Design and synthesis of promiscuous high-affinity monoamine transporter ligands: Unraveling transporter selectivity

Article abstract of DOI:10.1021/jm050766f

A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-piperidines and 4-[2-[(bisphenyl)methoxy]ethyl]-piperidines with different types of substituents in the phenylpropyl side-chain were synthesized and examined for their ability to bind to the dopamine tra

Full text of DOI:10.1021/jm050766f

1766
J. Med. Chem. 2006, 49, 1766-1772
Design and Synthesis of Promiscuous High-Affinity Monoamine Transporter Ligands:
Unraveling Transporter Selectivity
Elisabeth Greiner,† Terrence L. Boos,† Thomas E. Prisinzano,†,§ Maria G. De Martino,†,| Brian Zeglis,† Christina M. Dersch,‡
Jamila Marcus,‡ John S. Partilla,‡ Richard B. Rothman,‡ Arthur E. Jacobson,† and Kenner C. Rice*,†
Laboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, DHHS, Bethesda, Maryland 20892, Clinical Psychopharmacology
Section, NIDA, Addiction Research Center, National Institutes of Health, DHHS, Baltimore, Maryland 21224, College of Pharmacy,
The UniVersity of Iowa, 115 South Grand AVenue, Iowa City, Iowa 52242-1112, and Department of Pharmaceutical Studies, Faculty of
Pharmacy, UniVersita’ degli Studi di Roma “La Sapienza”, P.le Aldo Moro 5, 00185 Rome, Italy
ReceiVed August 4, 2005
A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-piperidines and 4-[2-[(bisphenyl)methoxy]ethyl]-
piperidines with different types of substituents in the phenylpropyl side-chain were synthesized and examined
for their ability to bind to the dopamine transporter (DAT), the serotonin transporter (SERT), and the
norepinephrine transporter (NET). All of the compounds showed high binding affinities for the DAT in the
low to subnanomolar range. Their ability to bind to the SERT and the NET, while maintaining their high
affinity for the DAT, could be altered by substitution in positions C2 and C3 of the phenylpropyl side-
chain. This approach gave rise to a new set of compounds with selectivity for the DAT, the DAT and the
SERT, or the DAT and the NET. Six compounds (7, 9, 11, 12, 14, and 20) with relatively low SERT/DAT
ratios were selected for additional study in biogenic amine uptake inhibition assays based on the biogenic
amine transporter binding results. Some of the new ligands can serve as pharmacological tools to block
DAT or DAT and another transporter simultaneously.
Introduction
cocaine was shown to produce impaired myocardial NET
function in rats.12
Cocaine is known to be one of the most widely abused drugs
because of its powerful reinforcing properties. Its abuse has had
great effects on public health, exacerbating the spread of HIV-
1, hepatitis B and C, and drug resistant tuberculosis.1 Cocaine
binds with moderate and roughly equal affinities to dopamine
transporters (DATs) and serotonin transporters (SERTs), which
are monoamine transporters (Ki ) 341 ( 25, 129 ( 9, and
13 038 ( 983 nM for DAT, SERT, and norepinephrine
transporter (NET) binding, respectively, using [125I]RTI-55 for
DAT and SERT, and [3H]nisoxetine for NET).2 Cocaine inhibits
the presynaptic reuptake of neurotransmitters, such as dopamine
(DA), serotonin (5-HT), and norepinephrine (NE) (e.g., [3H]DA
) 478 ( 25, [3H]5-HT ) 304 ( 10, and [3H]NE ) 779 ( 30
nM).3,4 However, the main target for cocaine has been consid-
ered to be the dopamine transporter (DAT). The mesolimbic
dopaminergic system has been said to mediate reinforcement
and the dependence-producing properties of abused drugs,3,5-8
and drug-induced changes in this system may be one of the
factors that can drive the compulsive use of cocaine.8,9 Recent
work2,10,11 suggests that both the serotonin transporter (SERT)
and the norepinephrine transporter (NET) may also play
prominent roles in cocaine addiction.4,12-17 Results from experi-
ments with knock-out mice and behavioral intervention experi-
ments indicated that the serotonergic system might further the
reinforcing effect of cocaine.18-20 NET plays an important role
in the regulation of cardiac function, and perinatal exposure to
1-{2-[Bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)-
piperazine (1) (GBR 12 909, Scheme 1), which is currently
being tested in phase I clinical trials, was one of the first high-
affinity DAT inhibitors. To date, most analogues of 121 have
been synthesized with two general goals in mind: to determine
structure-activity relationships (SAR) at the DAT and to
identify ligands with high affinity and selectivity for the DAT
(e.g., compound 2 (Scheme 1), the 2-hydroxy derivative of 1).
In contrast to the extensive studies on DAT-selective ligands,
fewer studies have focused on the SAR relevant to the
development of ligands with diverse levels of transporter
selectivity for two of the three or all of the three transporter
types.22-25 New ligands with high DAT affinity combined with
affinity and selectivity for the SERT, for example, could have
potential as treatment agents for stimulant abuse.4 Recently, we
reported on a series of ligands that completely lacked selectivity,
thus blocking all three transporter types simultaneously.22
Compounds that vary in their transporter affinity and selectivity
may help unravel the pharmacological mechanisms relevant to
stimulant abuse. To further elucidate the role of the different
transporter systems in cocaine reward and craving, novel ligands
with different selectivities for each of the three transporter sites
must be obtained.4 We have now explored a new series of
analogues of 1 in which we altered the phenylpropyl side-chain
with the hope of modifying their selectivity. If this could be
accomplished, it might provide a framework for the customi-
zation of transporter selectivity. A compound with appropriate
affinity for each transporter might lead to an optimized
medication for stimulant abuse with the highest efficacy and
fewest side effects. A single drug with the desired profile would
have the advantage of incorporating the effects of multiple drugs
* To whom correspondence should be addressed. Phone: 301-496-1856.
Fax: 301-402-0589. E-mail: kr21f@nih.gov.
† Laboratory of Medicinal Chemistry, National Institutes of Health.
‡ Clinical Psychopharmacology Section, National Institutes of Health.
§ The University of Iowa.
| Universita’ degli Studi di Roma “La Sapienza”.
10.1021/jm050766f CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/04/2006

UnraVeling Transporter SelectiVity
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1767
Scheme 1a
a Reagents: (a) ((R)-(+)- or (S)-(-))-3-Chloro-1-phenylpropanol, K2CO3, and MeOH; (b) ((R)-(+) or (S)-(-))-1-chloro-4-phenyl-propan-2-ol, K2CO3,
NaI, and EtOH; (c) HN3, DIAD, (C6H5)3P, and THF; and (d) (1) ((S)-(+) or (R)-(-))-R-methylhydrocinnamic acid, EDCI, and CH2Cl2 (2) LiAlH4, H2SO4,
and THF.
that, if needed, would multiply the potential of pharmacokinetic
complications.
procedure,30 was reacted with 4 followed by a LiAlH4 reduction
to afford 21. Phenylcyclopropyl compounds 22 and 23 were
prepared from the R,R- and S,S-trans-2-phenylcarboxylic acids
obtained through optical resolution using dehydroabietylamine.31
Chemistry
The key intermediates, 4-[2-[(bisphenyl)methoxy]ethyl-
piperidine (3) and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl-
piperidine (4), were synthesized in three steps from com-
mercially available 1-piperidineethanol.26 N-protection with
benzoyl chloride and ether formation using benzhydrol or 4,4′-
difluorobenzhydrol, respectively, in toluene, under azeotropic
distillation conditions was followed by N-deprotection under
basic conditions to give 3 and 4, respectively (Scheme 1).26 C2-
hydroxylated analogues 5-10 were prepared from chiral syn-
thons according to the literature, with modifications.21 The
(S)-(+)/(R)-(-)-1-chloro-3-phenylpropan-2-ol and (S)-(+)/
(R)-(-)-1-chloro-3-phenylbutan-2-ol isomers were synthesized
via regioselective epoxide ring opening by a Grignard reagent,
phenylmagnesium bromide or benzylmagnesium bromide, and
CuI in THF at -40 °C. Compounds 3 and 4 were alkylated
with (S)-(+)/ (R)-(-)-1-chloro-3-phenylpropan-2-ol and (S)-(+)/
(R)-(-)-1-chloro-3-phenylbutan-2-ol, respectively, in MeOH
under reflux conditions using K2CO3 and NaI to afford the
appropriate R or S isomers. Analogous amino-derivatives 11
and 12 were synthesized from 7 and 8 in two steps. In a one-
pot reaction, a stereospecific transformation of the hydroxyl
derivatives to an azide by a modified Mitsunobu reaction was
followed by a Staudinger reduction to the amine with inversion
of the configuration at the stereochemical center.27,28 C2-
methylated enantiomers 13 and 14 were synthesized by coupling
4 with (+)-R-methylhydrocinnamic acid and (-)-R-methyl
hydrocinnamic acid,29 respectively, using EDCI, and subse-
quently reducing the amide functionality by treatment with
LiAlH4. Derivatives 19, 20, 22, and 23 (Scheme 2) were
synthesized by a similar procedure, including a coupling reaction
with the appropriate acid followed by LiAlH4 reduction. 3,4-
Dihydro-2-naphthoic acid, which was synthesized in three steps
from 4-phenylbutyric acid ethyl ester, following a published
Results and Discussion
Our goal for this study was to find compounds with high
affinity for the DAT (preferably with Ki < 10 nM), combined
with an affinity for either the SERT or the NET. Compound 1
(Scheme 1), a nonselective monoamine transporter inhibitor,
served as the basic template. Previous data21 suggested that
enantioselectivity in transporter binding could be achieved with
a hydroxy-substituted derivative of 1, when the hydroxy group
is in the C2 position. Compound 2 (Scheme 1), the C2-hydroxy
substituted analogue of 1, was among the most selective DAT
ligands.21 Hence, it seems that the substitution pattern in the
side chain of the ligand might have a distinct influence on its
ability to bind to the different transporters. Thus, in our attempt
to improve the affinity for a second transporter for ligands with
good affinity for DATs, we examined the following effects of
modifications in the phenylpropyl moiety: (A) substitution (OH,
NH2, and CH3) in the side chain in positions C2 and C3; (B)
the effect of chirality; and (C) the conformational constraint of
side-chain flexibility through the incorporation of a double-bond
or additional rings.
We started our study with the synthesis of C2 and C3
hydroxy-substituted 4-[2-[bis(4-fluorophenyl)methoxyethyl]-
piperidines (7, 8, 13, and 14, Scheme 1) and 4-[2-bisphenyl]-
methoxyethyl]piperidines (5, 6, 15, and 16, Schemes 1 and 2).
This resulted in a set of compounds with high binding affinity
for the DAT, comparable to those of their respective analogues
from the piperazine series (Table 1).21
In accordance with our previous findings,21 desfluoro ana-
logues 5, 6, 15, and 16 were generally more selective for binding
to the DAT than the bis-4-fluorophenyl analogues. Bis-4-
fluorophenyl analogues 7, 8, 17, and 18 displayed a somewhat
higher affinity for the DAT and improved affinity for the SERT.

1768 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Greiner et al.
Scheme 2a
a Reagents: (a) ((R)-(+) or (S)-(-))-3-Chloro-1-phenylpropanol, K2CO3, and DMF; (b) (1) ((S)- or (R)-)-3-phenylbutyric acid, EDCI, and CH2Cl2 (2)
LiAlH4, H2SO4, and THF; (c) as in method b, using 3,4-dihydro-2-naphthoic acid; and (d) as in method b, using (R,R)- or (S,S)-trans-2-
phenylcyclopropanecarboxylic acid.
Table 1. Binding Affinities at the DAT, SERT, and NET
(Ki ( SD, nM)
compda
R/S
DATb
SERTb
126 ( 5
230 ( 7
NETb
SERT/DAT
NET/DAT
115
1c
2d
3.7 ( 0.4
0.75 ( 0.03
426 ( 33
34
S
307
5
6
7
8
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
6.9 ( 0.3
1.4 ( 0.2
5.1 ( 0.6
0.4 ( 0.1
2.1 ( 0.2
1.6 ( 0.2
12 ( 1
6.3 ( 0.5
0.9 ( 0.14
8 ( 0.9
1.8 ( 0.2
2.1 ( 0.2
0.8 ( 0.1
0.9 ( 0.1
2.2 ( 0.2
1.3 ( 0.14
1.1 ( 0.1
0.5 ( 0.02
1.4 ( 0.2
286 ( 22
450 ( 30
91 ( 9
785 ( 36
485( 19
1221 ( 99
361 ( 16
460 ( 41
736 ( 97
941 ( 45
851 ( 102
103 ( 13
380 ( 45
>5600
42
332
18
205
6
114
359
240
902
215
457
78
135
118
47
3200
101
394
515
253
259
40
82 ( 5
9
13 ( 1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
38 ( 4
24
6
68 ( 5
76 ( 5
12
61
13
158
107
51
26
26
22
118
32
97
53 ( 2
100 ( 6
280 ( 15
230 ( 35
43 ( 3
210 ( 12
330 ( 15
440 ( 15
560 ( 75
340 ( 30
43 ( 4
22 ( 0.8
58 ( 3
30 ( 2
127 ( 7
16 ( 1
136 ( 5
947 ( 52
359 ( 41
1894
256
a Prepared and tested as oxalate salts. b Values determined as in Lewis et al.36 Binding affinities at the DAT and SERT are labeled with [125I]RTI-55 and
at the NET with [3H]nisoxetine. c Data from Boos et al.37 d Data from Hsin et al.21
Desfluoro analogues 5, 6, 15, and 16 displayed SERT/DAT
selectivity ratios up to 330-fold (6), whereas corresponding bis-
4-fluorophenyl analogues 7, 8, 17, and 18 showed generally
lower SERT/DAT selectivity (Table 1). Chirality had a distinct
influence on SERT/DAT selectivity in both the bis-4-fluoro-
phenyl and in the desfluoro series. The S isomers with the
hydroxy group in the C2 position showed higher SERT/DAT
selectivity than their R configured analogues (6 is 8-fold more
selective than 5, and 8 is 11-fold more selective than 7). Shifting
the substituent to the C3 position (15-18, Scheme 2) mostly
abolished this effect, and the enantiomeric differences in SERT/
DAT selectivity were less pronounced. None of these analogues
showed high affinity for the NET. Side-chain elongation to four
carbon atoms with a hydroxy group in the C2 position gave
rise to enantiomers 9 and 10. Altthough their binding affinities
for the DAT are similar to those of their counterparts 7 and 8,
SERT affinity was, as we desired, further increased by this
modification. The R isomer 9 is much less selective for DATs
and SERTs than 7, 8, and 10. Compound 9 had good affinity
for DAT (Ki ) 2 nM) and reasonable affinity for SERT (Ki )
13 nM, Table 1).
Because the bis-4-fluorophenyl compounds proved to be more
active at the DAT and the bis-4-fluorophenyl moiety of the
molecule seemed to be slightly better tolerated at the NET, we
decided to use the 4-[2-[bis(4-fluorophenyl)methoxy]ethyl-1-
phenylpropylpiperidine backbone for further modifications
(Scheme 1). Introduction of an amino group into the C2 position
resulted in compounds 11 and 12. These compounds show
slightly lower DAT affinities than their hydroxy substituted
analogues 7 and 8, whereas their SERT affinities were in the

UnraVeling Transporter SelectiVity
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1769
Ki values for the inhibition of [3H]DA uptake. The Ki values
for the inhibition of SERT binding were also similar to the Ki
values for the [3H]5-HT uptake inhibition, except for those of
11 and 12, which were about 3 times less potent in the uptake
inhibition assay than in the SERT binding assay. Greater
discrepancies were observed in the NET assays. In this case,
all agents were between 2.3-fold and 10-fold more potent in
the [3H]NE uptake inhibition assay than in the NET binding
assay. The discrepant results in the NET assays likely result
from the use of [3H]nisoxetine to label the NET because recent
studies showed that this ligand generally yields Ki values
significantly higher than that observed in [3H]NE uptake
assays.33 The use of [125I]RTI-55 to label NET in HEK cells
that express the NET, which is now our current practice, helps
to resolve this problem. An additional factor that can contribute
to the differences between binding and functional Ki values is
the fact that the assays are done under very different condi-
tions.34 Thus, in agreement with the findings of Reith et al.,33
in cases where it is critical to determine the functional selectivity
of biogenic amine transporter ligands, uptake inhibition assays
are probably superior to biogenic amine transporter binding
assays.
Table 2. Uptake-Inhibition Studies for Selected Compounds
(Ki ( SD, nM)
compda R/S [3H]DAb [3H]5-HTb [3H]NEb 5-HT/DA NE/DA
7
9
11
12
14
20
R
R
R
S
S
S
1.7 ( 0.14
1.4 ( 0.05
17 ( 1.4
41 ( 2.3 143 ( 14
19 ( 0.9 79 ( 8.6
229 ( 10 402 ( 37
24
14
13
18
33
36
84
56
24
26
42
19
13 ( 0.9
228 ( 8
338 ( 32
160 ( 18
40 ( 3.6
3.8 ( 0.23 124 ( 5
2.1 ( 0.14
75 ( 5.9
a Prepared and tested as oxalate salts. b Values determined as in refs 32-
34.
same range (Table 1). Their enantioselectivity was in accordance
with the trend we observed in the hydroxy substituted series. R
isomer 11 was less SERT/DAT selective. However, the amino
group seemed to be even less tolerated at the NET than the
hydroxy substituent, so we continued by exploring other
substituents.
Substitution of the hydroxy group with a methyl group in
positions C2 and C3 did not affect DAT binding, and all of the
compounds displayed DAT binding affinities in the low
nanomolar to subnanomolar range (e.g., Ki ) 0.9 nM for 11,
Table 1). C3-substituted, S-configured analogue 20 displayed
the highest SERT affinity (Ki ) 30 nM) in this set, whereas
the other analogues, 13, 14, and 19, showed only moderate
affinity for the SERT. The absolute configuration of the methyl
group was more important for the affinity of the C2-substituted
isomers at the DAT and SERT than for the C3-methylated
analogues. Unlike the corresponding hydroxy analogue, C2-
methyl substituted R isomer 13 was significantly more SERT/
DAT selective than its S isomer 14 (Table 1). Although 13 had
a higher affinity than that of 14 for SERTs, the SERT/DAT
ratio (61, Table 1) was higher than that for 14 because of the
exceptionally high affinity of 15 at the DAT. The SERT/DAT
ratio of ca. 13 for analogue 16 was much better for our purposes,
although the affinities of 14 for both transmitters (DAT Ki )
8, SERT Ki ) 100 nM) was not very high. The binding affinities
of the methyl-substituted analogues at the NET were generally
poor, but a methyl substituent anywhere in the side chain seemed
to improve NET affinity or decrease DAT/NET selectivity.
Because the polar, electrophilic hydroxy substituent in the
side chain was not needed to maintain the high binding affinity
at the DAT, we thought it would be of interest to investigate
the effect of substituents that, perhaps like the methyl and
hydroxyl moieties, might influence the interaction of the ligand
with DATs, SERTs, and/or NETs through a steric effect. We
decided to increase the steric effect by reducing the flexibility
of the side chain through an additional ring.21-23 The introduc-
tion of an unsaturated six-membered ring with a double bond
between C2 and C3 resulted in compound 21 with a high affinity
for the DAT (Ki ) 1 nM) and moderate affinity for the SERT
(Ki ) 127 nM). Because 21 displayed the highest affinity for
the NET (Ki ) 43 nM) in this series, it might prove useful as
a prototype for compounds able to simultaneously block the
DAT and the NET. The trans-cyclopropylmethyl derivatives
22 and 23 also showed a high affinity for the DAT (Ki ) 0.5
and 1.4 nM, respectively). Their binding affinities for the SERT
were comparable to those of the methylated analogues. How-
ever, NET affinity seemed to be decreased by this modification.
On the basis of the biogenic amine transporter binding results
(Table 1), we selected six compounds (7, 9, 11, 12, 14, and 20)
with relatively low SERT/DAT ratios for additional study in
biogenic amine uptake inhibition assays, conducted as de-
scribed.32-34 The results (see Table 2) showed that the Ki values
for the inhibition of DAT binding was generally similar to the
Conclusions
Some of the compounds listed in Table 1 (8, 13, 17, 18, and
22) had exceptionally high, subnanomolar affinity for DAT,
whereas the others showed a high affinity for the DAT in the
low nanomolar range. Their binding affinities for the SERT and
the NET varied, depending on the nature of the substituent in
the C2 position of the phenylpropyl side chain, and could be
further affected by the remote introduction of chirality. Intro-
duction of a hydroxy substituent with an S configuration in the
C2 position (6, 8) led to highly selective DAT ligands. Two
compounds with an R-hydroxy group (9) or an R-amino group
(11) in the C2 position showed high affinities for DATs and
good affinities for the SERT. The binding data indicate that
these compounds might be useful for determining the effects
of the simultaneous blockade of two transporters, DATs and
SERTs. However, functional data from uptake-inhibition studies
clearly suggest that 9 would be more efficacious than 11 for
that purpose. The highest binding affinity for the NET was
observed with a compound where the movement of the side-
chain was restrained by an additional ring system (22). Although
progress was made toward finding ligands able to interact with
both DATs and SERTs or DATs and NETs, their affinities for
the SERTs and NETs need to be increased. Our results are
consistent with the following hypotheses: (1) the steric effects
of the substituent influence the binding of a ligand at the SERT
and the NET, as may hydrogen bonding (e.g., compound 9),
(2) the restrictions in the flexibility of the side chain have a
lesser influence, and (3) the electronic effects of polar substit-
uents in these positions apparently interfere with NET binding.
Compounds with customized transporter properties could serve
as pharmacological tools to determine to what extent the
blockade of two of the three transporters is beneficial as a
medication for cocaine abuse, as compared to the blockade of
DATs alone. A better understanding of these effects may
facilitate the development of more effective treatment agents
with fewer side effects.
Experimental Section
All melting points were determined on a Thomas-Hoover
melting-point apparatus and are uncorrected. The 1H NMR spectra
were recorded on a Varian XL-300 instrument with DMSO-d6 as

1770 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Greiner et al.
solvent, with the values given in ppm (TMS as internal standard)
and J (Hz) assignments of 1H resonance coupling. Chemical
ionization mass spectra (CIMS) were obtained using a Finnigan
1015 mass spectrometer. Electron ionization (EIMS) mass spectra
were obtained using a VG-Micro Mass 7070F mass spectrometer.
Thin-layer chromatography (TLC) was performed on 250 mm
Analtech GHLF silica gel plates using n-hexane/EtOAc, 7:3, as
the solvent system. Elemental analyses were performed by Atlantic
Microlabs, Inc., Norcross, GA. (S)-(+)-1-Chloro-3-phenylpropan-
2-ol and (R)-(-)-1-chloro-3-phenylpropan-2-ol were purchased from
Aldrich Chemical Co., Milwaukee, WI. Enantiomeric purity was
assessed by HPLC (Shimadzu LC-6A with a Shimadzu SPD-6AV
UM detector (at 254 nm) using Daicel’s Chiralcel OD column (0.46
× 5 cm2 coupled to 0.46 × 25 cm2). The mobile phase was hexanes/
2-propanol/diethylamine (95:5:0.1) at a flow rate of 0.7-1 mL/
min. The chiral compounds (all of the hydroxy- and amino-
substituted compounds) were either found to be optically pure
(>99%) by chiral HPLC or were prepared from optically pure
starting material.
(R)-(+)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(4-phen-
ylbutan-2-ol)-piperidine Oxalate (9). Into a suspension of Mg
(0.54 g, 0.0222 mol) and catalytic amounts of I2 in Et2O (25 mL)
was added about a quarter of the total amount of benzyl bromide
(total of 3.8 g, 0.0222 mol) in Et2O (10 mL), and the reaction was
initiated by slight heating. The rest of the benzyl bromide solution
was added dropwise to maintain a gentle reflux. After addition,
the mixture was heated to efflux for 30 min before the Grignard
reagent was transferred into a dry flask. CuI (1.6 g, 0.0083 mol)
was added, and the solution was cooled to -78 °C. (R)-(-)-
Epichlorohydrin (0.5 g, 0.0056 mol) was added in a dropwise
manner. The mixture was warmed to 0 °C and stirred for 1 h before
NH4Cl (saturated solution, 100 mL) was added. The mixture was
extracted with EtOAc (2 × 60 mL). The combined organic layers
were washed with H2O (3 × 50 mL) and brine (3 × 50 mL), and
dried over Na2SO4. The solvent was removed under reduced
pressure, affording a crude oil. Purification by column chromatog-
raphy (silica gel, hexanes/EtOAc, 85:15) yielded 1-chloro-4-phenyl-
propan-2-ol as a clear oil. Compound 9 was prepared in 66% yield
using the procedure described for 7 from 4 as colorless crystals:
mp 144-145 °C; [R]D20 +1.9 (c 1.06, MeOH); 1H NMR (DMSO-
d6): δ 7.1-7.4 (m, 13H), 5.5 (s, 1H, CH-O), 4.3 (d, 1H, CH-
OH, J ) 3.6), 3.4 (m, 4H); MS m/z (CI): 480.3 [M + 1]+. Anal.
(C30H35NO2F2‚C2H2O4): C, H, N.
(R)-(-)-4-(2-Benzhydryloxyethyl)-1-(3-phenylpropan-2-ol)-
piperidine Oxalate (5). A mixture of 3 (1.8 g, 0.0047 mol,
free base), (R)-(-)-3-chloro-1-phenylpropanol35 (0.8 g, 0.005 mol),
and K2CO3 (1.9 g, 0.0141 mol) in MeOH (30 mL) was heated to
reflux for 12 h. The mixture was extracted with CH2Cl2 (3 × 50
mL). The combined organic layers were washed with saturated NaCl
(2 × 50 mL) and dried (Na2SO4). Removal of the solvent under
reduced pressure afforded a crude oil that was purified by column
chromatography (silica gel, CH2CH2/MeOH, 9:1). The resulting oil
was dissolved in Et2O (50 mL), and oxalic acid (1.1 equiv) was
added. The mixture was cooled in an ice bath to induce crystal-
lization. The precipitate was collected and dried to afford 1.2 g
(S)-(-)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(4-phen-
ylbutan-2-ol)-piperidine Oxalate (10). Compound 10 was prepared
in 49% yield using the procedure described for 7 from 5 (2.5 g,
0.0075 mol) and (S)-1-chloro-4-phenyl-butan-2-ol as colorless
crystals: mp 146-147 °C; [R]D20 -1.6 (c 1.20, MeOH); 1H NMR
(DMSO-d6): δ 7.1-7.4 (m, 13H), 5.5 (s, 1H, CH-O), 4.3 (d, 1H,
CH-OH, J ) 3.6), 3.4 (m, 4H); MS m/z (CI): 480.3 [M + 1]+.
Anal. (C30H35NO2F2‚C2H2O4): C, H, N.
20
(44%) of a white solid: mp 156-158 °C; [R]D -8.7 (c 0.975,
1
(R)-(-)-1-(2-Amino-3-phenylpropyl)-4-[2-[bis-(4-fluorophen-
yl)methoxy]ethyl]piperidine Dioxalate (11). NaN3 (6.5 g, 0.100
mol) was suspended into warm H2O. Benzene (100 mL) was added,
and the mixture was cooled to 0 °C. H2SO4 (4.9 g, 0.05 mol) was
added in a dropwise manner while the temperature was kept below
10 °C. After the mixture was cooled to 0 °C, the organic layer was
decanted and dried over Na2SO4. Diisopropylazodicarboxylate
(DIAD, 0.42 g, 0.0021 mol) was added dropwise to a solution of
7 (1.0 g, 0.0021 mol), triphenylphosphine (660 mg, 0.0025 mol),
and hydrazoic acid/benzene (2.5 mL, 4%) in THF (50 mL) at 5
°C. This mixture was stirred at room temperature for 3 h, and
triphenylphosphine (0.55 g, 0.0021 mol) was added in one portion.
The solution was heated to 40 °C, until the evolution of gas ceased.
H2O (1 mL) was added, and the solution was stirred for an
additional 3 h. The solvents were removed under reduced pressure,
and the residue was dissolved in CH2Cl2/2N HCl (100 mL, 1:1).
The aqueous layer was separated, basified, and extracted with
CH2Cl2 (2 × 25 mL). The combined organic layers were washed
with H2O (1 × 100 mL) and brine (1 × 100 mL) and dried over
Na2SO4. Removal of the solvent under reduced pressure afforded
a crude oil that was purified by column chromatography (silica
gel, hexane/EtOAc, 9:1). The resulting oil was dissolved in Et2O
(50 mL), and oxalic acid (1.1 equiv) was added. The mixture was
cooled in an ice bath to induce crystallization. The precipitate was
collected and dried to afford 1.2 g (80%) of colorless crystals: mp
145-147 °C; [R]D20 -7.3 (c 1.04, MeOH); 1H NMR (DMSO-d6):
δ 7.1-7.4 (m, 13H), 5.4 (s, 1H, CH-O); MS m/z (CI): 465 [M +
1]+. Anal. (C29H34N2OF2‚2C2H2O4): C, H, N.
MeOH); H NMR (DMSO-d6): δ 7.2-7.4 (m, 15H), 5.4 (s, 1H,
CH-O), 2.8-3.2 (m, 5H), 2.7 (d, 2H, J ) 6); MS m/z (CI): 430.3
[M + 1]+. Anal. (C29H35NO2‚C2H2O4): C, H, N.
(S)-(+)-4-(2-Benzhydryloxyethyl)-1-(3-phenylpropan-2-ol)-
piperidine Oxalate (6). Compound 6 was prepared in 34%
yield using the procedure described for 5, as colorless crystals:
mp 156-158 °C; [R]D20 +8.5 (c 1.05, MeOH); 1H NMR (DMSO-
d6): δ 7.2-7.4 (m, 15H); 5.4 (s, 1H, CH-O); 2.7 (d, 2H, J ) 6);
MS m/z (CI): 430.3 [M + 1]+. Anal. (C29H35NO2‚C2H2O4):
C, H, N.
(R)-(-)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(3-phenyl-
propan-2-ol)-piperidine Oxalate (7). A mixture of 4 (2.0 g, 0.0047
mol, free base), K2CO3 (1.9 g, 0.0141 mol), catalytic amounts of
NaI, and (R)-(-)-3-chloro-1-phenylpropanol35 (0.8 g, 0.005 mol)
in abs EtOH (30 mL) was heated at reflux for 12 h. The solvent
was removed under reduced pressure, and H2O (150 mL) was added
to the residue. The mixture was extracted with Et2O (3 × 50 mL).
The combined Et2O layers were washed with saturated NaCl (2 ×
100 mL) and dried (Na2SO4). Removal of the solvent under reduced
pressure afforded a crude oil that was purified by column chro-
matography (silica gel, CH2Cl2/MeOH, 9:1). The product was
dissolved in 2-propanol. Oxalic acid (1.1 equiv) and H2O (0.5 mL)
were added, the solution was cooled in an ice bath, and the
precipitate was collected to afford 7 (2.0 g, 77%) as a colorless
20
solid: mp 72-75 °C; [R]D -8.5 (c 1.13, MeOH); 1H NMR
(DMSO-d6): δ 7.1-7.4 (m, 13H), 5.5 (s, 1H, CH-O), 4.2 (m,
1H, CH-OH), 3.4 (m, 4H), 2.7 (d, 2H, J ) 6.0 Hz); MS m/z (CI):
466.2 [M + 1]+. Anal. (C29H33NO2F2‚C2H2O4‚0.25H2O): C, H,
N.
(S)-(+)-1-(2-Amino-3-phenylpropyl)-4-[2-[bis-(4-fluorophenyl)-
methoxy]ethyl]piperidine Dioxalate (12). Compound 12 was
prepared in 70% yield using the procedure described for 11 from
(S)-(+)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(3-phenyl-
propan-2-ol)-piperidine Oxalate (8). Compound 8 was prepared
in 66% yield using the procedure described for 7 from 4 (2.0 g,
0.0047 mol) and (S)-(+)-3-chloro-1-phenylpropanol (0.8 g, 0.005
20
7 (2.0 g, 0.0044 mol) as colorless crystals: mp 147-148 °C; [R]D
+7.6 (c 1.03, MeOH); 1H NMR (DMSO-d6): δ 7.1-7.4 (m, 13H),
5.4 (s, 1H, CH-O); MS m/z (CI): 465 [M + 1]+. Anal.
(C29H34N2OF2‚2C2H2O4): C, H, N.
20
mol) as colorless crystals: mp 73-76 °C; [R]D +8.0 (c 1.15,
1
MeOH); H NMR (DMSO-d6): δ 7.1-7.4 (m, 13H), 5.5 (s, 1H,
R-(-)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(2-methyl-
3-phenylpropyl)piperidine Oxalate (13). A solution of 4 (1.3 g,
0.0039 mol, free base), (S)-(+)-R-methylhydrocinnamic acid29 (0.7
g, 0.0039 mol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodi-
CH-O), 4.2 (m, 1H, CH-OH), 3.4 (m, 4H), 2.7 (d, 2H, J ) 6.6
Hz); MS m/z (CI): 466.2 [M + 1]+. Anal. (C29H33NO2F2‚C2H2O4‚
0.25H2O): C, H, N.

UnraVeling Transporter SelectiVity
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1771
20
imide hydrochloride (EDCI) (0.9 g, 0.005 mol) in dry CH2Cl2 (25
mL) was stirred at room temperature for 12 h. The solvent was
removed under reduced pressure, and EtOAc (125 mL) was added
to the residue. The combined EtOAc layers were washed succes-
sively with 1 M HCl (2 × 50 mL), 10% K2CO3 (2 × 50 mL), and
saturated NaCl (50 mL) and dried (Na2SO4). The solvent was
removed under reduced pressure to afford 1.8 g (95%) of the
corresponding amide as an oil, which was used without further
characterization. To a suspension of LiAlH4 (0.7 g, 0.0195 mol) in
dry THF (100 mL) at 0 °C, 100% H2SO4 (d ) 1.84, 0.9 g, 0.009
mol) was cautiously added. Upon completion of the addition, the
mixture was stirred at room temperature for 1 h. A solution of the
crude amide in dry THF (50 mL) was added in a dropwise manner.
The resulting mixture was stirred for 2 h, and then 10% NaOH
(150 mL) was added cautiously. The layers were separated, and
the aqueous layer was extracted with ethyl acetate (2 × 100 mL).
The combined organic layers were washed with H2O (100 mL)
and saturated NaCl (2 × 100 mL) and dried (Na2SO4). Removal
of the solvent under reduced pressure afforded a crude oil that was
purified by chromatography (silica gel, EtOAc/n-hexane, 3:7). The
product was dissolved in Et2O, and an excess of oxalic acid was
added. The precipitate was collected and dried to afford 13 (1.0 g,
56%), as colorless crystals: mp 118-122 °C; [R]D20 -1.4 (c 1.00,
mol) as colorless crystals: mp 97-102 °C; [R]D -16.4 (c 1.07,
1
MeOH); H NMR (DMSO-d6): δ 7.1-7.4 (m, 13H), 5.4 (s, 1H,
CH-O), 4.6 (m, 1H, CH-OH); MS m/z (CI): 466.3 [M + 1]+.
Anal. (C29H35NO2‚C2H2O4): C, H, N.
R-(-)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(3-phenyl-
butyl)-piperidine Oxalate (19). Compound 19 was prepared in
60% yield using the procedure described for 13 from 4 (2.0 g,
0.0060 mol, free base) using (R)-3-phenylbutyric acid (1.0 g, 0.0061
mol) to give colorless crystals: mp 154-156 °C; [R]D20 -2.93 (c
1.09, MeOH); 1H NMR (DMSO-d6): δ 7.1-7.4 (m, 13H), 5.4 (s,
1H, CH-O), 0.7 (d, 3H, J ) 6.3 Hz); MS m/z (CI): 464.3 [M +
1]+. Anal. (C30H35F2NO‚C2H2O4): C, H, N.
S-(+)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(3-phenyl-
butyl)-piperidine (20). Compound 20 was prepared in 40% yield
using the procedure described for 15 from 4 (2.0 g, 0.0060 mol,
free base) and (S)-3-phenylbutyric acid (1.0 g, 0.0061 mol), as
colorless crystals: mp 155-157 °C; [R]D20 +2.80 (c 1.00, MeOH);
1H NMR (DMSO-d6): δ 7.1-7.4 (m, 13H), 5.4 (s, 1H, CH-O),
1.2 (d, 3H, J ) 7.2 Hz); MS m/z (CI): 464.3 [M + 1]+. Anal.
(C30H35F2NO‚C2H2O4‚0.5H2O): C, H, N.
4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(3,4-dihydronaph-
thalen-2-ylmethyl)-piperidine Oxalate (21). Compound 21 was
prepared in 64% yield using the procedure described for 13 from
4 (1.5 g, 0.0047 mol, free base), 3,4-dihydro-2-naphthoic acid (0.8
g, 0.0047 mol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodi-
imide hydrochloride (EDCI, 1.0 g, 0.002 mol). The crude oil was
dissolved in Et2O, and an excess of oxalic acid was added. The
precipitate was collected and recrystallized from 2-propanol to
afford 21 as colorless crystals: mp 157-161 °C; 1H NMR (DMSO-
d6): δ 7.0-7.4 (m, 12H), 6.6 (s, 1H, olefinic), 5.5 (s, 1H, CH-
O); MS m/z (CI): 474.4 [M + 1]+. Anal. (C31H33NOF2‚C2H2O4‚
0.5H2O): C, H, N.
trans-(R,R)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(2-
phenyl-cyclopropylmethyl)-piperidine Oxalate (22). Compound
22 was prepared in 92% yield using the procedure described for
13, with (R,R)-trans-2-phenylcyclopropanecarboxylic acid: mp
129-130 °C; [R]D -42.2 (c 1.01, MeOH); H NMR (DMSO-
d6): δ 7.1-7.4 (m, 13H), 5.5 (s, 1H, CH-O); MS m/z (CI): 462
[M + 1]+. Anal. (C30H33F2NO‚C2H2O4‚0.25H2O): C, H, N.
trans-(S,S)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(2-phen-
yl-cyclopropylmethyl)-piperidine Oxalate (23). Compound 23 was
prepared in 93% yield using the procedure described for 13 with
(S,S)-trans-2-phenylcyclopropanecarboxylic acid: mp 123-126 °C;
[R]D20 +39.03 (c 1.03, MeOH); 1H NMR (DMSO-d6): δ 7.1-7.4
(m, 13H), 5.5 (s, 1H, CH-O); MS m/z (CI): 462 [M + 1]+. Anal.
(C30H33F2NO‚C2H2O4): C, H, N.
1
CHCl3); H NMR (DMSO-d6): δ 7.1-7.4 (m, 13H), 5.5 (s, 1H,
CH-O), 0.8 (d, 3H, J ) 6.3 Hz); MS m/z (CI): 464.1 [M + 1]+.
Anal. (C30H35NOF2‚C2H2O4‚0.5H2O): C, H, N.
S-(+)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(2-methyl-
3-phenylpropyl)piperidine Oxalate (14). Compound 14 was
prepared in 67% yield using the procedure described for 13 from
4 (1.3 g, 0.0039 mol, free base) and (R)-(-)-R-methylhydrocinnamic
acid29 (0.7 g, 0.0039 mol) as colorless crystals: mp 120-124 °C;
20
1
[R]D +1.4 (c 1.00, CHCl3); H NMR (DMSO-d6): δ 7.1-7.4
(m, 13H), 5.4 (s, 1H, CH-O), 0.7 (d, 3H, J ) 6.3 Hz); MS m/z
(CI): 464.1 [M + 1]+. Anal. (C30H35NOF2‚C2H2O4‚0.5H2O): C,
H, N.
(R)-(+)-4-(2-Benzhydryloxyethyl)-1-(3-phenylpropan-3-ol)-
piperidine Oxalate (15). A mixture of 3 (1.5 g, 0.0039 mol),
K2CO3 (1.6 g, 0.0117 mmol), and (R)-(+)-3-chloro-1-phenyl-
propanol (0.7 g, 0.0041 mol) in DMF (30 mL) was heated for 12
h at 85 °C. H2O (200 mL) was added, and the mixture was extracted
with EtOAc (3 × 70 mL). The combined EtOAc layers were washed
with H2O (2 × 100 mL) and saturated NaCl (2 × 50 mL) and
dried (Na2SO4). Removal of the solvent under reduced pressure
afforded a crude oil that was dissolved in Et2O. An excess of oxalic
acid was added, and the precipitate was collected, washed with
Et2O (100 mL) and dried to afford 15 (1.5 g, 74%), as a colorless
20
1
20
1
solid: mp 98-102 °C; [R]D +15.6 (c 1.05, MeOH); H NMR
(DMSO-d6): δ 7.1-7.4 (m, 15H), 5.5 (s, 1H, CH-O), 4.6 (m,
1H, CH-OH), 3.4 (m, 4H), 2.8-3.2 (m, 4H), 2.1-1.8 (m, 5H),
1.2-1.6 (m, 4H); MS m/z (CI): 430.3 [M + 1]+. Anal. (C29H35NO2‚
C2H2O4‚0.25H2O): C, H, N.
Acknowledgment. This research was supported by the NIH
Intramural Research Program of the National Institute of
Diabetes and Digestive and Kidney Diseases and the National
Institute on Drug Abuse. We thank Victor Livengood (NIDDK)
for the mass spectral analyses.
(S)-(-)-4-(2-Benzhydryloxyethyl)-1-(3-phenylpropan-3-ol)-
piperidine Oxalate (16). Compound 16 was prepared in 84%
yield using the procedure described for 15 from 3 (1.3 g, 0.0039
mol, free base) and (S)-(-)-3-chloro-1-phenyl-propanol (0.7 g,
0.0041 mol) as colorless crystals: mp 97-101 °C; [R]20 -16.7
D
Supporting Information Available: Table of elemental analy-
ses for purified products described in this article. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
(c 1.07, MeOH); H NMR (DMSO-d6): δ 7.2-7.4 (m, 5H), 5.4
(s, 1H, CH-O), 4.6 (t, 1H, J ) 6.9 Hz); MS m/z (EI): 429.3 [M]+.
Anal. (C29H35NO2‚C2H2O4‚0.25 H2O): C, H, N.
(R)-(+)-4-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-1-(3-phenyl-
propan-3-ol)-piperidine Oxalate (17). Compound 17 was prepared
in 95% yield using the procedure described for 15 from 4 (1.5 g,
0.0036 mol) and (R)-(+)-3-chloro-1-phenyl-propanol (0.7 g, 0.0041
mol), as colorless crystals: mp 98-103 °C; [R]D20 +16.0 (c 1.08,
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