), 7.03 (dd, 2H,
J = 6.9, 8.4 Hz), 6.95 (d, 1H, J = 7.5 Hz), 5.28 (dd, 2H, J = 12.3,
42.6 Hz), 4.38 (t, 2H, J = 6.6, 7.2 Hz), 3.45 (m, 3H), 3.14 (m, 3H),
2.92 (m, 1H), 2.75 (d, 1H, J = 16.2 Hz), 2.50 (m, 3H), 2.07 (m, 2H),
1.78 (m, 2H), 1.61 (m, 2H), 0.97 (dd, 3H, J = 7.2, 7.5 Hz). MS (EI,
[M+]) m/z 450.
Compound 8 (27 mg, 0.06 mmol) and NaI (11 mg, 0.07 mmol)
were mixed in MeCN (10 mL) and the mixture was refluxed for
1 h. 1-(2-Methoxyphenyl)piperazine (14 mg, 0.07 mmol) and
K2CO3 (17 mg, 0.12 mmol) were added and the mixture was re-
fluxed overnight. The reaction mixture was concentrated, diluted
with CH2Cl2 and water. After separation, the organic phase was
washed with brine and dried. The solvents were removed and
the residue was subjected to chromatography (CH2Cl2/
MeOH = 25:1, 1% NH4OH) to give final compound 15 as a colorless
oil (20 mg, 56%). 1H NMR (300 MHz, CDCl3): d 8.09 (d, 1H,
J = 8.4 Hz), 7.57 (s, 1H), 7.18 (q, 2H, J = 7.6 Hz), 6.94 (m, 7H), 5.29
(dd, 2H, J = 12.0, 29.7 Hz), 4.38 (t, 2H, J = 6.9 Hz), 3.85 (s, 3H),
3.36 (dd, 1H, J = 7.5, 3.0 Hz), 3.14 (m, 7H), 2.90 (m, 1H), 2.74 (m,
1H), 2.53 (m, 4H), 2.43 (m, 4H), 2.02 (m, 3H), 1.63 (m, 4H), 0.97
(t, 3H, J = 7.8 Hz). 13C NMR (100 MHz, CDCl3): d 155.1, 152.2,
144.5, 141.1, 138.6, 135.5, 133.0, 131.4, 128.0, 127.5, 126.2,
125.5, 123.6, 122.9, 122.3, 121.4, 120.9, 118.1, 112.1, 111.0, 63.1,
59.5, 57.6, 56.5, 55.3, 53.4, 50.5, 50.2, 48.9, 35.2, 29.3, 28.2, 23.7,
19.6, 12.0. MS (EI, [M+]) m/z 606; HR-MS (EI) calcd for
5.5.1. 11-(3-(4-((4-(2-Methoxyphenyl)piperazin-1-yl)butyl)-1H-
1,2,3-triazol-1-yl) propoxy)-N-propylnoraporphine (11a)
Yield 95%; 1H NMR (300 MHz, CDCl3): d 8.09 (d, 1H, J = 7.5 Hz),
7.13 (m, 4H), 6.94 (m, 4H), 6.85 (d, 2H, J = 8.1 Hz), 4.50 (m, 2H),
4.16 (m, 1H), 3.85 (s, 3H), 3.83 (m, 1H), 3.38 (d, 1H, J = 12.9 Hz),
3.15 (m, 7H), 2.93 (m, 2H), 2.74 (m, 7H), 2.43 (m, 6H), 1.65 (br s,
6H), 0.98 (t, 3H, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): d 155.4,
152.1, 147.6, 140.9, 138.5, 135.4, 133.1, 131.4, 128.0, 127.6,
126.1, 125.7, 123.5, 123.0, 121.4, 121.3, 120.9, 118.2, 112.0,
111.0, 65.1, 59.6, 58.2, 56.4, 55.3, 53.3, 50.1, 48.9, 46.9, 35.1,
30.0, 29.2, 27.2, 25.9, 25.3, 19.5, 12.0. MS (EI, [M+]) m/z 634; HR-
MS (EI) calcd for C39H50N6O2: 634.3995, found: 634.3996.
5.5.2. 11-(3-(4-((4-(2-Methoxyphenyl)piperazin-1-yl)propyl)-
1H-1,2,3-triazol-1-yl) propoxy)-N-propylnoraporphine (11b)
Yield 88%; 1H NMR (300 MHz, CDCl3): d 8.10 (d, 1H, J = 8.4 Hz,),
7.04 (m, 10H), 4.53 (m, 2H), 4.16 (m, 1H), 3.85 (s, 3H), 3.84 (m, 1H),
3.35 (m, 1H), 3.15 (m, 7H), 2.91 (m,1H), 2.72 (m, 8H), 2.45 (m, 6H),
1.88 (m, 2H), 1.62 (m, 2H), 0.97 (t, 3H, J = 7.8 Hz). 13C
NMR(100 MHz, CDCl3) d 155.4, 152.2, 147.6, 141.2, 138.6, 135.6,
133.2, 131.4, 128.0, 127.6, 126.0, 125.6, 123.5, 122.9, 121.3,
120.9, 118.1, 111.9, 111.1, 65.0, 59.6, 57.8, 56.5, 55.3, 53.4, 50.5,
48.9, 46.9, 35.2, 30.0, 29.4, 26.6, 23.5, 19.6, 12.1. MS (EI, [M+])
m/z 620; HR-MS (EI) calcd for C38H48N6O2: 620.3839, found:
620.3813.
5.5.3. 11-(3-(4-((4-(2-Methoxyphenyl)piperazin-1-yl)ethyl)-1H-
1,2,3-triazol-1-yl) propoxy)-N-propylnoraporphine (11c)
Yield 90%; 1H NMR (300 MHz, CDCl3): d 8.10 (d, 1H, J = 8.4 Hz),
7.04 (m, 10H), 4.52 (m, 2H), 4.16 (m, 1H), 3.85 (s, 3H), 3.84 (m, 1H),
3.38 (m, 1H), 3.15 (m, 7H), 2.91 (m,3H), 2.76 (m, 6H), 2.45 (m, 6H),
1.62 (m, 2H), 0.97 (t, 3H, J = 7.8 Hz,). 13C NMR (100 MHz, CDCl3) d
155.4, 152.1, 145.9, 141.1, 138.5, 135.5, 133.2, 131.4, 128.0,
127.6, 126.0, 125.6, 123.4, 122.9, 121.8, 121.3, 120.9, 118.1,
111.8, 111.0, 64.9, 59.5, 57.8, 56.5, 55.3, 53.2, 50.5, 48.9, 46.9,
35.2, 30.0, 29.3, 23.2, 19.6, 12.0. MS (EI, [M+]) m/z 606; HR-MS
(EI) calcd for C37H46N6O2: 606.3682, found: 606.3685.
C
37H46N6O2: 606.3678, found: 606.3682.
5.4. General procedure for preparation of alkynes 10a–d
An appropriate arylpiperazines (1.0 equiv), alkynyl tosylate
(1.0 equiv), K2CO3 (2.0 equiv) and sodium iodide (cat.) were dis-
solved in acetone. The resulting mixture was refluxed overnight.
The solvent was removed, and the crude material was dissolved
in CH2Cl2 and water. After filtration, the solvent was removed
and the residue was subjected to chromatography to give corre-
sponding alkynes 10a–d.
5.5.4. 11-(3-(4-((4-(2-Methoxyphenyl)piperazin-1-yl)methyl)-
1H-1,2,3-triazol-1-yl) propoxy)-N-propylnoraporphine (11d)
Yield 91%; 1H NMR (300 MHz, CDCl3): d 8.10 (d, 1H, J = 8.4 Hz),
7.04 (m, 10H), 4.55 (m, 2H), 4.16 (m, 1H), 3.85 (s, 3H), 3.84 (m, 1H),
3.70 (s, 2H), 3.38 (m, 1H), 3.15 (m, 7H), 2.91 (m, 1H), 2.73 (m, 5H),
5.4.1. 1-(2-Methoxyphenyl)-4-(hex-5-ynyl)piperazine (10a)
Yield 95%; 1H NMR (300 MHz, CDCl3): d 6.88 (m, 4H), 3.83 (s,
3H), 3.08 (br s, 4H), 2.63 (br s, 4H), 2.39 (m, 2H), 2.22 (m, 2H),
1.94 (t, 1H, J = 1.2 Hz), 1.60 (m, 4H).
2.50 (m, 4H), 2.21 (m, 1H), 1.62 (m, 2H), 0.97 (t, 3H, J = 7.8 Hz). 13
C
NMR (100 MHz, CDCl3) d 155.4, 152.1, 143.8, 141.1, 138.5, 135.5,
133.2, 131.4, 128.0, 127.6, 126.0, 125.6, 123.5, 123.3, 122.9,
121.9, 121.4, 120.9, 118.1, 111.9, 111.0, 64.9, 59.6, 56.5, 55.3,
53.2, 53.0, 50.4, 48.9, 47.0, 35.2, 29.9, 29.3, 19.6, 12.0. MS (EI,
[M+]) m/z 592; HR-MS (EI) calcd for C36H44N6O2: 592.3526, found:
592.3532.
5.4.2. 1-(2-Methoxyphenyl)-4-(pent-4-ynyl)piperazine (10b)
Yield 88%; 1H NMR (300 MHz, CDCl3): d 6.92 (m, 4H), 3.86 (s,
3H), 3.09 (br s, 4H), 2.66 (br s, 4H), 2.51 (m, 2H), 2.25 (m, 2H),
1.95 (m, 1H), 1.77 (m, 2H).

N. Ye et al. / Bioorg. Med. Chem. 19 (2011) 1999–2008
2007
5.6. Preparation of 11-O-(3-azidopropyl)-N-propylnoraporphine
(13)
138.4, 135.4, 132.8, 131.6, 127.8, 127.3, 126.3, 125.5, 123.2,
122.8, 120.9, 120.6, 120.6, 118.1, 111.4, 111.0, 68.4, 59.5, 58.3,
56.2, 55.3, 53.3, 50.5, 48.9, 35.3, 29.3, 27.4, 23.5, 19.6, 12.1. MS
(EI, [M+]) m/z 525; HR-MS (EI) calcd for C34H43N3O2: 525.3355,
found: 525.3333.
To a solution of 50% aq NaOH (4 mL), 11-hydroxyl-N-propylno-
raporphine 5 (30 mg, 0.10 mmol), and 1-bromo-3-chloropropane
(0.03 mL, 0.30 mmol), a catalytic amount of tetrabutylammonium
bromide (TBAB) was added. The mixture was stirred at rt for 1 h,
and then diluted with EtOAc. The organic phase was washed with
brine, and then dried. The solvents were removed and the residue
was subjected to chromatography (petroleum ether/EtOAc = 3:1,
1% Et3N) to give compound 13 as yellow oil (35 mg, 92%). 1H
NMR (300 MHz, CDCl3): d 8.24 (m, 1H), 7.39 (m, 2H), 7.25 (m,
1H), 7.11 (m, 2H), 4.48 (m, 1H), 4.28 (m, 1H), 3.95 (m, 2H), 3.57
(d, 1H, J = 12.6 Hz), 3.33 (m, 3H), 3.11 (m, 1H), 2.96 (m, 1H), 2.70
(m, 3H), 2.48 (m, 2H), 1.82 (m, 2H), 1.18 (t, 3H, J = 7.5 Hz). 13C
NMR (100 MHz, CDCl3): d 155.6, 138.6, 135.5, 133.0, 131.5, 127.8,
127.4, 126.0, 125.6, 123.4, 121.0, 111.5, 65.0, 59.5, 56.6, 48.9,
41.7, 35.3, 32.3, 29.4, 19.6, 12.1. MS (EI, [M+]) m/z 355; HR-MS
(EI) calcd for C22H26NOCl: 355.1703, found: 355.1700.
5.9. Preparation of N-(3-(4-(2-methoxyphenyl)piperazin-1-
yl)propyl)-N-(3-(N-propylnoraporphin-11-yloxy)-
propyl)methanesulfonamide (17)
To a solution of alcohol 14 (40 mg, 0.10 mmol) and Et3N (0.06 mL,
0.41 mmol) in CH2Cl2 (10 mL), was added MsCl (0.025 mL,
0.30 mmol) slowly at 0 °C. The reaction was stirred at the same tem-
perature for 15 min and then at rt for 2 h. The reaction mixture was
washed with NH4Cl, NaHCO3 and brine subsequently. After removal
of the solvent, the residue was subjected to chromatography
(CH2Cl2/MeOH = 60:1, 1% NH4OH) to give mesylate 16 as red oil
(45 mg, 82%). 1H NMR (300 MHz, CDCl3): d 8.06 (d, 1H, J = 7.8 Hz),
7.18 (m, 2H), 7.05 (d, 1H, J = 7.8 Hz), 6.90 (dd, 2H, J = 7.8 Hz,
11.7 Hz), 4.19 (m, 3H), 3.94 (m, 1H), 3.06–3.43 (m, 6H), 2.97 (s,
3H), 2.90 (m, 1H), 2.80 (s, 3H), 2.75 (m, 1H), 2.36–2.63 (m, 3H),
2.15 (m, 2H), 1.94 (m, 2H), 1.61 (m, 2H), 0.96 (t, 3H, J = 7.2 Hz).
Mesylate 16 (45 mg, 0.08 mmol) and NaI (18 mg, 0.12 mmol)
were mixed in MeCN (8 mL) and the resulting mixture was refluxed
for 1 h. 1-(2-Methoxyphenyl)piperazine (18 mg, 0.09 mmol) and
K2CO3 (22 mg, 0.16 mmol) were added and the mixture continued
to reflux overnight. The reaction mixture was diluted with CH2Cl2
and water. After separation, the organic phase was washed with
brine, and dried. The solvent was evaporated and the residue was
chromatographed (CH2Cl2/MeOH = 30:1, 1% NH4OH) to give apor-
logue 17 as yellow oil (41 mg, 80%). 1H NMR (300 MHz, CDCl3): d
8.10 (d, 1H, J = 8.4 Hz,), 6.83-7.23 (m, 9H), 4.25 (m, 1H), 3.98 (m,
1H), 3.90 (s, 3H), 3.45 (m, 3H), 3.21 (m, 9H), 2.95 (m,1H), 2.90 (s,
3H), 2.85 (m, 1H), 2.60 (m, 5H), 2.40 (m, 4H), 2.15 (m, 2H), 1.75 (m,
2H), 1.67 (m, 2H), 0.97 (t, 3H, J = 7.8 Hz). 13C NMR(100 MHz, CDCl3):
d 156.0, 152.2, 141.2, 138.5, 135.5, 133.0, 131.5, 127.9, 127.4, 126.1,
125.6, 123.3, 122.8, 121.1, 120.9, 118.1, 111.5, 111.2, 65.7, 59.5, 56.5,
55.3, 53.3, 50.5, 48.9, 46.8, 45.7, 37.8, 35.3, 29.3, 26.0, 19.6, 12.0. MS
(EI, [M+]) m/z 646; HR-MS (EI) calcd for C37H50N4O4S: 646.3553,
found: 646.3640.
5.7. Preparation of 3-(3-(N-propylnoraporphin-11-
yloxy)propylamino)propan-1-ol (14)
Chloride 13 (43 mg, 0.12 mmol) and 3-aminopropan-1-ol
(90 mg, 1.20 mmol) were mixed in n-BuOH (8 mL) and the mixture
was refluxed for 24 h. The solvent was evaporated and the residue
was chromatographed (CH2Cl2/MeOH = 20:1, 1% NH4OH) to give
alcohol 14 as brown oil (40 mg, 83%). 1H NMR (300 MHz, CDCl3):
d 8.08 (d, 1H, J = 7.8 Hz), 7.18 (m, 2H), 7.04 (d, 1H, J = 7.8 Hz),
6.90 (m, 2H), 4.19 (m, 1H), 3.98 (m, 1H), 3.77 (t, 2H, J = 5.1,
5.4 Hz), 3.36 (d, 1H, J = 11.4 Hz), 3.13 (m, 3H), 2.85 (m, 8H), 2.51
(m, 3H), 2.0 (m, 2H), 1.65 (m, 4H), 0.97 (dd, 3H, J = 7.2, 7.5 Hz).
13C NMR (100 MHz, CDCl3): d 155.8, 138.5, 135.5, 132.9, 131.5,
127.9, 127.4, 126.1, 125.6, 123.3, 120.9, 111.5, 66.8, 64.2, 59.5,
56.6, 49.9, 48.9, 47.0, 35.3, 30.5, 29.5, 29.4, 19.6, 12.1. MS (EI,
[M+]) m/z 394; HR-MS (EI) calcd for C25H34N2O2: 394.2620, found:
394.2612.
5.8. Preparation of 11-(4-(4-(2-methoxyphenyl)piperazin-1-
yl)butoxy)-N-propylnoraporphine (15)
To a solution of 50% aq NaOH (4 mL), 11-hydroxy-aporphine 5
(28 mg, 0.10 mmol), and 1-bromo-4-chlorobutane (51 mg,
0.30 mmol), was added a catalytic amount of tetrabutylammonium
bromide. The reaction was stirred at rt for 1 h and then diluted
with EtOAc. The organic phase was washed with brine and dried
over anhydrous Na2SO4. The solvent was evaporated and the resi-
due was chromatographed (petroleum ether/EtOAc = 3:1, 1% Et3N)
to give chloride 12 as yellow oil (30 mg, 82%). 1H NMR (300 MHz,
CDCl3): d 8.11 (d, 1H, J = 7.5 Hz), 7.21 (m, 2H), 7.06 (d, 1H,
J = 7.2 Hz), 6.91 (m, 2H), 4.16 (m, 1H), 3.97 (m, 1H), 3.69 (m, 2H),
3.35 (m, 1H), 3.14 (m, 3H), 2.93 (m, 1H), 2.77 (d, 1H, J = 16.2 Hz),
2.52 (m, 3H), 2.01 (s, 4H), 1.62 (m, 2H), 0.98 (t, 3H, J = 7.2 Hz).
Chloride 12 (30 mg, 0.08 mmol) and NaI (14 mg, 0.09 mmol)
were dissolved in MeCN (8 mL) and the mixture was refluxed for
1 h. 1-(2-Methoxyphenyl)piperazine (18 mg, 0.09 mmol) and
K2CO3 (22 mg, 0.16 mmol) were added. The mixture was refluxed
overnight. After removal of solvents, the mixture was diluted with
CH2Cl2 and water, and then washed with brine and dried. After
evaporation of the solvent, the residue was chromatographed
(CH2Cl2/MeOH = 40:1, 1% NH4OH) to give aporlogue 15 as colorless
oil (33 mg, 80%). 1H NMR (300 MHz, CDCl3): d 8.10 (d, 1H,
J = 8.4 Hz), 7.04 (m, 10H), 4.17 (m, 1H), 4.12 (m, 1H), 3.98 (s, 3H),
3.39 (m, 1H), 3.15 (m, 7H), 2.93 (m,1H), 2.65 (m, 5H), 2.51 (m,
4H), 1.91 (m, 2H), 1.85 (m, 2H), 1.67 (m, 2H), 0.97 (t, 3H,
J = 7.8 Hz). 13C NMR (100 MHz, CDCl3): d 156.0, 152.2, 141.2,
5.10. Binding assay of new compounds at the D1, D2, D3 and
5-HT1A, 5-HT2A receptors
The affinity of compounds to the D1, D2 and D3 dopamine
receptors, and the 5-HT1A and 5-HT2A receptors were determined
by competition binding assay. Membrane homogenates of
5-HT1A, 5-HT2A-CHO cells, D1-, D2-, and D3-HEK293 cells were
prepared as described previously. Duplicated tubes were incu-
bated at 30 °C for 50 min with increasing concentrations
(1 nM–100 lM) of respective compound and with 0.7 nM
[3H]8-OH-DPAT (for 5-HT1A), [3H]Ketanserin (for 5-HT2A),
[3H]SCH23390 (for D1), or [3H]Spiperone (for D2 and D3) in a fi-
nal volume of 200
4 mM MgCl2, pH 7.4. Nonspecific binding was determined by
parallel incubations with either 10 M WAY100635 for 5-HT1A
lL binding buffer containing 50 mM Tris,
l
,
Ketanserin for 5-HT2A, SCH23390 for D1 or Spiperone for D2, D3
dopamine receptors, respectively. The reaction was started by
addition of membranes (15 lg/tube) and stopped by rapid filtra-
tion through Whatman GF/B glass fiber filter and subsequent
washing with cold buffer (50 mM Tris, 5 mM ethylenediamine-
tetraacetic acid (EDTA, pH 7.4) using a Brandel 24-well cell har-
vester. Scintillation cocktail was added and the radioactivity was
determined in a MicroBeta liquid scintillation counter. The IC50
and Ki values were calculated by nonlinear regression (PRISM
Graphpad, San Diego, CA) using a sigmoidal function.
,

2008
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This work was supported by grants from Chinese National Sci-
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ence & Technology Major Project on ‘Key New Drug Creation and
Manufacturing Program’, (2009ZX09301-001, 2009ZX09103-062,
2009ZX09102-023), and Shanghai Commission of Science and
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