Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents: Chiral hydroxyl-containing derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy) ethyl]-4-(3-ph

Article abstract of DOI:10.1021/jm010430f

In our search for long-acting agents for the treatment of cocaine abuse, a series of optically pure hydroxylated derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)pip

Full text of DOI:10.1021/jm010430f

J . Med. Chem. 2002, 45, 1321-1329
1321
Develop m en t of Lon g-Actin g Dop a m in e Tr a n sp or ter Liga n d s a s P oten tia l
Coca in e-Abu se Th er a p eu tic Agen ts: Ch ir a l Hyd r oxyl-Con ta in in g Der iva tives of
1-[2-[Bis(4-flu or op h en yl)m eth oxy]eth yl]-4-(3-p h en ylp r op yl)p ip er a zin e a n d
1-[2-(Dip h en ylm eth oxy)eth yl]-4-(3-p h en ylp r op yl)p ip er a zin e
Ling-Wei Hsin,†,‡ Christina M. Dersch,§ Michael H. Baumann,§ David Stafford,| J ohn R. Glowa,|
Richard B. Rothman,§ Arthur E. J acobson,† and Kenner C. Rice*,†
Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, 8 Center Drive MSC 0815, Bethesda, Maryland 20892, Clinical Psychopharmacology
Section, IRP, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, and Department of
Pharmacology and Therapeutics, LSUMC-Shreveport, 1501 Kings Highway, P.O. Box 33932, Shreveport, Louisiana 71130
Received September 11, 2001
In our search for long-acting agents for the treatment of cocaine abuse, a series of optically
pure hydroxylated derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)-
piperazine (1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12909
and GBR 12935, respectively) were synthesized and evaluated in vitro and in vivo. The
enantiomers of the 2-hydroxylated analogues displayed substantial enantioselectivity. The S
enantiomers displayed higher dopamine transporter (DAT) affinity and the R enantiomers were
found to interact at the serotonin transporter (SERT) with higher affinity. The two-carbon
spacer between the hydroxyl group and the piperazine ring was essential for enantioselectivity,
and the length of the alkyl chain between the phenyl group and the piperazine ring influenced
binding affinity and selectivity for the DAT and SERT. Phenylethyl analogues had a higher
binding affinity for the SERT and a weaker affinity and selectivity for the DAT than the
corresponding phenylpropyl analogues. Thus, (S)-(+)-1-[4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-
piperazinyl]-3-phenylpropan-2-ol (6) displayed the highest affinity to the DAT, and (S)-(+)-1-
[4-[2-(diphenylmethoxy)ethyl]piperazinyl]-3-phenylpropan-2-ol (8) had the highest selectivity.
The latter (8) is one of the most DAT selective ligands known. In accord with the in vitro data,
6 showed greater potency than 7 in elevating extracellular dopamine levels in a microdialysis
assay and in inhibiting cocaine-maintained responding in rhesus monkeys.
In tr od u ction
into presynaptic terminals resulting in increased neuro-
transmission in the mesolimbic dopaminergic system.10-12
On the basis of these observations, a number of studies
have been aimed at the discovery and development of
potent and selective DA reuptake inhibitors.13 These
inhibitors may reduce the effects of cocaine and there-
fore are potential treatment agents for cocaine abuse.
Cocaine is a widely abused drug,1-6 causing public
health and societal problems; it plays a major role in
the rapid spread of the HIV virus7,8 and drug-resistant
tuberculosis.9 Unlike the several opioid-dependent treat-
ment agonists that are available (e.g., methadone, levo-
R-acetylmethadol, and buprenorphine), there are, as yet,
no effective therapeutic agents that can lessen the abuse
of cocaine.
In the central nervous system, cocaine blocks the
reuptake of several neurotransmitters, such as dopam-
ine (DA), serotonin (5-HT), and norepinephrine (NE),
by interacting with dopamine transporter (DAT), sero-
tonin transporter (SERT), and norepinephrine trans-
porter sites, respectively. Over the past decade, numer-
ous studies have indicated that the reinforcing properties
of cocaine are largely mediated by the binding of cocaine
to the DAT and the subsequent blockade of DA reuptake
A variety of structural classes of DAT ligands have
been used as templates for the design and synthesis of
potential cocaine abuse therapeutic agents, including
cocaine analogues,14 tropanes,15 benztropines,16,17 mazin-
dol,18,19 and disubstituted piperazines.20-22 Research in
this laboratory has focused on the development of novel
analogues of the disubstituted piperazines GBR 12909
(1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpro-
pyl)piperazine, 1) and GBR 12935 (1-[2-(diphenylmeth-
oxy)ethyl]-4-(3-phenylpropyl)piperazine, 2; Chart 1).23
Compound 1, a potent and selective DAT inhibitor
agent, can suppress the reinforcing and euphorigenic
effects of cocaine, but it has a relatively short duration
of action (ca. 6 h). The repeated administration of 1 has
been shown to decrease cocaine-maintained responding
in rhesus monkeys for almost 2 weeks, without the
development of tolerance and without affecting similar
responding maintained by food.24 Using 1 as a cocaine
abuse therapeutic agent, however, would require com-
pliance with repeated administration. To obviate that
* To whom correspondence should be addressed. Tel: (301)496-1856.
Fax: (301)402-0589. E-mail: kr21f@nih.gov.
† Laboratory of Medicinal Chemistry, National Institute of Diabetes
and Digestive and Kidney Diseases.
‡ Current address: School of Pharmacy, College of Medicine,
National Taiwan University, No. 1 Sec. 1, Room 1336, J en-Ai Road,
Taipei 10018, Taiwan.
§ Clinical Psychopharmacology Section, National Institute on Drug
Abuse.
| Department of Pharmacology and Therapeutics, LSUMC-Shreve-
port.
10.1021/jm010430f CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/06/2002

1322 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6
Hsin et al.
Ch a r t 1
Ta ble 1. Binding Affinities (Ki ( SD)a at the DAT and SERT
and Ki Ratios of Hydroxylated Analogues of 1 and 2
necessity, we have synthesized compounds containing
an aliphatic alcohol that, on conversion to a long-chain
ester and subsequent formulation in an oily vehicle,
provided a prodrug with a relatively long half-life. This
approach has been used25 for potential cocaine-abuse
therapeutic agents and has, as well, been successfully
employed in the treatment of neuroleptic disorders.26
Lewis et al.25 found that a racemic N-3-hydroxyl-3-
phenyl analogue of 1 (3) (Chart 1) exhibited a pharma-
cological profile25 similar to that of 1. When formulated
as a depot preparation (4), a single injection decreased
cocaine-maintained responding in monkeys more than
80% within several days of the injection while food-
maintained responding was unaffected. This selective
effect lasted for nearly a month.27
binding affinity, Ki (nM)
SERT/DAT
no.
DAT
SERT
ratio
1
2
3.7 ( 0.4
3.7 ( 0.3
2.1 ( 0.05
2.3 ( 0.08
0.75 ( 0.03
12 ( 0.3
2.3 ( 0.07
25 ( 0.7
11 ( 1
130 ( 5
620 ( 13
120 ( 7
120 ( 4
230 ( 7
160 ( 4
2160 ( 80
1800 ( 90
77 ( 2
35
168
57
52
307
13
939
72
7
0.5
47
2
52
32
31
28
5
3 (()
5 (()
6 (S)
7 (R)
8 (S)
9 (R)
10 (S)
11 (R)
12 (S)
13 (R)
14 (()
15 (()
22 (S)
23 (R)
24
26 ( 0.9
30 ( 2
13 ( 1
1400 ( 34
330 ( 23
2500 ( 50
3800 ( 95
135 ( 5
85 ( 3
170 ( 20
48 ( 3
120 ( 7
4.4 ( 0.5
3.0 ( 0.3
8.0 ( 0.4
With these promising results in mind, we synthesized
other hydroxylated analogues (5-15) and phenethyl
analogue 24, and now, we report their binding affinities
for DAT and SERT (Table 1) in comparison with 1-3,25
22,25 and 2325 (the enantiomers of 3; Chart 1). Com-
pounds 6-13 are optically active. These, if amenable
for use in a depot preparation, could eliminate problems
attributable to side effects that might occur with a
racemate. We further examined the most promising
compounds 6 and 7 by in vivo microdialysis assays and
in the inhibition of cocaine self-administration in rhesus
monkeys, in comparison with 1.
36 ( 2
a
The Ki values of the test ligands were determined in the above
assays as described in the Biological Methods.
(S)-(+)-1-Chloro-3-phenylpropan-2-ol (18) and (R)-
(-)-1-chloro-3-phenylpropan-2-ol29 (19) were prepared
via regioselective epoxide ring-opening by phenyllithi-
um, using BF3-OEt2 as the activator, at -78 °C in
tetrahydrofuran (THF). Piperazines 16 and 17 were
alkylated with 18 or 19 at 60 °C in DMF, using
diisopropylethylamine (DIPEA) and NaI, to afford the
desired products 6 or 7 and 8 or 9, respectively (Scheme
2). The enantiomeric excess (ee) values of chiral com-
pounds 6-9 were determined by F19-NMR (nuclear
magnetic resonance) spectra of the corresponding MTPA
esters, and all of them were above 99%.
Ch em istr y
The monosubstituted piperazines, 1-[2-[bis(4-fluoro-
phenyl)methoxy]ethyl]piperazine (16) and 1-[2-(diphen-
ylmethoxy)ethyl]piperazine (17) were synthesized in two
steps according to the literature,23 with modification.
The racemic 2-hydroxylated 1 analogue, 5, was prepared
in high yield (Table 2) by heating (2,3-epoxypropyl)-
benzene with 16 in N,N-dimethylformamide (DMF;
Scheme 1). Initially, 5 was successfully transformed to
its MTPA ester,28 but the effort to separate the diaster-
eomers failed. Thus, we decided to directly synthesize
the optically pure hydroxyl-containing derivatives using
chiral synthons.
N-Alkylation of 16 and 17 with (S)-(+)-2-chloro-1-
phenylethanol (20) or (R)-(-)-2-chloro-1-phenylethanol
(21), using the same reaction conditions as above
(DIPEA and NaI in DMF at 60 °C), afforded 10 and 12
and 11 and 13, respectively, in modest yields (Scheme
3). However, a significant amount of isomeric byprod-
ucts 14 or 15 were produced and isolated in this

Potential Cocaine-Abuse Therapeutic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6 1323
Ta ble 2. Physical Properties
20
[R]D (deg)
(solvent)
cmpd
empirical formula
mp (°C)
yield (%)
5 (()
6 (S)
7 (R)
8 (S)
9 (R)
10 (S)
11 (R)
12 (S)
13 (R)
14 (()
15 (()
24
C
C
C
C
C
C
C
C
C
C
C
C
28H32F2N2O2‚2C4H4O4
28H32F2N2O2‚2C4H4O4
28H32F2N2O2‚2C4H4O4
28H34N2O2‚2C4H4O4
28H34N2O2‚2C4H4O4
27H30F2N2O2‚2C4H4O4
27H30F2N2O2‚2C4H4O4
27H32N2O2‚2C4H4O4
27H32N2O2‚2C4H4O4
27H30F2N2O2‚2C4H4O4
27H32N2O2‚2C4H4O4
27H30F2N2O‚2C4H4O4
171-172
171-172
168-169
174-175
173.5-174.5
182-183
182-183
181-182
184-185
145-146
147-149
192-193
95
79
83
80
78
44
44
33
33
+6.5 (CH3OH)
-6.2 (CH3OH)
+8.1 (CH3OH)
-7.0 (CH3OH)
+12.9 (DMF)
-11.8 (DMF)
+12.9 (DMF)
-13.1 (DMF)
38 (from 20), 30 (from 21)
16 (from 20), 27 (from 21)
95
Sch em e 1a
mediate I, readily formed by a fast iodide-chloride ion-
exchange reaction. Base-catalyzed elimination could
afford intermediate II. Nucleophilic epoxide ring-open-
ing at the less-hindered position could give chiral
product III, whereas nucleophilic epoxide ring-opening
at the benzylic position by the iodide ion, followed by
an SN2 reaction, would be likely to produce chiral
product V. Although most of the hydrogen chloride (or
iodide) in situ was neutralized by DIPEA, a trace
amount of free acid (protons) would be enough to
catalyze epoxide ring-opening at the benzylic position
to form the intermediate VI. The addition of the
nucleophile to intermediate VI could produce a racemate
(V + VII). If this mechanism pertains, III should
possess a high ee value, but the isomeric products V
and VII could only exist as enantiomeric mixtures with
a low ee value.
a
Reagents and conditions: 16, DMF, 60 °C.
Sch em e 2a
P h a r m a cology
In previous papers, we determined both the DA and
the 5-HT transporter binding Ki values and the Ki
values of test agents for the inhibition of [3H]DA and
[3H]5-HT reuptake. One reason for doing so was to
identify agents with high binding affinity and low
potency in the functional assay. Such agents might, for
example, act as cocaine antagonists without inhibiting
[3H]DA uptake. However, our experience demonstrated
that compounds with high uptake binding ratios actu-
ally have ratio values of about 1 when the binding assay
is conducted under uptake conditions.30,31 In light of
these data, we no longer determine reuptake Ki values.
In a recent study,25 the benzylic hydroxyl analogues,
3, 22, and 23, were found to be similar to 1 in binding
affinities for the DAT and SERT (Table 1). Furthermore,
there was no significant difference between the phar-
macological profiles of the two enantiomers 22 and 23
and the racemate 3, both in vitro and in vivo. In this
study, the racemic 2-hydroxylated analogue 5 also
displayed about the same DAT and SERT binding
affinities as those of 1, 3, 22, and 23 (Table 1). However,
an evaluation of enantiomers 6 and 7 in our novel series
of chiral hydroxylated analogues of 1 showed a quite
different structure-activity relationship (SAR).
a
Reagents and conditions: (a) PhLi, BF3-OEt2, THF, -78 °C.
(b) 16 or 17, N,N-diisopropylethylamine, NaI, DMF, 60 °C.
coupling reaction. The ee values of the desired products
10-13 were determined by chiral high-performance
liquid chromatography (HPLC), and all were higher
than 98%. Interestingly, when the crude compounds 14
and 15 were analyzed using the same HPLC conditions,
only slight ee (10-20%) was found, due to the substan-
tial racemization that occurred in the reaction. Recrys-
tallization of the maleate salts of 14 and 15 provided
pure, optically inactive, racemates. A possible mecha-
nism for the racemization (Chart 2) involves an inter-
In contrast to the benzylic-hydroxylated analogues
2225 and 23,25 the 2-hydroxylated enantiomers 6 and 7
showed significant enantioselectivity in binding affinity
(DAT and SERT). Analogue 6 had a subnanomolar
binding affinity to DAT (Ki ) 0.75 nM) and a higher
affinity than 1 and enantiomer 7 (5- and 16-fold,
respectively). The enantiomer 7 was more potent in

1324 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6
Hsin et al.
Sch em e 3a
a
Reagents and conditions: 16 or 17, N,N-diisopropylethylamine, NaI, DMF, 60 °C.
Ch a r t 2
SERT binding than 6. Analogue 6 is much more selec-
tive than 1 and 7 in DAT binding.
between three functional groups (i.e., the phenyl group,
the hydroxyl substituent, and the nitrogen atom (N1)
in the piperazine ring) appeared to be most significant.
In ligands 3, 22, and 23, the hydroxyl group is separated
from the phenyl group and N1 by one- and three-carbon
atoms, respectively, whereas in ligands 6 and 7 the
hydroxyl group is separated from both the phenyl group
and the N1 by two-carbon atoms. To further evaluate
some of the factors that might be responsible for this
dramatic change in the SAR, we evaluated the phar-
macological properties of additional derivatives. We
replaced the phenylpropyl group in 1 and 6-9 with a
phenylethyl group to afford the analogues 10-13 and
24.23 The DAT and SERT binding affinities of 2423 have
not been previously published. In these compounds, the
hydroxyl group is separated from the phenyl group by
a one-carbon unit (as in 3, 22, and 23) and separated
from N1 by a two-carbon unit (as in 5-7).
We have noted that bis-4-fluorophenyl analogues (e.g.,
1) generally displayed higher affinity, but less selectiv-
ity, to the DAT than the comparable diphenyl analogues
(e.g., 2).30 To see whether this pattern of affinity and
selectivity was also true with the chiral hydroxylated
derivatives, we introduced a 2-hydroxyl substituent in
2 to afford 8 and 9. The S isomer 8 displayed a higher
affinity and selectivity for the DAT, while the R isomer
9 showed a slightly higher affinity for the SERT. These
diphenyl ligands, 8 and 9, had a little less affinity for
DAT and much less affinity for SERT than the corre-
sponding bis-4-fluorophenyl analogues 6 and 7; thus,
they were considerably more selective in binding to the
DAT. Analogue 8 is one of the most selective ligands
known in binding to the DAT.
When we examined the structural differences between
the benzylic hydroxyl ligands25 3, 22, and 23 (Chart 1)
and the 2-hydroxyl ligands 6 and 7, the distances
Phenethyl analogue 24 showed a slightly decreased
DAT binding affinity, a substantially increased SERT

Potential Cocaine-Abuse Therapeutic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6 1325
binding affinity, and therefore a much lower selectivity
for DAT binding vs SERT binding than the parent
compound 1. All of the 2-hydroxyl substituted phenyl-
ethyl analogues, 10-13, were less potent in binding to
the DAT and more potent in SERT binding as compared
to the corresponding phenylpropyl analogues (6-9). As
a result, they all demonstrated lower selectivity for DAT
binding vs SERT binding. Furthermore, these phenyl-
ethyl ligands also displayed the same enantioselectivity
as their corresponding phenylpropyl analogues: (i) the
S isomer is more potent and selective in DAT binding
affinity than the R isomer; (ii) the R isomer has a higher
affinity for SERT than the S isomer. Thus, a 2-hydroxyl
substituent is an important structural element for
enantioselective binding to the DAT and SERT.
The presence of a 2R-hydroxyl group, a bis-4-fluoro-
phenyl substituent, and a phenylethyl, instead of a
phenylpropyl chain, appear to be factors that induce an
increase in the SERT binding affinity. Thus, 11, which
contains all three of these factors, was found to be the
only SERT selective ligand in this hydroxylated ana-
logue series. Ligands 14 and 15, which are racemic
1-phenyl substituted isomers of 10-13, showed inter-
esting binding profiles. They retained the DAT binding
affinity of the 2-phenyl substituted isomers (i.e., 10-
13), but the binding affinity to the SERT decreased
significantly. However, these binding data were deter-
mined using racemic samples; the possibility that the
two enantiomers possess substantially different selec-
tivities could not be ruled out.
Micr od ia lysis
To evaluate the DA reuptake inhibition properties of
6 and 7 in vivo, extracellular dopamine (ECDA) levels
were determined in rat nucleus accumbens using a
microdialysis assay in conscious, freely moving ani-
mals.32 Baseline dialysate DA levels were 1.73 pg/5 µL
sample (1.89 nM) and did not differ across treatment
groups (total n ) 36 rats). After various doses of 6 were
administered, a 2-5-fold increase in the ECDA levels
was observed, similar to that found with 1 (Figure 1).
In accord with in vitro data, enantiomer 7 showed lower
potency than enantiomer 6 and 1. The ECDA level
increased 2-fold above baseline after a 3 mg/kg dose of
7 was administered, whereas a 1 mg/kg dose of 6 or 1
produced the same effect. Furthermore, because 6 and
1 showed similar pharmacological profiles (i.e., slow
onset, long-acting, and low efficacy on DAT reuptake
inhibition) and since the enantiomer might avoid the
side effects sometimes seen in racemates, 6 may be a
potential cocaine abuse therapeutic agent with low
abuse liability, which increases DA neurotransmission
to prevent withdrawal.
F igu r e 1. Effects of compound 1 and its hydroxylated
enantiomers (6 and 7) on extracellular DA levels in rat nucleus
accumbens. Rats received single iv doses of the drug or saline
vehicle at time zero. Dialysate samples were collected at 20
min intervals and assayed for DA using HPLC-EC. Data are
pg/5 µL sample expressed as the mean ( SEM for N ) 4-5
rats/group.
maintained responding are shown in Figure 2. Each
drug dose dependently decreased cocaine-maintained
responding to a different extent. Among these ligands,
6 was the most potent, whereas 7 was the least effective
in this behavioral test. Reference compound 1 displayed
an intermediate potency between those of the enanti-
omers 6 and 7 in this in vivo model.
The greater potency of 6 in the behavioral assay and
the in vivo enantioselectivity of 6 and 7 were consistent
with their affinities for the DAT and their different
potencies in increasing the ECDA level. These results
are in accord with the idea that high affinity ligands
for DAT effectively reduce cocaine-maintained respond-
ing.
Beh a vior a l Effects
The two enantiomers 6 and 7 and the reference
compound 1 were also tested for behavioral effects that
influenced food- and cocaine-maintained responding in
rhesus monkeys. These compounds all decreased cocaine-
maintained responding to a greater extent than food-
maintained responding, and none of them significantly
increased responding during the fixed interval (FI)
components. The effects of different doses of 1, 6, and 7
relative to the effects of vehicle pretreatment on cocaine-
Con clu sion s
The 2-hydroxylated analogues showed a quite differ-
ent SAR from the benzylic hydroxylated analogues. The
enantiomers of 2-hydroxyl substituted ligands displayed
substantial enantioselectivity in their binding affinity
to the DAT and SERT and in inhibiting the reuptake
of DA and 5-HT. The S enantiomers were more potent

1326 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6
Hsin et al.
F igu r e 2. Behavioral effect of 6, 7, and 1 at various dose levels, relative to vehicle pretreatment, on cocaine-maintained responding
in rhesus monkeys.
and selective in DAT binding affinity than the corre-
sponding R enantiomers; the latter were more potent
in SERT binding.
esterification and then formulated as extended release
dosage forms.
Exp er im en ta l Section
The bis-4-fluorophenyl analogues displayed greater
affinity in binding to the DAT, while the diphenyl
analogues were more selective for binding to the DAT.
The length of the alkyl chain between the phenyl group
and the N1 on the piperazine ring significantly influ-
enced DAT and SERT binding affinity and binding
selectivity for the DAT vs SERT. The N-phenylethyl
ligands were more potent for binding to the SERT and
less potent for binding to the DAT and, thus, had lower
DAT selectivity than the corresponding N-phenylpropyl
analogues. The two-carbon atom distance between the
hydroxyl group and the N1 appears to be essential for
enantioselectivity, whereas the distance between the
phenyl group and the N1 had little or no effect on the
enantioselectivity of the R and S enantiomers.
Analogue 6 displayed the highest affinity, and 8
possessed the highest selectivity for binding to the DAT.
They are among the most potent and selective ligands
that have been found in these assays. As noted, they
also displayed substantial enantioselectivity in the
microdialysis assay and in behavioral experiments, and
6 always showed greater potency than 7. These data
exemplify the importance of synthesizing and studying
the pharmacological activities of chiral compounds.
Compound 5, the racemic relative of 6, showed only a
little higher affinity and was not much more selective
for DAT than 1 (Table 1).
Melting points were determined on a Thomas-Hoover
capillary melting point apparatus and are uncorrected. El-
emental analyses were performed by Atlantic Microlabs,
Atlanta, GA, and were within (0.4% for the elements indi-
cated. Except where noted, all of the mass spectra (chemical
ionization) were obtained using a Finnigan 1015 mass spec-
trometer. High-resolution mass spectroscopy measurements
(HRMS) were obtained using a V. G. Micro Mass 7070F mass
spectrometer. Optical rotations were obtained using a Perkin-
Elmer 341 polarimeter and are reported at the sodium D-line
(589 nm), unless otherwise noted. 1H NMR spectra of the free
bases were recorded in CDCl3 using a Varian XL-300 spec-
trometer. 19F NMR spectra were utilized in determination of
ee in chiral compounds and were determined at 282 MHz in
CDCl3 using a Varian XL-300 spectrometer. Chemical shifts
are expressed in parts per million (ppm) on the δ scale relative
to a tetramethylsilane (TMS) internal standard. Thin-layer
chromatography (TLC) was performed on 250 µm Analtech
GHLF 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 Fluka 40-63 µm
silica gel 60. No attempt was made to optimize yields. The (S)-
(+)-2-chloro-1-phenylethanol and (R)-(-)-2-chloro-1-phenyl-
ethanol were purchased from the Aldrich Chemical Co.,
Milwaukee, WI.
Gen er a l P r oced u r es for t h e Det er m in a t ion of ee of
Hyd r oxyl-Con ta in in g Der iva tives: Mosh er Ester An a ly-
sis. The Mosher ester derivatives of the hydroxylated ana-
logues of 1 and 2 were prepared according to the literature
method28 with modification. To a solution of the alcohol (20
mg) and triethylamine (0.2 mL) in CH2Cl2 (3 mL) were added
DMAP (20 mg) and (R)-(-)-MTPA-Cl (30 µL). The reaction
mixture was stirred at room temperature and monitored by
TLC, ensuring complete reaction before quenching with 3-(di-
methylamino)propylamine (0.2 mL). After the solution was
stirred for another 15 min, silica gel was added and the solvent
The high affinity and selectivity for DAT binding and
the promising results from in vivo biological data
indicate that 6 and 8 are potential candidates for the
development of cocaine abuse therapeutic agents. Fur-
thermore, because they bear a hydroxyl substituent, 6
and 8 may be converted to oil soluble prodrugs by

Potential Cocaine-Abuse Therapeutic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6 1327
was evaporated. The residue was loaded onto a short column
of silica gel and eluted with 50-100% EtOAc in n-hexane to
afford the Mosher ester as a pale yellow solid. The diastere-
omeric excess was then determined by 19F or 1H NMR.
Ch ir a l HP LC An a lysis. The free base of the sample was
dissolved in 1% 2-propanol (IPA) in n-hexane. Then, the
sample solution (10 µL) was eluted using 1-10% IPA in
n-hexane as mobile phase on the CHIRALCEL OD column
(250 mm × 4 mm, DAICEL). The ee values were calculated
based on the UV absorption (254 nM) areas of the two
enantiomers.
Gen er a l P r oced u r e for th e Con ver sion of th e F r ee
Ba ses to th e Cor r esp on d in g Bis-m a lea te Sa lts. Maleic
acid (6.6 mmol) was added to a boiling solution of the free base
(3 mmol) in MeOH (30-40 mL). After the solution was cooled
to room temperature, a white crystalline solid formed and
precipitated. The crystals were collected by filtration and
washed with cold MeOH. The product was dried in a vacuum
oven (1 mm Hg, 45-50 °C, 12 h) to afford the desired
bis-maleate salts. The salts were further purified by recrys-
tallization with MeOH if necessary.
procedure and yielded colorless oils. 10: 1H NMR (300 MHz,
CDCl3): δ 7.27-7.39 (m, 9H), 6.99-7.04 (m, 4H), 5.35 (s, 1H),
4.73 (dd, J ) 9.7, 4.9 Hz, 1H), 3.57 (t, J ) 5.9 Hz, 2H), 2.43-
2.78 (m, 13H). MS: m/z 453 (MH+). Anal. 10‚2 maleate
(C27H30F2N2O2‚2C4H4O4) C, H, N. 14: 1H NMR (300 MHz,
CDCl3): δ 7.17-7.36 (m, 9H), 6.95-7.04 (m, 4H), 5.28 (s, 1H),
3.93-4.00 (m, 1H), 3.63-3.70 (m, 2H), 3.50 (t, J ) 5.9 Hz, 2H),
2.62 (t, J ) 5.9 Hz, 2H), 2.39-2.58 (m, 9H). MS (CI): m/z 453
(MH+). Anal. 14‚2 maleate (C27H30F2N2O2‚2C4H4O4) C, H, N.
(R)-(-)-2-[4-[2-[Bis(4-flu or op h en yl)m et h oxy]et h yl]p i-
p er a zin yl]-1-p h en yleth a n -1-ol (11) a n d 14. Compounds 11
and 14 were obtained using 16 and (R)-2-chloro-1-phenyl-
ethanol according to the general procedure and yielded color-
less oils. 11: MS: m/z 453 (MH+). Anal. 11‚2 maleate
(C27H30F2N2O2‚2C4H4O4) C, H, N.
(S)-(+)-2-[4-[2-(Dip h en ylm eth oxy)eth yl]p ip er a zin yl]-1-
ph en yleth an -1-ol (12) an d (()-2-[4-[2-(Diph en ylm eth oxy)-
eth yl]p ip er a zin yl]-2-p h en yleth a n -1-ol (15). Compounds 12
and 15 were synthesized using 17 and (S)-2-chloro-1-phenyl-
ethanol according to the general procedure and yielded color-
less oils. 12: 1H NMR (300 MHz, CDCl3): δ 7.24-7.38 (m,
15H), 5.38 (s, 1H), 4.72 (dd, J ) 10.3, 4.4 Hz, 1H), 3.61 (t, J )
5.9 Hz, 2H), 2.42-2.75 (m, 13H). MS: m/z 417 (MH+). Anal.
12‚2 maleate (C27H32N2O2‚2C4H4O4) C, H, N. 15: 1H NMR (300
MHz, CDCl3): δ 7.16-7.33 (m, 15H), 5.32 (s, 1H), 3.91-3.99
(m, 1H), 3.61-3.70 (m, 2H), 3.54 (t, J ) 5.9 Hz, 2H), 2.63 (t,
J ) 5.9 Hz, 2H), 2.46-2.59 (m, 8H), 2.37 (broad s, 1H). MS:
m/z 417 (MH+). Anal. 15‚2 maleate (C27H32N2O2‚2C4H4O4) C,
H, N.
(R)-(-)-2-[4-[2-(Dip h en ylm eth oxy)eth yl]p ip er a zin yl]-
1-p h en yleth a n -1-ol (13) a n d 15. Compounds 13 and 15 were
prepared using 17 and (R)-2-chloro-1-phenylethanol according
to the general procedure and yielded colorless oils. 13: MS:
m/z 417 (MH+). Anal. 13‚2 maleate (C27H32N2O2‚2C4H4O4) C,
H, N.
(()-1-[4-[2-[Bis(4-flu or op h en yl)m et h oxy]et h yl]p ip er -
a zin yl]-3-p h en ylp r op a n -2-ol (5). A solution of 16 (4.63 g,
13.9 mmol) and (2,3-epoxypropyl)benzene (1.87 g, 13.9 mmol)
in DMF (30 mL) was heated at 60 °C for 48 h. The reaction
mixture was quenched with water and extracted with ether,
and then, the combined organic extracts were washed with
brine, dried (MgSO4), filtered, and evaporated. The residue was
chromatographed (silica gel, 5% MeOH in CH2Cl2) to afford 5
1
(6.17 g, 95%) as a pale yellow oil. H NMR (300 MHz, CDCl3):
δ 7.22-7.32 (m, 9H), 6.97-7.03 (m, 4H), 5.32 (s, 1H), 3.87-
3.96 (m, 1H), 3.55 (t, J ) 5.9 Hz, 2H), 2.81 (dd, J ) 13.7, 6.8
Hz, 1H), 2.31-2.70 (m, 14H). MS: m/z 467 (MH+). Anal. 5‚2
maleate (C28H32F2N2O2‚2C4H4O4) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of 2-Hyd r oxy-
la ted An a logu es of 1 a n d 2. (S)-(+)-1-[4-[2-[Bis(4-flu o-
r op h en yl)m eth oxy]eth yl]p ip er a zin yl]-3-p h en ylp r op a n -
2-ol (6). A mixture of 16 (4.00 g, 12.0 mmol), 18 (3.00 g, 17.6
mmol), NaI (3.60 g, 24.0 mmol), and N-ethyldiisopropylamine
(6.30 mL, 36.0 mmol) in DMF (25 mL) was stirred at 65 °C
under argon for 48 h. The reaction was quenched with water,
and then, the resulting mixture was extracted with ether. The
organic layer was washed with brine, dried (MgSO4), filtered,
and evaporated. The oily residue was chromatographed (silica
gel, 4% MeOH in CH2Cl2) to afford 6 (4.45 g, 79%) as an oil.
1H NMR (300 MHz, CDCl3): δ 7.22-7.32 (m, 9H), 6.97-7.03
(m, 4H), 5.32 (s, 1H), 3.87-3.96 (m, 1H), 3.55 (t, J ) 5.9 Hz,
2H), 2.81 (dd, J ) 13.7, 6.8 Hz, 1H), 2.31-2.70 (m, 14H). 13C
NMR (75 MHz, CDCl3): δ 163.8, 160.5, 138.3, 137.8, 129.3,
128.5, 128.4, 126.3, 115.4, 115.1, 82.4, 67.1, 66.7, 63.3, 57.6,
53.6, 53.0, 41.2. MS: m/z 467 (MH+). Anal. 6‚2 maleate
(C28H32F2N2O2‚2C4H4O4) C, H, N.
(R)-(-)-1-[4-[2-[Bis(4-flu or op h en yl)m et h oxy]et h yl]p i-
p er a zin yl]-3-p h en ylp r op a n -2-ol (7). Compound 7 was syn-
thesized using 16 and 19 according to the general procedure
and yielded an oil. MS: m/z 467 (MH+). Anal. 7‚2 maleate
(C28H32F2N2O2‚2C4H4O4) C, H, N.
(S)-(+)-1-[4-[2-(Dip h en ylm eth oxy)eth yl]p ip er a zin yl]-3-
p h en ylp r op a n -2-ol (8). Compound 8 was synthesized using
17 and 18 according to the general procedure and yielded a
colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.22-7.35 (m,
15H), 5.36 (s, 1H), 3.87-3.96 (m, 1H), 3.58 (t, J ) 5.9 Hz, 2H),
2.27-2.85 (m, 15H). MS: m/z 431 (MH+). Anal. 8‚2 maleate
(C28H34N2O2‚2C4H4O4) C, H, N.
(S)-1-Ch lor o-3-p h en ylp r op a n -2-ol (18). To a solution of
BF3‚OEt2 (22.8 mL, 180 mmol) in THF (140 mL) at -78 °C
was added dropwise phenyllithium (1.8 M in cyclohexanes-
ether, 100 mL, 180 mmol), followed by a solution of (S)-(+)-
epichlorohydrin (97% ee, 4.7 mL, 60 mmol) in THF (20 mL).
After the solution was stirred for 1 h, the reaction mixture
was quenched with saturated aqueous NaHCO3 (100 mL),
allowed to warm to room temperature, and evaporated under
reduced pressure. The aqueous residue was extracted with
ether (200 mL × 2), and then, the combined organic extracts
were washed with brine, dried (MgSO4), filtered, and evapo-
rated. The crude product was purified by flash column chro-
matography (silica gel, 15% EtOAc in n-hexane) to afford 18
1
(7.96 g, 78%) as a colorless oil. H NMR (300 MHz, CDCl3): δ
7.21-7.34 (m, 5H), 4.02 (m, 1H), 3.58 (dd, J ) 11.2, 3.9 Hz,
1H), 3.47 (dd, J ) 11.2, 5.8 Hz, 1H), 2.86 (d, J ) 6.6 Hz, 2H),
2.40 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 137.1, 129.4, 128.7,
126.8, 72.1, 49.0, 40.4. HRMS m/z calcd for C9H11ClO+,
170.0498; found, 170.0494. 188 (M + NH4+); [R]20 +3.6° (c )
D
0.56, CHCl3).
(R)-1-Ch lor o-3-p h en ylp r op a n -2-ol (19).29 Compound 19
was synthesized from (R)-(-)-epichlorohydrin as described
above to afford 19 in 72% yield as a colorless oil: [R]20 -3.7°
D
(c ) 0.52, CHCl3).
1-[2-[Bis(4-flu or op h en yl)m et h oxy]et h yl]-4-(2-p h en yl-
eth yl)p ip er a zin e (24). Compound 24 was synthesized and
converted to a dimaleate salt. It was previously prepared as
the dihydrochloride salt, mp 207-8 °C.23 1H NMR (300 MHz,
CDCl3): δ 7.20-7.30 (m, 9H), 6.98-7.04 (m, 4H), 5.34 (s, 1H),
3.58 (t, J ) 5.9 Hz, 2H), 2.79-2.84 (m, 2H), 2.69 (t, J ) 5.9
Hz, 2H), 2.50-2.64 (m, 10H). MS: m/z 437 (MH+). Anal. 24‚2
maleate (C27H30F2N2O‚2C4H4O4) C, H, N.
Biologica l Meth od s: Bin d in g Assa y. Binding assays for
the DAT and SERT followed published procedures33 and used
0.01 nM [125I]RTI-5534 (s.a. ) 2200 Ci/mmol). Briefly, 12 mm
× 75 mm polystyrene test tubes were prefilled with 100 µL of
drugs, 100 µL of radioligand ([125I]RTI-55), and 50 µL of a
“blocker” or buffer. Drugs and blockers were made up in 55.2
mM sodium phosphate buffer, pH 7.4 (BB), containing 1 mg/
(R)-(-)-1-[4-[2-(Dip h en ylm eth oxy)eth yl]p ip er a zin yl]-
3-p h en ylp r op a n -2-ol (9). Compound 9 was synthesized using
17 and 19 according to the general procedure and yielded a
colorless oil. MS: m/z 431 (MH+). Anal. 9‚2 maleate (C28H34N2-
O2‚2C4H4O4) C, H, N.
(S)-(+)-2-[4-[2-[Bis(4-flu or op h en yl)m et h oxy]et h yl]p i-
p er a zin yl]-1-p h en yleth a n -1-ol (10) a n d (()-2-[4-[2-[Bis-
(4-flu or op h en yl)m et h oxy]et h yl]p ip er a zin yl]-2-p h en yl-
eth a n -1-ol (14). Compounds 10 and 14 were synthesized using
16 and (S)-2-chloro-1-phenylethanol according to the general

1328 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6
Hsin et al.
mL bovine serum albumin (BB/BSA). Radioligands were made
up in a protease inhibitor cocktail containing 1 mg/mL BSA
[BB containing chymostatin (25 µg/mL), leupeptin (25 µg/mL),
ethylenediaminetetraacetic acid (100 µM), and EGTA (100
µM)]. The samples were incubated in triplicate for 18-24 h
at 4 °C (equilibrium) in a final volume of 1 mL. Brandel cell
harvesters were used to filter the samples over Whatman GF/B
filters, which were presoaked in wash buffer (ice-cold 10 mM
Tris-HCl/150 mM NaCl, pH 7.4) containing 2% poly(ethylen-
imine).
sessions for each dose of pretreatment drug or vehicle phase
were averaged and represented a stable effect.
Ack n ow led gm en t. We thank Noel Whittaker and
Wesley White (NIDDK, NIH) for mass spectral data and
acknowledge the NIDA for partial financial support of
this work. We also thank Robert Horel (Clinical Psy-
chopharmacology Section, IRP, NIDA) for expert techni-
cal assistance.
Micr od ia lysis Assa y. Male Sprague-Dawley rats (300-
450 g) were obtained from Charles River Laboratories (Wilm-
ington, MA). The animal housing facilities were fully accred-
ited by the American Association of the Accreditation of
Laboratory Animal Care, and all experiments were performed
according to the guidelines delineated by the Institutional
Animal Care and Use Committee of the National Institute on
Drug Abuse (NIDA), Intramural Research Program (IRP).
Surgical implantation of indwelling jugular catheters and
intra-accumbens guide cannulae was carried out as previously
described.32 Rats were housed individually after surgery and
were allowed at least 1 week to recover. On the evening prior
to testing, extension tubes were connected to the catheters,
and microdialysis probes (2 mm × 0.5 mm exchange surface,
CMA/12, CMA/Microdialysis) were inserted into the nucleus
accumbens via the guide cannulae. The next morning, dialy-
sate samples were collected at 20 min intervals and im-
mediately assayed for DA using microbore HPLC-EC as
described elsewhere.35 Once three baseline samples were
obtained, various doses of 6, 7, 1, or a saline vehicle were
administered via the jugular catheter. Dialysate samples were
collected every 20 min for 2 h postinjecton. Drug solutions were
prepared immediately before use, and doses are expressed as
the salt. Data were evaluated by one-way (acute drug treat-
ment) analysis of variance with repeated measures.
Beh a vior a l Meth od s. Three individually housed, adult
male rhesus monkeys (Macaca mulatta), weighing between 7.8
and 9.2 kg, served as subjects in these studies. Each monkey
was maintained at about 90% of its free-feeding weight to allow
the use of food-maintained responding as a control perfor-
mance. These monkeys had been previously equipped with a
chronically indwelling catheter/port system.36 Experimental
sessions were conducted 5 days a week in separate sound- and
light-attenuating chambers, in a manner similar to previous
reports.24,27 Lever-pressing was maintained by a multiple
chained FI 10 min FR 30 (food) chained FI 10 min FR 30
(cocaine) schedule. The completion of the FI chain component
produced the second component of the chain schedule and
availability of food or cocaine under an FR schedule. In the
FR component, a maximum of 10 reinforcers could be deliv-
ered. Each (FI and FR) component of the multiple schedule
included a 60 s limited hold (LH) period: in the FI, if no
responses occurred within 60 s after 10 min, the stimuli were
extinguished and the FR component was started; in the FR
component, the availability of that reinforcer was canceled and
the ratio requirements and the LH period were reset. Each
session was composed of four repetitions of the following
sequence: FI 10 min, FR 30 (food), FI 10 min, FI 30 (cocaine).
Green lights were illuminated during the food-availability
periods, and red lights were illuminated during the cocaine-
availability periods. The unit dose of cocaine used as a
reinforcer was 5.6 µg/kg/injection throughout the experiment.
The effects of 4-5 doses of compounds 6 and 7 or vehicle (a
mixture of distilled water and saline) were examined for five
consecutive sessions for each drug. For each drug, the effects
of the vehicle were assessed first, and then, an ascending series
of doses were tested. The range of doses was chosen to include
a dose large enough to decrease responding substantially. The
order of drug testing was mixed among the animals, except 1
was always tested last. Doses of each drug or vehicle were
infused intravenously over about 15 min starting 30 min prior
to the session onset. The dependent measures collected were
the average response rates in the food and cocaine components
of each session. For each subject, data from the last three
Refer en ces
(1) J ohanson, C. E.; Fischman, M. W. The Pharmacology of Cocaine
Related to Its Abuse. Pharmacol. Rev. 1989, 41, 3-52.
(2) Das, G. Cocaine Abuse in North Americasa Milestone in History.
J . Clin. Pharmacol. 1993, 33, 296-310.
(3) Benowitz, N. L. Clinical Pharmacology and Toxicology of Co-
caine. Pharmacol. Toxicol. 1993, 72, 3-12.
(4) Musto, D. F. Opium, Cocaine, and Marijuana in American
History. Sci. Am. 1991, 265, 40-47.
(5) Warner, E. A. Cocaine Abuse. Ann. Intern. Med. 1993, 119, 226-
235.
(6) White, P. T. Cocasan Ancient Herb Turns Deadly. Natl.
Geographic 1989, 175, 3-47.
(7) McCoy, C. B.; Metsch, L. R.; Inciardi, J . A.; Anwyl, R. S.;
Wingerd, J .; Bletzer, K. Sex, Drugs, and the Spread of HIV/AIDS
in Belle Glade, Florida. Med. Anthrop. Quart. 1996, 10, 83-93.
(8) Hser, Y.-I.; Chih-Ping, C.; Hoffman, V.; Anglin, M. D. Cocaine
Use and High-Risk Sexual Behavior among STD Clinic Patients.
Sex. Transm. Dis. 1999, 26, 82-86.
(9) Mitscher, L. A.; Baker, W. Tuberculosis: A Search for Novel
Therapy Starting with Natural Products. Med. Res. Rev. 1998,
18, 363-374.
(10) Wise, R. A. Catecholamine Theories of Reward. A Critical
Review. Brain Res. 1978, 152, 215-247.
(11) Kuhar, M. J .; Ritz, M. C.; Boja, J . W. The Dopamine Hypothesis
of the Reinforcing Properties of Cocaine. Trends Neurosci. 1991,
14, 299-302.
(12) Ritz, M. C.; Lamb, R. J .; Goldberg, S. R.; Kuhar, M. J . Cocaine
Receptors on Dopamine Transporters Are Related to Self-
Administration of Cocaine. Science 1987, 237, 1219-1223.
(13) Rothman, R. B.; Glowa, J . R. A Review of the Effects of
Dopaminergic Agents on Humans, Animals, and Drug-Seeking
Behavior, and Its Implications for Medication Developments
Focus on GBR-12909. Mol. Neurobiol. 1995, 11, 1-19.
(14) Carroll, F. I.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . Cocaine
ReceptorsBiochemical-Characterization and Structure-Activity
Relationships of Cocaine Analogues at the Dopamine Trans-
porter. J . Med. Chem. 1992, 35, 969-981.
(15) Madras, B. K.; Spealman, R. D.; Fahey, M. A.; Neumeyer, J . L.;
Saha, J . K.; Milius, R. A. Cocaine Receptors Labeled by [3H]2â-
Carbomethoxy-3â-(fluorophenyl)tropane. Mol. Pharmacol. 1989,
36, 518-524.
(16) Meltzer, P. C.; Liang, A. Y.; Madras, B. K. The Discovery of an
Unusually Selective and Novel Cocaine Analogue-Difluoropine-
Synthesis and Inhibition of Binding at Cocaine Recognition Sites.
J . Med. Chem. 1994, 37, 2001-2010.
(17) Newman, A. H.; Allen, A. C.; Izenwasser, S.; Katz, J . L. Novel
3R-(Diphenylmethoxy)tropane AnaloguessPotent Dopamine Up-
take Inhibitors without Cocaine-Like Behavioral Profiles. J .
Med. Chem. 1994, 37, 2258-2261.
(18) Aeberli, P.; Eden, P.; Gogerty, J . H.; Houlihan, W. J .; Penberthy,
C. 5-Aryl-2,3-dihydro-5H-imidazo[2,1-a]isoindol-5-ols. A Novel
Class of Anorectic Agents. J . Med. Chem. 1975, 18, 177-182.
(19) Berger, P.; Gawin, F.; Kosten, T. R. Treatment of Cocaine Abuse
with Mazindol. Lancet 1989, 1, 283-283.
(20) Andersen, P. H. Biochemical and Pharmacological Characteriza-
tion of [3H]GBR-12935 Binding in Vitro to Rat Striatal
MembranesLabeling of the Dopamine Uptake Complex. J .
Neurochem. 1987, 48, 1887-1896.
(21) Berger, P.; J anowsky, A.; Vocci, F.; Skolnick, P.; Schweri, M.
M.; Paul, S. M. [3H]GBR-12935: A Specific High Affinity Ligand
for Labeling the Dopamine Transport Complex. Eur. J . Phar-
macol. 1985, 107, 289-290.
(22) Bonnet, J . J .; Protais, P.; Chagraoui, A.; Costentin, J . High-
Affinity [3H]GBR 12783 Binding to a Specific Site Associated
with the Neuronal Dopamine Uptake Complex in the Central-
Nervous-System. Eur. J . Pharmacol. 1986, 126, 211-222.
(23) Van der Zee, P.; Koger, H. S.; Goojtes, J .; Hespe, W. Aryl 1,4-
Dialk(en)ylpiperazines as Selective and Very Potent Inhibitors
of Dopamine Uptake. Eur. J . Med. Chem. 1980, 15, 363-370.
(24) Glowa, J . R.; Wojnicki, F. H. E.; Matecka, D.; Rice, K. C.;
Rothman, R. B. Effects of Dopamine Reuptake Inhibitors on
Food- and Cocaine-Maintained Responding: II. Comparisons
with Other Drugs and Repeated Administrations. Exp. Clin.
Psychopharmacol. 1995, 3, 232-239.

Potential Cocaine-Abuse Therapeutic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6 1329
(25) Lewis, D. B.; Matecka, D.; Zhang, Y.; Hsin, L.-W.; Dersch, C.
M.; Stafford, D.; Glowa, J . R.; Rothman, R. B.; Rice, K. C.
Oxygenated Analogues of 1-[2-(Diphenylmethoxy)ethyl]- and
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)pi-
perazines (GBR 12935 and GBR 12909) as Potential Extended-
Action Cocaine-Abuse Therapeutic Agents. J . Med. Chem. 1999,
42, 5029-5042.
on the Use of [3H]DA-Uptake-Inhibition to Transporter-Binding-
Inhibition Ratios for the In Vitro Evaluation of Putative Cocaine
Antagonists. Life Sci. 1993, 53, PL267-PL272.
(32) Baumann, M. H.; Char, G. U.; de Costa, B. R.; Rice, K. C.;
Rothman, R. B. GBR 12909 Attenuates Cocaine-Induced Activa-
tion of Mesolimbic Dopamine Neurons in the Rat. J . Pharmacol.
Exp. Ther. 1994, 271, 1216-1222.
(33) Rothman, R. B.; Lewis, B.; Dersch, C.; Xu, H.; Radesca, L.; de
Costa, B. R.; Rice, K. C.; Kilburn, R. B.; Akunne, H. C.; Pert, A.
Identification of a GBR 12935 Homolog, LR 1111, Which is Over
4000-Fold Selective for the Dopamine Transporter, Relative to
Serotonin and Norepinephrine Transporters. Synapse 1993, 14,
34-39.
(34) Rothman, R. B.; Cadet, J . L.; Akunne, H. C.; Silverthorn, M. L.;
Baumann, M. H.; Carroll, F. I.; Goodman, C. B.; Rice, K. C.; de
Costa, B. R.; Partilla, J . S.; Wang, J .-B.; Uhl, G. R.; Glowa, J .
R.; Dersch, C. M. Studies of the Biogenic Amine Transporters.
IV. Demonstration of a Multiplicity of Binding Sites in Rat
Caudate Membranes for the Cocaine Analogue [125I]RTI-55. J .
Pharmacol. Exp. Ther. 1994, 270, 296-309.
(35) Baumann, M. H.; Ayestas, M. A.; Dersch, C. M.; Brockington,
A.; Rice, K. C.; Rothman, R. B. Effects of Phentermine and
Fenfluramine on Extracellular Dopamine and Serotonin in Rat
Nucleus Accumbens: Therapeutic Implications. Synapse 2000,
36, 102-113.
(26) Longer, M. A.; Robinson, J . R. Remington’s Pharmaceutical
Sciences, 18th ed.; Mack Publishing Co.: Easton, 1990; pp 1676-
1693.
(27) Glowa, J . R.; Fantegrossi, W. E.; Lewis, D. B.; Matecka, D.; Rice,
K. C.; Rothman, R. B. Sustained Decrease in Cocaine-Main-
tained Responding in Rhesus Monkeys with 1-[2-[Bis(4-fluo-
rophenyl)methoxy]ethyl]-4-(3-hydroxyl-3-phenylpropyl)piperazi-
nyl Decanoate, a Long-Acting Ester Derivative of GBR 12909.
J . Med. Chem. 1996, 39, 4689-4691.
(28) Klunder, J . M.; Onami, T.; Sharpless, K. B. Arenesulfonate
Derivatives of Homochiral Glycidol: Versatile Chiral Building
Blocks for Organic Synthesis. J . Org. Chem. 1989, 54, 1295-
1304.
(29) Takano, S.; Yanase, M.; Sekiguchi, Y.; Ogasawara, K. Practical
Synthesis of (R)-γ-Amino-â-Hydroxybutanoic Acid (GABOB)
from (R)-Epichlorohydrin. Tetrahedron Lett. 1987, 28, 1783-
1784.
(30) Matecka, D.; Lewis, D.; Rothman, R. B.; Dersch, C. M.; Wojnicki,
F. H. E.; Glowa, J . R.; DeVries, A. C.; Pert, A.; Rice, K. C.
Heteroaromatic Analogues of 1-[2-(Diphenylmethoxy)ethyl]- and
1-[2[Bis(4-Fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)pi-
perazines (GBR 12935 and GBR 12909) as High-Affinity Dopam-
ine Reuptake Inhibitors. J . Med. Chem. 1997, 40, 705-716.
(31) Rothman, R. B.; Becketts, K. M.; Radesca, L. R.; Dersch, C. M.
Studies of the Biogenic Amine Transporters. II. A Brief Study
(36) Wojnicki, F. H. E.; Bacher, J . B.; Glowa, J . R. Use of Subcutane-
ous Vascular Access Ports in Rhesus Monkeys. Lab. Anim. Sci.
1994, 44, 491-494.
J M010430F