Design and synthesis of 2- and 3-substituted-3-phenylpropyl analogs of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of amino, fluoro, hydroxyl, methoxyl, methyl, methylene, and oxo substituents on affinity for the dopamine and serotonin transporters

Article abstract of DOI:10.1021/jm701270n

Novel derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3- phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp² hybridized substituents had a detrimental effect on affinity for DAT. In the series, the 2-fluoro-substituted (S)-10 had the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted (R)-8 showed essentially the same affinity for DAT and SERT. The oxygenated 16 and 18 possessed the best selectivity for DAT.

Full text of DOI:10.1021/jm701270n

J. Med. Chem. 2008, 51, 2795–2806
2795
Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and
1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of Amino, Fluoro, Hydroxyl,
Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and
Serotonin Transporters
Ling-Wei Hsin,*,† Li-Te Chang,† Richard B. Rothman,‡ Christina M. Dersch,‡ Arthur E. Jacobson,§ and Kenner C. Rice§
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan UniVersity, Number 1, Section 1, Jen-Ai Road, Room 1336, Taipei,
Taiwan 10018, ROC, Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and the
National Institute on Alcohol Abuse and Alcoholism, DHHS, Bethesda, Maryland 20892, and Clinical Psychopharmacology Section, Chemical
Biology Research Branch, National Institute on Drug Abuse, Addiction Research Center, National Institutes of Health, DHHS, Baltimore,
Maryland 21224
ReceiVed October 9, 2007
Novel derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909,
1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents
in positions C2 and C3 of the phenylpropyl side chain were synthesized and evaluated for their ability to
bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent
in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas
the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone
electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp2 hybridized
substituents had a detrimental effect on affinity for DAT. In the series, the 2-fluoro-substituted (S)-10 had
the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted (R)-8 showed
essentially the same affinity for DAT and SERT. The oxygenated 16 and 18 possessed the best selectivity
for DAT.
Introduction
Recently, SERT and NET have also been thought to play
prominent roles in cocaine addiction.14–24 Cocaine binds to DAT
and SERT with moderate affinity (Ki ) 341 and 129 nM,
respectively)15 and blocks the reuptake of [3H]DA and [3H]5-
HT (IC50 ) 478 and 304 nM, respectively).12,18 In behavioral
intervention and knockout mice experiments, the serotonergic
system has been found to influence the reinforcing effects of
cocaine.14,25–27 In contrast to the extensive structure–activity
relationship (SAR) studies for DAT-selective ligands, fewer
SAR studies have been focused on the discovery and develop-
ment of ligands with a variety of transporter selectivity for both
DAT and SERT.14,28–31 Novel ligands that differ in their
transporter affinity and SERT/DAT ratio may help reveal the
pharmacological mechanisms relevant to stimulant abuse and
also lead to a high efficacy medication for cocaine abuse, with
few adverse reactions. Such a medication may also reduce the
incidence of HIV infection.32
Cocaine has caused many public health and societal problems1,2
because of its extensive abuse in many countries throughout
the world, exacerbating the spread of HIV-13,4 and hepatitis B
and C, as well as drug-resistant tuberculosis.5 Cocaine is known
to block the reuptake of several neurotransmitters in the central
nervous system, such as dopamine (DAa), serotonin (5-HT), and
norepinephrine (NE), by interacting with the dopamine trans-
porter (DAT), serotonin transporter (SERT), and norepinephrine
transporter (NET) sites, respectively. Abundant studies have
indicated that the reinforcing, locomotor-stimulating, and de-
pendence-producing properties of cocaine are mainly mediated
by the binding of cocaine to the DAT and subsequent blockade
of DA reuptake into presynaptic terminals resulting in increased
neurotransmission in the mesolimbic dopaminergic system.6–12
Therefore, DAT has been considered to be the main target to
reduce the effects of cocaine, and DAT ligands with high
potency and selectivity have been sought as potential therapeutic
agents for cocaine abuse.13
Our research has focused on the discovery of novel analogs
of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropy-
l)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethyl]-
4-(3-phenylpropyl)piperazine (GBR12935, 2;33 Chart 1). In an
effort to develop long-acting cocaine abuse therapeutic agents,
Lewis et al. prepared a series of oxygenated analogs of 1 and
2 and found that a racemic 3-hydroxyl-3-phenyl analog ((()-
3) of 1 exhibited a pharmacological profile similar to that of
1.34 Later, the decanoate ester of (()-3, prodrug (()-4, was
synthesized and formulated as a depot preparation. One dose
of (()-4 successfully suppressed cocaine-maintained responding
in rhesus monkeys without affecting food intake for nearly 30
days.35 Our continued studies on the SAR of the hydroxyl-
containing analogs of 1 and 2 have shown that the S- and
* To whom correspondence should be addressed. Tel.: +886-2-2395-
2310. Fax: +886-2-2351-2086. E-mail: lwhsin@ntu.edu.tw.
†
Institute of Pharmaceutical Sciences, National Taiwan University.
Clinical Psychopharmacology Section, National Institute on Drug
‡
Abuse.
§
Drug Design and Synthesis Section, Chemical Biology Research
Branch, NIDA and NIAAA. This work was initiated while these authors
were members of the Drug Design and Synthesis Section, Laboratory of
Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney
Diseases, NIH.
a Abbreviations: DA, dopamine; 5-HT, serotonin; NE, norepinephrine;
DAT, dopamine transporter; SERT, serotonin transporter; NET, norepi-
nephrine transporter; EDCI, N-(3-dimethylaminopropyl)-N′-ethylcarbodi-
imide hydrochloride; DIPEA, N,N-diisopropylethylamine.
10.1021/jm701270n CCC: $40.75
2008 American Chemical Society
Published on Web 04/05/2008

2796 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9
Hsin et al.
Chart 1
information could help us identify the steric and electronic
effects of the 2- and 3-substitutions in analogs of 1 and 2
involved in the binding interaction with DAT and SERT, and
may lead to the discovery of novel high-affinity DAT ligands
possessing a range of affinities for SERT.
Herein, we report the synthesis and SAR of optically pure
2-substituted-3-phenylpropyl derivatives 7-10, 3-substituted-
3-phenylpropyl analogs 13-16, and 2-substituted-3-phenylpro-
pyl derivatives 17-22 of 1 and 2 with amino, fluoro, hydroxyl,
methoxyl, methyl, methylene, and oxo substituents at the 2- or
3-position of the 3-phenylpropyl moiety (Chart 2). The roles
of the 2- and 3-substituents in these transporter ligands on their
affinity and selectivity for DAT and SERT are discussed.
Table 1. Binding Affinities (Ki ( SD)a at the DAT and SERT and Ki
Ratios of 2- and 3-Substituted Analogs of 1 and 2
binding affinity, Ki (nM)
Chemistry
no.
DAT
SERT
SERT/DAT ratio
The monosubstituted piperazines, 1-[2-[bis(4-fluorophenyl)-
methoxy]ethyl]piperazine (25) and 1-[2-(diphenylmethoxy)eth-
yl]piperazine (26; Chart 2) were synthesized in two steps
according to the literature,33 with modification.36 The 2-methyl-,
2-amino-, and 2-methoxy-substituted analogs of 1 were prepared
via similar reaction sequences, in which 25 was coupled with
an appropriate acid using N-(3-dimethylaminopropyl)-N′-eth-
ylcarbodiimide hydrochloride (EDCI) followed by reduction
with a suitable aluminum hydride (Scheme 1).
Coupling of (()-2-methyl-3-phenylpropionic acid and 25
provided amide (()- 27. Compound (()-7 was synthesized by
reduction of (()-27 with LiAlH4. Optically pure (+)-7 and (-)-7
were then prepared from (()-7 using semipreparative chiral
high-performance liquid chromatography (HPLC) followed by
recrystallization of their maleate salts.
N-tert-butyloxycarbonyl (Boc)-protected (S)-29 and (R)-29
were prepared starting from commercially available N-Boc-
protected L- and D-phenylalanines, respectively. EDCI coupling
followed by reduction with diisobutylaluminum hydride
(DIBALH) yielded (S)-29 and (R)-29 retaining high ee values.
Removing the Boc protective groups of (S)-29 and (R)-29 using
hydrogen chloride afforded (S)-8 and (R)-8, respectively.
The optically pure synthons (S)-2-methoxy-3-phenylpropanoic
acid ((S)-30) and (R)-2-methoxy-3-phenylpropanoic acid ((R)-
30) for the preparation of (S)-31 and (R)-31 were synthesized
from L- and D-3-phenyllactic acids, respectively, by selective
methylation of the aliphatic hydroxyl groups using an excess
amount of NaH in tetrahydrofuran (THF). Alane reduction of
(S)-31 and (R)-31 gave (S)-9 and (R)-9, respectively.
1
2
3.7 ( 0.4
3.7 ( 0.3
4.4 ( 0.5
3.0 ( 0.3
0.75 ( 0.03
12 ( 1
130 ( 5
35
168
31
28
307
13
957
72
7
11
2
1
8
9
620 ( 10
135 ( 5
(S)-3
(R)-3
(S)-5
(R)-5
(S)-6
(R)-6
(+)-7
(-)-7
(S)-8
(R)-8
(S)- 9
(R)- 9
(S)-10
(R)-10
11
12
13
14
15
16
17
18
19
85 ( 3
230 ( 7
160 ( 4
2.3 ( 0.07
25 ( 0.7
17 ( 1
2200 ( 80
1800 ( 90
120 ( 3
17 ( 1
190 ( 8
39 ( 2
88 ( 5
20 ( 1
22 ( 1
29 ( 3
220 ( 10
250 ( 20
290 ( 10
540 ( 20
220 ( 6
27 ( 1
2.7 ( 0.2
22 ( 1
109
25
5
48 ( 2
210 ( 4
18 ( 0.9
30 ( 2
1300 ( 30
190 ( 30
1800 ( 180
150 ( 7
1800 ( 60
250 ( 8
2500 ( 90
430 ( 20
3300 ( 160
310 ( 30
2000 ( 110
88 ( 3
6
11
59
39
254
38
250
4
8
6
14
2
3
4.0 ( 0.4
7.0 ( 0.6
6.5 ( 0.4
10 ( 1
100 ( 7
410 ( 60
57 ( 3
150 ( 4
54 ( 6
450 ( 50
140 ( 4
110 ( 4
8.0 ( 0.4
20
21
22
23
24
1400 ( 50
110 ( 3
190 ( 7
36 ( 2
(S)-32
(R)-32
38
0.8
2
5
a The Ki values of the test ligands were determined in the above assays
Treatment of enantiomerically pure 2-hydroxyl-substituted
(S)-5 and (R)-536 with (diethylamino)sulfur trifluoride (DAST)
produced desired 2-fluoro-substituted (R)-10 and (S)-10 and
rearranged products (R)-32 and (S)-32, respectively, in a ratio
of 5:3 (Scheme 2). The possible mechanism for this unexpected
result is shown in Chart 3. Reaction of (S)-5 with DAST yielded
intermediate (S)-I and hydrogen fluoride (HF). The basic
nitrogen atom could be protonated by HF to form (S)-II, which
would be attacked by fluoride ion to provide (R)-10. On the
other hand, the aziridinium intermediate (S)-III could be formed
by anchimeric assistance of the unprotonated nitrogen atom of
(S)-I. Nucleophilic substitution of fluoride ion at the less
hindered position of (S)-III yielded (R)-32. If the fluoride ion
was able to overcome the steric effect to attack the more
hindered position of (S)-III, (S)-10 would be formed and, thus,
the ee value of (R)-10 would be substantially reduced. Because
both the isolated (R)-10 and (R)-32 showed very high optical
purity, the nucleophilic substitution of (S)-III by fluoride ion
was highly regioselective. The ee values of chiral compounds
7-10 and 32 were determined by analytical chiral HPLC and
were above 98%.
as described in Biological Methods.
R-enantiomers of the 2-hydroxylated derivatives (e.g., (S)-5 and
(R)-5) possessed quite different pharmacological profiles,36,37
whereas the 3-hydroxylated enantiomers (e.g., (S)-3 and (R)-3)
displayed very similar biological activities.34 In the 2-hydroxyl
series, the S-isomers demonstrated substantially higher affinity
for the DAT and were more potent DA reuptake inhibitors than
the corresponding R-isomers, whereas the R-isomers showed
higher affinity for the SERT and were more potent in inhibiting
the reuptake of 5-HT than the S-isomers.36,37 The alcohols (S)-5
and (S)-6 are among the most potent and selective DAT ligands
yet known (Table 1).
Based on these observations that the pharmacological profiles
(including DAT and SERT binding affinities, transporter
selectivity, and enantioselectivity) could be dramatically changed
by minor structural modifications at the 2- and 3-positions of
the 3-phenylpropyl side chain of 1 and 2, we undertook the
design and synthesis of novel 2- and 3-substituted analogs of 1
and 2 to more definitively determine the SAR of the 2- and
3-substituted-3-phenylpropyl derivatives of 1 and 2. This

Role of Substituents on Dopamine and Serotonin Transporters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9 2797
Table 2. Physical Properties
cmpd
empirical formula
mp, °C
[R]D20, deg (solvent)
yield, %a
(+)-7
(-)-7
(S)-8
(R)-8
(S)-9
(R)-9
(S)- 10
(R)-10
13
14
15
16
17
18
19
20
21
22
23
24
(S)-32
(R)-32
C29H34F2N2O·2C4H4O4
C29H34F2N2O·2C4H4O4
C28H33F2N3O
185–186
185–186
oil
+2.3(DMF)
-2.5(DMF)
NDb
42 (from 27)
42 (from 27)
88
91
77
94
25
28
52
42
54
25
86
77
70
71
32
75
91
86
15
18
C28H33F2N3O
oil
NDb
C29H34F2N2O2 ·2C4H4O4
C29H34F2N2O2 ·2C4H4O4
C28H31F3N2O·2C4H4O4
C28H31F3N2O·2C4H4O4
C29H32F2N2O·2C4H4O4
C29H34N2O·2C4H4O4
C29H34F2N2O2 ·2C4H4O4
C29H36N2O2 ·2C4H4O4
C28H30F2N2O2 ·2C4H4O4
C28H32N2O2 ·2C4H4O4
C29H32F2N2O·2C4H4O4
C29H34N2O·2C4H4O4
C29H34F2N2O2 ·2C4H4O4
C29H36N2O2 ·2C4H4O4
C27H28F2N2O2 ·2C4H4O4
C27H30N2O2 ·2C4H4O4
C28H31F3N2O·2C4H4O4
C28H31F3N2O·2C4H4O4
187–188
187–188
181–182
180–181
164–166
168–170
181–182
174–175
166–167
164–165
182–183
186–187
184–185
177–178
176–177
178–179
145–146
147–148
+5.4(DMF)
–5.2 (DMF)
+1.0(DMF)
-1.2(DMF)
-17 (DMF)
+15 (DMF)
a No attempt was made to optimize yields. b ND: not determined.
Chart 2
3-Methylene and 3-methyl-3-hydroxyl derivatives of 1 and
2 were synthesized from 3-oxo-substituted 11 and 1234 (Scheme
3). Accelerated Wittig-type olefination of 11 and 12 with the
CH2I2-TiCl4-Zn-PbCl2 system38 provided 13 and 14 in
moderate yields. Tertiary alcohols 15 and 16 were prepared via
Grignard reaction of 11 and 12, respectively, with methylmag-
nesium bromide.
Coupling of 2-benzyl-acrylic acid39,40 with 25 and 26 yielded
amides 33 and 34, respectively (Scheme 5). The 2-methylene
analogs 19 and 20 were then produced by reduction of 33 and
34 with alane. N-Alkylation of 25 and 26 with 1-chloro-2-
methyl-3-phenyl-2-propanol41 (35), using K2CO3 and NaI,34
afforded the desired tertiary alcohols 21 and 22, respectively.
Acetophenones 2342 and 24 were prepared in high yields by
heating 2-bromoacetophenone with 25 and 26, respectively, in
the presence of diisopropylethylamine (DIPEA) in N,N-dim-
ethylformamide (DMF).
Treatment of 5 and 636 under Swern oxidation conditions
afforded 2-oxo-substituted 17 and 18, as depicted in Scheme 4.
Initial attempts to synthesize the 2-methylene analogs 19 and
20 and the 2-methyl-2-hydroxyl derivatives 21 and 22, following
the same reaction conditions for the preparation of the corre-
sponding 3-substituted analogs, failed. We recognized that the
3-positions of ketones 17 and 18 were located between the
phenyl and carbonyl functionalities and, therefore, the increased
acidity of these positions was detrimental to both the Wittig-
type olefination and Grignard reaction. Thus, alternative routes
were sought in which the 2-methylene and 2-methyl-2-hydroxyl
substitutions were introduced in earlier stages.
Results and Discussion
Previous data suggested that the 2-substituted (S)-5 and (R)-5
demonstrated enantioselectivity in DAT and SERT binding,
while the corresponding 3-substituted (S)-3 and (R)-3 showed
no difference in transporter binding.34,36 Therefore, the binding
affinities of 7–10, the analogs of 5, for DAT and SERT were
determined to investigate the steric and electronic effects of

2798 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9
Hsin et al.
Scheme 1a
a Reagents and conditions: (a) (()-2-methyl-3-phenylpropionic acid, EDCI, CH2Cl2, rt; (b) LiAlH4, THF, rt; (c) semipreparative chiral HPLC; (d) N-t-
Boc-L-phenylalanine or N-t-Boc-D-phenylalanine, EDCI, CH2Cl2, rt; (e) DIBAL-H, THF, rt; (f) HCl, MeOH, rt; (g) (S)-30 or (R)-30, EDCI, CH2Cl2, rt; (h)
AlH3, THF, rt.
Scheme 2a
a Reagents and conditions: (a) (diethylamino)sulfur trifluoride, CH2Cl2, -78 °C-rt.
structural modifications in the 2-position of the phenylpropyl
side chain of 1.
2-amino-substitution significantly enhanced the binding affinity
for SERT. Compound (R)-8 was the most potent SERT ligand
in the series and showed approximately the same affinity for
DAT and SERT (Ki ) 20 and 22 nM, respectively). Hence,
(R)-8 may be a potential lead for the development of dual-action
transporter ligands.
Methylation of the 2-hydroxyl group not only decreased DAT
binding affinity, but also abolished the enantioselectivity of (S)-5
and (R)-5. The transporter binding patterns of 2-methoxy-
substituted analogs (S)-9 and (R)-9 were very similar to that of
2-methyl-substituted analogs (S)-7 and (R)-7, which implied that
the methyl group has an adverse steric effect in DAT binding.
To study the role of the lone electron pairs of oxygen in the
hydroxyl group of (S)-5 without the interference of steric effects,
as in the case of 9, 2-fluoro-substituted analogs (S)-10 and (R)-
The 2-methyl-substituted analogs (+)-7 and (-)-7 had less
affinity than 1, (S)-5, and (R)-5 in DAT binding, while showing
similar SERT affinity as 1 and (R)-5 (Table 1). Curiously, there
was no meaningful difference in transporter binding affinities
between the two enantiomers (+)-7 and (-)-7. Furthermore,
the pharmacological profiles of (+)-7 and (-)-7 were quite
similar to that of 2-hydroxyl-substituted (R)-5. To determine
whether the 2-hydroxyl group of (S)-5 played an essential role
in affinity and selectivity to DAT, the 2-amino-substituted
analogs (S)-8 and (R)-8 and 2-methoxy-substituted analogs (S)-9
and (R)-9 were studied. The DAT binding affinities of (S)-8,
(S)-9, (R)-8, and (R)-9 were in the range of 20–39 nM, which
were lower than that of 1, (S)-5, and (R)-5. Interestingly, the

Role of Substituents on Dopamine and Serotonin Transporters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9 2799
Chart 3
tion of C-S3-1 might not be as stable as the five-membered
ring conformation of C-S5 and, therefore, other conformers,
such as C-S3-2, with an extended zigzag side chain similar to
C-1, might be the major conformer of (S)-3. This hypothesis
could explain why the transporter binding profiles of 1, (S)-3,
and (R)-3 were approximately the same. Thus, a proper
configuration of substituents with an available lone-pair of
electrons, such as 2-(S)-OH and 2-(S)-F, which would allow
the DAT-binding favorable conformer to be stabilized by their
electronic effects, was the most critical factor causing the
observed increase in DAT affinity. However, these steric and
electronic effects did not promote high SERT affinity. Therefore,
(S)-5 and (S)-10 are among the most DAT selective ligands that
have been found.
Initially, we thought the 2-amino group would be a strong
electron-donating group and, therefore, may result in analogs
with high DAT affinity and selectivity. In contrast to the 2-fluoro
and 2-hydroxyl analogs, the 2-amino-substituted analogs (S)-8
and (R)-8 had only moderate affinity for DAT. Because the
nitrogen lone-pair of electrons in the 2-amino groups of (S)-8
and (R)-8 were protonated under physiological conditions, there
was no available electron lone pair to be able to act as a
hydrogen bond acceptor. Actually, the protonated 2-ammonium
group would be more likely to act as a hydrogen bond donor.
Furthermore, the potential electrostatic and steric repulsion
between the two cationic N4- and 2-ammonium groups (Chart
5) could substantially destabilize the syn-conformers C-S8-1
and C-R8-1 and, therefore, force (S)-8 and (R)-8 to adopt other
more stable conformations, such as C-S8-2 and C-R8-2, which
were significantly different from our postulated conformers with
high DAT affinity (e.g., C-1 and C-S5) in this series. Thus, the
quite different conformation of C-R8-2 might be responsible
for the high affinity of (R)-8 for SERT. Interestingly, the phenyl
groups in C-S5 and C-R8-2 were in the same spatial areas, while
the phenyl groups in both C-R5 and C-S8-2 were in different
spatial areas. This observation could help explain why the (R)-8
had higher DAT binding affinity than (S)-8 and the 2-amino-
substituted analogs (S)-8 and (R)-8 demonstrated enantioselec-
tivity in both DAT and SERT binding affinities.
10, were examined. In comparison with 1, (S)-10 showed
increased DAT binding affinity and decreased SERT binding
affinity and, therefore, much higher DAT selectivity (SERT/
DAT ratio ) 109). Compound (S)-10 was the most potent DAT
ligand (Ki ) 2.7 nM)) in this study. On the other hand, (R)-10
showed significantly lower DAT binding affinity and selectivity
versus SERT than (S)-10. Thus, the 2-fluoro-substituted analogs
(S)-10 and (R)-10 demonstrated the highest enantioselectivity
among this novel series of 2-substituted analogs of 1 and
possessed similar pharmacological profiles as that of 2-hydroxyl-
substituted analogs (S)-5 and (R)-5.
The diverse transporter binding affinities, SERT/DAT ratios,
and enantioselectivity of these 2-substituted analogs of 1 allowed
us to identify the steric and electronic effects of the 2-substituent
on the binding interaction to transporters. In previous SAR
studies, 36, a conformational-constrained analog of 1 (Chart 4),
demonstrated higher DAT affinity than 1.34 Under physiological
conditions, the N4-nitrogen atom in piperazine should be
protonated. Therefore, the conformer C-1 with an extended
zigzag phenylpropyl side chain might be the active conformation
of 1 for DAT binding (Chart 4). A similar conformationally
constrained analog of 1, 37, in which the potential high-affinity
conformer C-37 was unlikely to be as stable as C-1 due to the
additional steric repulsion, did demonstrate slightly lower DAT
and SERT affinities than 1.32
The hydroxyl groups in (S)-5 and (R)-5 could act as a
hydrogen bond donor or a hydrogen bond acceptor. The
pharmacological similarity between the fluoro- and hydroxyl-
substituted analogs led us to hypothesize that its action as a
hydrogen bond acceptor played a critical role in the enantiose-
lectivity. As shown in Chart 5, when the oxygen lone pairs in
(S)-5 and (R)-5 formed hydrogen bonds with the N4-ammonium
groups, conformationally constrained conformers C-S5 and
C-R5 would be the favorable conformers of (S)-5 and (R)-5,
respectively. As a result, the phenyl ring in (S)-5 and (R)-5
would be forced into opposite directions in space. The position
of the phenyl group in C-1 was between the likely positions of
the phenyl groups in C-S5 and C-R5, and this could explain
why the DAT affinity of 1 was between that of (S)-5 and (R)-5.
On the other hand, C-S3-1 could be the corresponding cyclic
conformer of (S)-3. However, the six-membered ring conforma-
Because the 2-fluoro-substituent was not a hydrogen bond
donor and 2-fluoro-substituted analogs possessed similar phar-
macological profiles as 2-hydroxy-substituted analogs, the ability
of the substituent to act as a hydrogen bond donor did not appear
to be essential to enantioselectivity. Thus, the lack of enanti-
oselectivity of the 2-methoxy-substituent (S)-9 and (R)-9 could
not be ascribed to its inability to act as a hydrogen bond donor,
but might be caused by the steric effect of the additional methyl
group. Hence, the presence of a small substituent with an
available electron lone-pair in a compound with the 2S config-
uration is likely to promote DAT binding affinity. Further work
should focus on the influence of steric and electronic effects on
transporter binding affinity by the introduction of relatively less
hindered sp2 hybridized oxo and methylene functionalities into
1 and 2.
Previously, Lewis et al. reported the synthesis and monoamine
transporter affinities of 3-oxo-substituted 11 and 12.34 In contrast
to the unsubstituted 1 and 2, and 3-hydroxylated (S)-3 and (R)-
3, 11 and 12 demonstrated much lower DAT binding affinity
and selectivity. This might be explained by the tendency of the
3-carbonyl group to conjugate with the aromatic phenyl ring,
restricting the conformational flexibility of the phenyl group
that might be essential for interaction with DAT.
Therefore, the 3-methylene-substituted 13 and 14 and
3-methyl-3-hydroxyl-substituted 1542 and 16 were prepared

2800 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9
Hsin et al.
Scheme 3a
a Reagents and conditions: (a) CH2I2, Zn, PbCl2, TiCl4, THF, rt; (b) CH3MgBr, THF, rt.
Scheme 4a
a Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, -60 °C-rt.
Scheme 5a
a Reagents and conditions: (a) 2-benzyl-acrylic acid, EDCI, CH2Cl2, 0 °C-rt; (b) AlH3, THF, rt; (c) 35, NaI, K2CO3, DMF, 70-80 °C; (d)
2-bromoacetophenone, DIPEA, DMF, 60 °C.
to explore the “conjugation hypothesis”. In terms of interac-
tion with DAT, 13 and 14 had higher affinity than 11 and
12, but less affinity than 1 and 2. Although the sp2 hybridized
3-methylene group in 13 and 14 might also be able to
conjugate with the phenyl group, the steric interaction
between the hydrogen atoms at the vinyl position and ortho-
position of the phenyl ring would tend to reduce the activation
energy for rotation of the phenyl group (Chart 6). The
resultant weaker conjugation resulted in higher DAT binding
affinity. The 3-methyl-3-hydroxyl-substituted analogs, 15 and
16, with quaternary carbon atoms at C3, had almost the same
binding affinity as 1 and 2 for DAT and demonstrated greater
DAT/SERT selectivity than 1 and 2. These data indicate that
a sp3 hybridized 3-position is important for high DAT binding

Role of Substituents on Dopamine and Serotonin Transporters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9 2801
Chart 6
Chart 4
substitution and the steric effect of the 2-methyl group.
Surprisingly, the DAT binding affinities of 19 and 20 were
significantly reduced (27- and 110-fold, respectively) as com-
pared to that of 1 and 2. Initially, we thought C-19-1, which
was one of the possible conformers of 19, should possess less
steric hindrance than C-S7 (i.e., a conformer of (S)-7) and,
therefore, has higher affinity for DAT than the 2-methyl-
substituted 7 (Chart 6). However, rotation of the CdC bond to
form conformer C-19-1 is likely to be energetically unfavorable
and, thus, C-19-1 might not exist in a significant amount at
room temperature. On the other hand, conformer C-19-2 should
be the more stable conformer of 19. In the case of C-19-2, steric
repulsion might occur between the vinyl hydrogen atoms and
the proton of the protonated N4-ammonium group. Moreover,
the vinyl hydrogen atoms could also interfere with the free
rotation of the phenyl group by interaction with the hydrogen
atoms at the ortho-positions of the phenyl ring. Therefore, high
DAT affinity conformations, such as C-1 and C-S5, could not
readily be adopted by 19 and 20. In the 3-phenylpropyl-
substituted series, 19 and 20 had the lowest affinity for DAT in
the bis(4-fluorophenyl)- and diphenyl-substituted analogs,
respectively.
Chart 5
Our hypothesis was supported by the data obtained from the
2-methyl-2-hydroxyl-substituted compounds 21 and 22. Com-
pared to the 2-methylene-substituted analogs 19 and 20,
compounds 21 and 22, with crowded tertiary 2-positions,
possessed higher binding affinity for both DAT and SERT.
Presumably, the postulated unfavorable steric repulsion in
C-19-2 was relieved. Furthermore, 21 demonstrated significantly
weaker DAT binding affinity and slightly lower SERT binding
affinity than 2-hydroxylated (S)-5 and (R)-5 and 2-methylated
(S)-7 and (R)-7. This indicates that the steric effect produced
by additional substitution at the 2-position is more unfavorable
to DAT binding affinity than to SERT binding affinity. However,
the binding data of 15, 16, 21, and 22 were determined using
racemic samples. The possibility that the two enantiomers of
these ligands possessed substantially different transporter binding
affinities could not be ruled out.
The tremendous differences in DAT binding affinity for
2-oxo-substituted 17 and 18 and 3-oxo-substituted 11 and 12
led us to synthesize acetophenones 2342 and 24 in which the
2-oxo-substituents theoretically can conjugate with the phenyl
group. Compounds 23 and 24 were similar to 11 and 12 in their
weak DAT binding affinities, while the unsubstituted acetophe-
none 3836 (Chart 2) exhibited high binding affinity for DAT
affinity, and the DAT and SERT binding affinities of 1 and
2 are not affected very much by the additional substituent at
the 3-position.
In contrast to the 3-oxo-substituted compounds 11 and 12,
which had weak affinity and low selectivity for DAT, the 2-oxo-
substituted 1742 and 18 showed high DAT binding affinity, and
demonstrated higher SERT/DAT ratios than 1 and 2. The DAT
affinity and selectivity of 17 and 18 were higher than that of
(R)-5 and (R)-6 and lower than that of (S)-5 and (S)-6,
respectively. Based on our hypothesis, the potential hydrogen
bonding between the carbonyl lone-pair of electrons and
ammonium groups of 17 and 18 would favor the formation of
conformer C-17, which was very similar to C-1 but likely to
be more stable (Chart 6). As described earlier, C-1-like
conformers were poorer SERT ligands, and in agreement with
the hypothesis, the SERT binding affinities for 17 and 18 were
lower than that of 1 and 2.
The 2-methylene-substituted analogs 19 and 20, were then
synthesized to explore the electronic effect of the 2-oxo-

2802 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9
Hsin et al.
(Table 1). These data further supported the hypothesis that
conjugation with the phenyl ring reduces binding affinity for
DAT. On the other hand, the 3-oxo-substituted 11 and 12, 2-oxo-
substituted 17 and 18, and acetophenone 24 demonstrated a
similar reduction (1.7∼4.0-fold) in SERT binding affinity as
compared to their corresponding unsubstituted analogs.
Interestingly, in the preparation of chiral 2-fluoro-substituted
analogs (S)-10 and (R)-10, the rearranged products (S)-32 and
(R)-32, which could be viewed as 1-fluoromethyl-substituted
analogs of 38, were formed enantioselectively in significant
amounts. In contrast to (S)-10 and (R)-10, in which the chirality
was critical to pharmacological activity, the 1-substituted (S)-
32 and (R)-32 did not demonstrate meaningful enantioselectivity.
Among the bis(4-fluorophenyl)-substituted analogs, (S)-32 and
(R)-32 were the weakest DAT ligands. Nevertheless, (S)-32
possessed higher SERT binding affinity than (R)-32 and was
the only SERT-selective ligand found in this study (SERT/DAT
ratio ) 0.8).
that would be more beneficial as a medication for stimulant
abuse than the blockade of DAT alone.43 The affinities of
these analogs for the DAT and SERT appeared to be
controlled by their electronic and steric effects and by the
position of the substituent. Identification of these effects
should facilitate the discovery and development of novel
ligands with desired monoamine transporter binding patterns,
and these may prove to be more effective treatment agents
for cocaine abuse with fewer adverse effects.
Experimental Section
Melting points were determined on a MEL-TEMP II apparatus
by Laboratory Devices and are uncorrected. NMR spectra were
recorded on Bruker DPX-200, Varian XL-300, and AMX-400 FT-
NMR spectrometers. Chemical shifts are expressed in parts per
million (ppm) on the δ scale relative to a tetramethylsilane (TMS)
internal standard. Chemical ionization (CI) mass spectra were
obtained using a Finnigan 1015 mass spectrometer. EI mass spectra
and high-resolution mass measurements (HRMS) were obtained
using a Finnigan MAT 95S mass spectrometer. Elemental analyses
were performed with a Heraeus varioIII-NCSH instrument or by
Atlantic Microlabs, Atlanta, GA, and were within (0.4% for the
elements indicated. Optical rotations were obtained using a Perkin-
Elmer 341 polarimeter and are reported at the sodium D-line (589
nm), unless otherwise noted. Thin-layer chromatography (TLC) was
performed on Merck (art. 5715) silica gel plates and visualized
under UV light (254 nm), upon treatment with iodine vapor, or
upon heating after treatment with 5% phosphomolybdic acid in
ethanol. Flash column chromatography was performed with Merck
(art. 9385) 40–63 µm silical gel 60. Anhydrous tetrahydrofuran was
distilled from sodium-benzophenone prior to use. No attempt was
made to optimize yields.
Determination of Enantiomeric Purity by Chiral HPLC
Analysis. The free base of the sample was dissolved in 1%
isopropanol (IPA) in n-hexane. Then the sample solution (10 µL)
was eluted using 1–20% IPA in n-hexane in the presence of 0.2%
diethylamine as mobile phase on the CHIRALCEL OD or AD
column (250 × 4 mm, DAICEL). The ee values were calculated
based on the UV absorption (254 nm) areas of the two enantiomers.
Synthetic Method A. 1-[4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]
piperazinyl]-2-methyl-3-phenylpropan-1-one ((()-27). To a
stirred solution of 25 (740 mg, 2.23 mmol) and (()-2-methyl-3-
phenylpropionic acid (366 mg, 2.23 mmol) in CH2Cl2 (10 mL) was
added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydro-
chloride (EDCI; 469 mg, 2.45 mmol) at 0 °C and then stirred at rt
for 1 h. The reaction was quenched with brine and then diluted
with CH2Cl2. The organic layer was washed with water, saturated
NaHCO3 and brine. Then the resultant solution was dried (MgSO4),
filtered, evaporated, and chromatographed (silica gel, 5% MeOH
in CH2Cl2) to afford (()-27 (870 mg, 82%) as a light yellow oil.
1H NMR (300 MHz, CDCl3) δ 7.24–7.28 (m, 9H), 7.16–7.20 (m,
4H), 5.30 (s, 1H), 3.45–3.68 (m, 4H), 3.21–3.32 (m, 2H), 2.94–3.01
(m, 2H), 2.55–2.71 (m, 3H), 2.27–2.46 (m, 3H), 1.93–1.99 (m, 1H),
1.16 (d, J ) 5.9 Hz, 3H); CIMS m/z 479 (MH+).
Conclusions
In this article, we report SAR studies focused on the 2- and
3-substituted analogs of 1 and 2. Binding affinities for the DAT
and SERT varied depending on the nature of the substituents
in the C2- and C3-positions of the phenylpropyl side chain.
Steric and electronic effects affected their affinity and selectivity
for DAT and SERT. The 2-substituted series showed a quite
different SAR than the 3-substituted series. In the C2 series,
the substituent in the S-configuration with a lone-electron pair
significantly enhanced ligand binding affinity for DAT, whereas
the steric effect of the substituent was detrimental to DAT
binding. In the C3 series, neither the lone-electron pair nor the
steric effect of the substituent seemed to affect DAT binding
affinity, while compounds with sp2-hybridized substituents,
possibly due to their lessened conformational mobility, had little
affinity for DAT. 2-Oxo-substitution retained the DAT binding
seen with their parent compound and slightly increased the
SERT/DAT ratio, whereas 3-oxo-substitution was detrimental
to the affinity and selectivity for DAT. The SERT binding
affinity was insensitive to most of the structural modifications
in this study, except for 2-amino-substitution, which caused
substantially increased SERT binding affinity and selectivity
over the DAT.
Novel derivatives with different transporter binding affinities
and selectivities were discovered. 2-Fluoro-substituted analogs
(S)-10 and (R)-10 displayed substantial enantioselectivity in their
binding affinity for the DAT and SERT. Compound (S)-10 had
higher affinity and selectivity for DAT than (R)-10. In the series,
(S)-10 had the highest DAT binding affinity and exhibited
excellent DAT selectivity over the SERT. Compounds (R)-8
and (S)-32 demonstrated approximately equal affinities for DAT
and SERT (SERT/DAT ratio ) 1 and 0.8, respectively).
Furthermore, (R)-8 demonstrated the highest SERT binding
affinity in this series. Thus, the 2-amino-substituted (R)-8 might
be a lead compound for the discovery of potent and dual-action
ligands able to simultaneously block the DAT and the SERT.
As in the previous SAR studies, diphenyl-substituted analogs
always showed higher SERT/DAT ratios than the corresponding
bis(4-fluorophenyl)-substituted analogs. In the series, 16 and
18 were both oxygenated derivatives of 2 and possessed the
highest selectivity for DAT (SERT/DAT ratio ) 254 and 250,
respectively).
Synthetic Method B. (S)-1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-
4-(2-methoxy-3-phenylpropyl)piperazine ((S)-9). To a solution
of (S)-31 (900 mg, 1.82 mmol) in THF (15 mL) was added a
solution of aluminum hydride (alane, 3.6 mmol) in THF (6 mL)
dropwise at rt and then stirred for 30 min. The reaction was
quenched with water and then 1 M aqueous HCl followed by 1 M
aqueous HOAc was added to the solution. The resultant mixture
was stirred for 10 min before being extracted with Et2O. The organic
layer was washed with saturated NaHCO3. The aqueous layer was
basified to pH ) 10 with 10 M NaOH and then extracted with
Et2O. The Et2O extracts were combined, washed with brine, dried
(MgSO4), filtered, and evaporated. The residue was chromato-
graphed (silica gel, 3.5% MeOH in CH2Cl2) to afford (S)-9 (676
mg) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.21–7.30
(m, 9H), 6.97–7.03 (m, 4H), 5.33 (s, 1H), 3.53–3.57 (m, 3H), 3.36
Compounds with customized DAT and SERT binding
profiles could be useful research tools to help determine the
DAT/SERT ratio needed for the blockade of DAT and SERT

Role of Substituents on Dopamine and Serotonin Transporters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9 2803
(s, 3H), 2.83 (d, J ) 4.9 Hz, 2H), 2.65 (t, J ) 5.9 Hz, 2H),
2.30–2.51 (m, 10H); CIMS m/z 481 (MH+). Anal. (S)-9·2 maleate
(C29H34F2N2O2 ·2C4H4O4) C, H, N.
(m, 13H); EIMS m/z 468 (M+). Anal. (S)-32 · 2 maleate
(C28H31F3N2O·2C4H4O4) C, H, N.
(R)-1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(2-
fluoro-3-phenylpropyl)piperazine ((R)-10) and (R)-1-(1-Benzyl-2-
fluoroethyl)-4-[2-[bis(4-fluorophenyl)methoxy]ethyl]piperazine
((R)-32). Compounds (R)-10 and (R)-32 were synthesized using
(S)-536 according to the procedure for the preparation of (S)-10
and (S)-32 and yielded (R)-10 and (R)-32 as colorless oils. Anal.
(R)-10 ·2 maleate (C28H31F3N2O·2C4H4O4) C, H, N. Anal. (R)-32 ·2
maleate (C28H31F3N2O·2C4H4O4) C, H, N.
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenyl-but-
3-enyl)piperazine (13). To a stirred suspension of activated zinc
(620 mg, 9.48 mmol) and lead(II) chloride (11 mg, 0.04 mmol) in
THF (8 mL) was added diiodomethane (0.32 mL, 3.95 mmol) at rt
under an argon atmosphere. This reaction was a slightly exothermic
process. After 1 h, TiCl4 (0.79 mL, 1 M in CH2Cl2) was added at
0 °C, and the resultant dark brown mixture was stirred at rt for 30
min. A solution of 1134 (369 mg, 0.79 mmol) in THF (2 mL) was
added dropwise at rt and stirred for 2 h. The mixture was diluted
with ether (140 mL), and the organic layer was washed with
aqueous NaHCO3 (150 mL) and brine, dried (MgSO4), filtered, and
evaporated. The residue was chromatographed (silica gel; Et2O/
CH2Cl2 ) 1/2) to afford 13 (191 mg) as an oil. 1H NMR (200
MHz, CDCl3) δ 6.96–7.43 (m, 13H), 5.34 (s, 1H), 5.31 (s, 1H),
5.10 (s, 1H), 3.57 (t, J ) 5.8 Hz, 2H), 2.64–2.76 (m, 4H), 2.44–2.54
(m, 10H); MS (EI, 70 eV) m/z 462 (M+), 203 (base); EIHRMS
calcd for C29H32F2N2O [M]+, 462.2483; found, 462.2475. Anal.
13·2 maleate (C29H32F2N2O·2C4H4O4) C, H, N.
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(2-methyl-3-
phenylpropyl)piperazine ((()-7). To a stirred solution of LiAlH4
(2.66 mL, 1.0 M in THF) in THF (10 mL) was added a solution of
(()-27 (850 mg, 1.78 mmol) in THF (3 mL) at rt and stirred for
10 min. The reaction was quenched with water and stirred for 15
min before 10 M aqueous NaOH was added. The resultant mixture
was stirred for another 15 min, and then celite followed by MgSO4
was added to the stirred solution. After 15 min, the mixture was
filtered, and evaporated. The residue was chromatographed (silica
gel, 4% MeOH in CH2Cl2) to afford (()-7 (691 mg, 84%) as a
colorless oil. mp 185–186 °C (dimaleate salt); 1H NMR (300 MHz,
CDCl3) δ 7.24–7.31 (m, 6H), 7.14–7.19 (m, 3H), 6.98–7.03 (m,
4H), 5.35 (s, 1H), 3.57 (t, J ) 5.9 Hz, 2H), 2.82 (dd, J ) 13.7, 4.9
Hz, 1H), 2.66 (t, J ) 5.9 Hz, 2H), 2.40–2.55 (m, 8H), 2.09–2.33
(m, 3H), 1.91–2.00 (m, 1H), 0.83 (d, J ) 6.8 Hz, 3H); CIMS m/z
465 (MH+). Anal. (()-7·2 maleate (C29H34F2N2O·2C4H4O4) C,
H, N.
(+)-1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(2-methyl-3-
phenylpropyl)piperazine
((+)-7)
and
(-)-1-[2-[Bis(4-
fluorophenyl)methoxy]ethyl]-4-(2-methyl-3-phenylpropyl)piperazine
((-)-7). The optically pure compounds (+)-7 and (-)-7 were
separated from (()-7 by HPLC using semipreparative chiral column
(Daicel chiralcel OD, 2 cm × 25 cm; UV detection at 254 nm;
flow rate 6 mL/min; 2% 2-propanol in n-hexane in the presence of
0.2% diethylamine) followed by recrystallization of their maleate
salts.
1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenyl-but-
3-enyl)piperazine (14). Compound 14 was synthesized using 1234
according to the procedure for the preparation of 13 and yielded
(R)-1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(2-amino-3-
phenylpropyl)piperazine ((R)-8). To a stirred solution of (R)-29
(360 mg, 0.636 mmol) in MeOH (5 mL) was added saturated
methanolic HCl (1 mL) at 0 °C, and then the resultant solution
was stirred at rt for 90 min. The reaction was quenched with Et3N,
and evaporated. Aqueous NaOH and EtOAc were added to the
residue, and the organic layer was washed with brine, dried
(MgSO4), filtered, and evaporated. The oily residue was chromato-
graphed (silica gel, MeOH/CH2Cl2/NH4OH ) 1:10:0.1) to afford
(R)-8 (270 mg) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.20–7.32
(m, 9H), 6.97–7.03 (m, 4H), 5.34 (s, 1H), 3.56 (t, J ) 5.9 Hz, 2H),
3.14–3.23 (m, 1H), 2.73 (dd, J ) 13.2, 4.4 Hz, 1H), 2.65 (t, J )
5.9 Hz, 2H), 2.26–2.53 (m, 11H), 1.59 (broad s, 2H); EIHRMS
calcd for C28H33F2N3O [M]+, 465.2592; found, 465.2588.
(S)-1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(2-amino-3-
phenylpropyl)piperazine ((S)-8). Compound (S)-8 was synthesized
using (S)-29 according to the procedure for the preparation of (R)-8
and afforded an oil. EIHRMS calcd for C28H33F2N3O [M]+,
465.2592; found, 465.2579.
1
an oil. H NMR (200 MHz, CDCl3) δ 7.26–7.39 (m, 15H), 5.37
(s, 1H), 5.30 (s, 1H), 5.09 (s, 1H), 3.60 (t, J ) 6.0 Hz, 2H),
2.66–2.76 (m, 4H), 2.44–2.56 (m, 10H); EIHRMS calcd for
C29H34N2O [M]+, 426.2671; found, 426.2654. Anal. 14·2 maleate
(C29H34N2O·2C4H4O4) C, H, N.
4-[4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]piperazinyl]-2
-phenylbutan-2-ol (15). To a solution of 1134 (379 mg, 0.816
mmol) in THF (5 mL) was added methylmagnesium bromide (3.96
mL, 1 M in THF) and stirred for 17 h at rt. The mixture was
quenched with water and evaporated. The residue was treated with
CH2Cl2 and water. The organic layer was washed with brine, dried
(MgSO4), filtered, and evaporated. The crude product was chro-
matographed (silica gel; Et2O/CH2Cl2 ) 1/2) to afford 15 (213 mg)
as an oil. 1H NMR (200 MHz, CDCl3) δ 6.96–7.46 (m, 13H), 5.32
(s, 1H), 3.55 (t, J ) 5.9 Hz, 2H), 1.80–2.69 (m, 15H), 1.49 (s,
3H); EIHRMS calcd for C29H34F2N2O2 [M]+, 480.2588; found,
480.2588. Anal. 15·2 maleate (C29H34F2N2O2 ·2C4H4O4) C, H, N.
4-[4-[2-(Diphenylmethoxy)ethyl]piperazinyl]-2-phenylbutan-
2-ol (16). Compound 16 was synthesized using 1234 according to
the procedure for the preparation of 15 and yielded an oil. 1H NMR
(200 MHz, CDCl3) δ 7.21–7.46 (m, 15H), 5.36 (s, 1H), 3.58 (t, J
) 5.8 Hz, 2H), 1.79–2.70 (m, 15H), 1.49 (s, 3H); EIHRMS calcd
for C29H36N2O2 [M]+, 444.2777; found, 444.2760. Anal. 16·2
maleate (C29H36N2O2 ·2C4H4O4) C, H, N.
1-[4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]piperazinyl]-3-
phenylpropan-2-one (17). To a stirred solution of oxalyl chloride
(584 mg, 4.60 mmol) in CH2Cl2 (4 mL) was added dropwise a
solution of DMSO (0.72 mL, 10 mmol) in CH2Cl2 (3 mL) at -60
°C. The reaction mixture was warmed to -20 °C before a solution
of (()-536 (980 mg, 2.10 mmol) in CH2Cl2 (3 mL) was added.
After the reaction mixture was stirred and allowed to warm to -10
°C, triethylamine (1.06 g, 10.5 mmol) was added. The resultant
mixture was warmed to rt and stirred for an additional 2 h, and
then water was added. The aqueous layer was extracted with
CH2Cl2, and the organic layers were combined, washed with brine,
dried (MgSO4), filtered, and evaporated. The oily residue was
chromatographed (silica gel, 3% MeOH in CH2Cl2) to afford 17
(837 mg) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ
7.22–7.32 (m, 9H), 7.00 (t, J ) 8.8 Hz, 4H), 5.33 (s, 1H), 3.74 (s,
2H), 3.55 (t, J ) 6.4 Hz, 2H), 3.20 (s, 2H), 2.67 (t, J ) 5.9 Hz,
(R)-1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(2-methoxy-3-
phenylpropyl)piperazine ((R)-9). Compound (R)-9 was synthe-
sized from (R)-31 according to the synthetic method B and yielded
a yellow oil. Anal. (R)-9·2 maleate (C29H34F2N2O2 ·2C4H4O4) C,
H, N.
(S)-1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]->4-(2-fluoro-3-
phenylpropyl)piperazine ((S)-10) and (S)-1-(1-Benzyl-2-
fluoroethyl)-4-[2-[bis(4-fluorophenyl)methoxy]ethyl]piperazine
((S)-32). To a stirred solution of (diethylamino)sulfur trifluoride
(0.53 mL, 4.0 mmol) in CH2Cl2 (8 mL) was added a solution of
(R)-536 (1247 mg, 2.67 mmol) in CH2Cl2 (8 mL) at -78 °C, and
then the resultant mixture was stirred and warmed to rt over 5 h.
The solution was washed with aqueous NaHCO3 followed by brine,
and then the organic layer was dried (MgSO4), filtered, evaporated,
and chromatographed (silica gel, 80–100% EtOAc in n-hexane) to
afford (S)-10 (305 mg) and (S)-32 (185 mg) as colorless oils. (S)-
1
10: H NMR (300 MHz, CDCl3) δ 7.21–7.32 (m, 9H), 6.97–7.03
(m, 4H), 5.33 (s, 1H), 4.77–4.99 (m, 1H), 3.55 (t, J ) 6.4 Hz, 2H),
2.99 (d, J ) 5.9 Hz, 1H), 2.92 (dd, J ) 6.8, 2.9 Hz, 1H), 2.65 (t,
J ) 5.9 Hz, 2H), 2.48–2.61 (m, 10H); EIMS m/z 468 (M+). Anal.
(S)-10·2 maleate (C28H31F3N2O·2C4H4O4) C, H, N. (S)-32: 1H
NMR (300 MHz, CDCl3) δ 7.20–7.31 (m, 9H), 6.97–7.03 (m, 4H),
5.34 (s, 1H), 4.27–4.60 (m, 2H), 3.57 (t, J ) 5.9 Hz, 2H), 2.49–3.00

2804 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9
Hsin et al.
1
2H), 2.47–2.56 (m, 8H); CIMS m/z 465 (MH+). Anal. 17·2 maleate
(C28H30F2N2O2 ·2C4H4O4) C, H, N.
a yellow oil. H NMR (300 MHz, CDCl3) δ 7.98–8.01 (m, 2H),
7.23–7.57 (m, 13H), 5.37 (s, 1H), 3.81 (s, 2H), 3.61 (t, J ) 5.9
Hz, 2H), 2.71 (t, J ) 6.4 Hz, 2H), 2.64 (m, 8H); CIMS m/z 415
(MH+). Anal. 24·2 maleate (C27H30N2O2 ·2C4H4O4) C, H, N.
(S)-1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-[2-(tert-
butyloxycarbonylamino)-3-phenylpropyl]piperazine ((S)-29). The
intermediate (S)-1-[4-[2-[bis(4-fluorophenyl)methoxy]ethyl]piper-
azinyl]-2-(tert-butyloxycarbonylamino)-3-phenylpropan-1-one ((S)-
28) was synthesized using 25 and N-t-Boc-L-phenylalanine accord-
ing to the synthetic method A and yielded a white glassy solid in
a yield of 90%. 1H NMR (300 MHz, CDCl3) δ 7.17–7.29 (m, 9H),
6.98–7.03 (m, 4H), 5.45 (d, J ) 8.8 Hz, 1H), 5.29 (s, 1H), 4.82
(dd, J ) 14.3, 8.3 Hz, 1H), 3.47–3.58 (m, 4H), 3.26–3.32 (m, 1H),
2.94–3.02 (m, 3H), 2.55 (t, J ) 5.4 Hz, 2H), 2.27–2.43 (m, 3H),
1.83–1.88 (m, 1H), 1.42 (s, 9H); CIMS m/z 580 (MH+). To a
solution of diisobutylaluminum hydride (DIBALH, 10 mmol) in
THF (20 mL) was added (S)-28 (1.20 g, 2.07 mmol) in THF (5
mL) dropwise at rt and then stirred for 3 h. The reaction was
quenched with water, and then 1 M HCl followed by 1 M aqueous
HOAc was added to the solution. The resultant mixture was stirred
for 10 min and then extracted with Et2O. The organic layer was
washed with saturated NaHCO3. The aqueous layer was basified
to pH ) 10 with 10 M NaOH and then extracted with Et2O. The
Et2O extracts were combined, washed with brine, dried (MgSO4),
filtered, and evaporated. The residue was chromatographed (silica
gel, 3.5% MeOH in CH2Cl2) to afford (S)-29 (910 mg, 78%) as an
1-[4-[2-(Diphenylmethoxy)ethyl]piperazinyl]-3-
phenylpropan-2-one (18). Compound 18 was synthesized using
(()-636 according to the procedure for the preparation of 17 and
afforded a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.22–7.34
(m, 15H), 5.36 (s, 1H), 3.74 (s, 2H), 3.59 (t, J ) 6.4 Hz, 2H), 3.19
(s, 2H), 2.69 (t, J ) 6.4 Hz, 2H), 2.46–2.58 (m, 8H); CIMS m/z
429 (MH+). Anal. 18·2 maleate (C28H32N2O2 ·2C4H4O4) C, H, N.
1-(2-Benzyl-allyl)-4-[2-(diphenylmethoxy)ethyl]
piperazine (19). To a stirred solution of AlH3 (1.4 mmol) in THF
(6 mL) was added 33 (270 mg, 0.57 mmol) in THF (3 mL) dropwise
at rt. The solution was stirred for 15 min and then quenched with
1 M NaOH. The mixture was extracted with ether (50 mL × 3),
and the organic layers were combined, washed with brine, dried
(MgSO4), filtered, and evaporated. The crude residue was chro-
matographed (silica gel; 3% MeOH in CH2Cl2) to afford 19 (185
1
mg) as an oil. H NMR (200 MHz, CDCl3) δ 7.19–7.31 (m, 9H),
6.95–7.04 (m, 4H), 5.34 (s, 1H), 4.97 (s, 1H), 4.84 (s, 1H), 3.57 (t,
J ) 6.0 Hz, 2H), 3.37 (s, 2H), 2.79 (s, 2H), 2.67 (t, J ) 6.0 Hz,
2H), 2.39 (bs, 4H), 2.27 (bs, 4H); EIHRMS calcd for C29H32F2N2O
[M]+, 462.2483; found, 462.2489. Anal. 19 · 2 maleate
(C29H32F2N2O·2C4H4O4) C, H, N.
1-(2-Benzyl-allyl)-4-[2-[bis(4-fluorophenyl)methoxy]ethyl]
piperazine (20). Compound 20 was synthesized using 34
according to the procedure for the preparation of 19 and yielded
1
1
oil. H NMR (300 MHz, CDCl3) δ 7.17–7.31 (m, 9H), 6.97–7.03
an oil. H NMR (200 MHz, CDCl3) δ 7.18–7.33 (m, 15H), 5.38
(m, 4H), 5.34 (s, 1H), 4.61 (d, J ) 6.0 Hz, 1H), 3.90–3.98 (m,
1H), 3.55 (t, J ) 5.9 Hz, 2H), 2.85–2.87 (m, 2H), 2.64 (t, J ) 5.9
Hz, 2H), 2.20–2.50 (m, 10H), 1.43 (s, 9H); CIMS m/z 566 (MH+).
(R)-1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-[2-(tert-
butyloxycarbonylamino)-3-phenylpropyl]piperazine (R)-29. The
intermediate (R)-1-[4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]pip-
erazinyl]-2-(tert-butyloxycarbonylamino)-3-phenylpropan-1-one ((R)-
28) was synthesized using 25 and N-t-Boc-D-phenylalanine accord-
ing to the synthetic method A and yielded a white glassy solid in
82% yield. Compound (R)-29 was then synthesized using (R)-28
according to the procedure for the preparation of (S)-29 and afforded
an oil in 79% yield.
(s, 1H), 4.97 (s, 1H), 4.84 (s, 1H), 3.62 (t, J ) 5.9 Hz, 2H), 3.37
(s, 2H), 2.80 (s, 2H), 2.72 (t, J ) 5.9 Hz, 2H), 2.58 (bs, 4H), 2.41
(bs, 4H); EIHRMS calcd for C29H34N2O [M]+, 426.2671; found,
426.2656. Anal. 20·2 maleate (C29H34N2O·2C4H4O4) C, H, N.
1-[4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]piperazinyl]-2-methyl-3-
phenylpropan-2-ol (21). To a stirred solution of 25 (472 mg, 1.42
mmol) in DMF (3 mL) was added 1-chloro-2-methyl-3-phenyl-2-
propanol41 (35, 1071 mg, 5.68 mmol). Potassium carbonate (590
mg, 4.26 mmol) was added, followed by sodium iodide (426 mg,
2.84 mmol). The reaction was stirred at 70–80 °C for 18–24 h,
cooled to rt, and poured into water (20 mL). The mixture was
extracted with ether (50 mL × 3), and the organic layers were
combined, washed with brine, dried (MgSO4), filtered, and evapo-
rated. The crude residue was chromatographed (silica gel; MeOH/
(S)-2-Methoxy-3-phenylpropanoic acid ((S)-30). To a stirred
solution of NaH (28.8 mmol) in THF (10 mL) was added a solution
of L-3-phenyllactic acid (2.00 g, 12.0 mmol) in THF (40 mL) at rt
and stirred for 10 min before iodomethane (1.5 mL, 24.0 mmol)
was added to the reaction mixture. After stirred at rt for 5 h, 1 M
aqueous HCl was added and the resultant mixture was evaporated.
The residue was treated with additional 1 M aqueous HCl and
extracted with Et2O. The extract was washed with brine, dried
(MgSO4), filtered, and evaporated to afford (S)-30 (2.10 g, 97%)
as an oil, which was used for the following synthesis without further
1
CH2Cl2 ) 1/30) to afford 21 (215 mg) as an oil. H NMR (200
MHz, CDCl3) δ 6.96–7.30 (m, 13H), 5.33 (s, 1H), 3.57 (t, J ) 5.8
Hz, 2H), 2.30–2.83 (m, 15H), 1.09 (s, 3H); EIHRMS calcd for
C29H32F2N2O2 [M - 2H]+, 478.2432; found, 478.2433. Anal. 21·2
maleate (C29H34F2N2O2 ·2C4H4O4) C, H, N.
1-[4-[2-(Diphenylmethoxy)ethyl]piperazinyl]-2-methyl-3-
phenylpropan-2-ol (22). Compound 22 was synthesized using 26
and 35 according to the procedure for the preparation of 21 and
yielded an oil. 1H NMR (200 MHz, CDCl3) δ 7.20–7.36 (m, 15H),
5.37 (s, 1H), 3.59 (t, J ) 5.9 Hz, 2H), 3.13 (bs, 1H), 2.28–2.82
(m, 14H), 1.07 (s, 3H); EIHRMS calcd for C29H34N2O2 [M - 2H]+,
1
purification. H NMR (300 MHz, CDCl3) δ 7.23–7.34 (m, 5H),
4.03 (dd, J ) 7.9, 3.9 Hz, 1H), 3.40 (s, 3H), 3.14 (dd, J ) 14.2,
4.4 Hz, 1H), 3.02 (dd, J ) 14.2, 8.3 Hz, 1H), 1.26 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 177.0, 136.7, 129.4, 128.5, 126.9, 81.2,
58.5, 38.6; CIMS m/z 198 (MNH4+).
442.2620;
(C29H36N2O2 ·2C4H4O4) C, H, N.
found,
442.2612.
Anal.
22 · 2
maleate
(R)-2-Methoxy-3-phenylpropanoic acid ((R)-30). Compound
(R)-30 was synthesized from D-3-phenyllactic acid according to the
procedure for the preparation of (S)-30 and afforded an oil in 93%
yield, which was used for the following synthesis without further
purification.
2-[4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]piperazinyl]-
1-phenylethanone (23). A mixture of 25 (2.00 g, 6.02 mmol),
2-bromoacetophenone (1.56 g, 7.82 mmol), and N-ethyldiisopro-
pylamine (2.1 mL, 12 mmol) in DMF (20 mL) was stirred at 60
°C under argon for 15 h. The reaction was quenched with water,
and then the resultant mixture was extracted with diethyl ether.
The organic layer was washed with brine, dried (MgSO4), filtered,
and evaporated. The oily residue was chromatographed (silica gel,
3% MeOH in CH2Cl2) to afford 23 (2.47 g) as a light brown oil.
1H NMR (300 MHz, CDCl3) δ 7.98–8.01 (m, 2H), 7.55–7.60 (m,
1H), 7.44–7.48 (m, 2H), 7.25–7.30 (m, 4H), 6.97–7.04 (m, 4H),
5.34 (s, 1H), 3.82 (s, 2H), 3.57 (t, J ) 5.9 Hz, 2H), 2.69 (t, J )
5.9 Hz, 2H), 2.62 (broad s, 8H); CIMS m/z 451 (MH+). Anal. 23·2
maleate (C27H28F2N2O2 ·2C4H4O4) C, H, N.
(S)-1-[4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]piperazinyl]-2-
phenylpropan-1-one ((S)-31). Compound (S)-31 was synthesized
using 25 and (S)-30 according to the synthetic method A and yielded
1
a light yellow oil in 96% yield. H NMR (300 MHz, CDCl3) δ
7.22–7.32 (m, 9H), 6.99–7.04 (m, 4H), 5.32 (s, 1H), 4.27 (t, J )
6.9 Hz, 1H), 3.44–3.64 (m, 6H), 3.32 (s, 3H), 3.02–3.05 (m, 2H),
2.61 (t, J ) 5.9 Hz, 2H), 2.34–2.51 (m, 3H), 2.16–2.23 (m, 1H);
CIMS m/z 495 (MH+).
(R)-1-[4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]piperazinyl]-2-
methoxy-3-phenylpropan-1-one ((R)-31). Compound (R)-31 was
synthesized using 25 and (R)-30 according to the synthetic method
A and yielded a light yellow oil in 82% yield.
2-[4-[2-(Diphenylmethoxy)ethyl]piperazinyl]-1-
phenylethanone (24). Compound 24 was synthesized using 26
according to the procedure for the preparation of 23 and afforded

Role of Substituents on Dopamine and Serotonin Transporters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9 2805
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2-Benzyl-1-[4-[2-[bis(4-fluorophenyl)methoxy]ethyl]
piperazinyl]propenone (33). Compound 33 was synthesized using
25 and 2-benzyl-acrylic acid40 according to the synthetic method
A and yielded an oil in 55% yield. 1H NMR (200 MHz, CDCl3) δ
7.18-7.28 (m, 9H) 7.00 (t, J ) 8.6 Hz, 4H), 5.28 (s, 1H), 5.19 (s,
1H), 4.98 (s, 1H), 3.62 (s, 2H), 3.58 (bs, 2H), 3.48 (t, J ) 5.8 Hz,
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(s, 2H), 3.58 (bs, 2H), 3.51 (t, J ) 5.8 Hz, 2H), 3.26 (bs, 2H), 2.54
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cell harvesters were used to filter the samples over Whatman GF/B
filters, which were presoaked in wash buffer (ice-cold 10 mM Tris-
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Acknowledgment. We thank Noel Whittaker and Wesley
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helping with the transporter binding assays. We acknowledge
the National Science Council of the Republic of China (Grant
No. NSC 95-2323-B-002-011) for financial support of this work.
The research of the Drug Design and Synthesis Section, CBRB,
NIDA, and NIAAA, was supported by the NIH Intramural
Research Programs of the National Institute of Diabetes and
Digestive and Kidney Diseases, the National Institute on Drug
Abuse (NIDA), and the National Institute of Alcohol Abuse
and Alcoholism, and NIDA supported the research of the
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Supporting Information Available: Theoretical and experi-
mental elemental analyses for compounds (()-7, (S)-9, (R)-9, (S)-
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