Piperidine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909): High affinity ligands for the dopamine transporter

Article abstract of DOI:10.1021/jm020264r

A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethylpiperidines were examined for their ability to bind to the dopamine transporter (DAT), the norepinephrine transporter, and the serotonin transporter (SERT). In particular, the role of the N-substituent on

Full text of DOI:10.1021/jm020264r

J . Med. Chem. 2002, 45, 4371-4374
4371
Brief Articles
P ip er id in e An a logu es 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 (GBR
12909): High Affin ity Liga n d s for th e Dop a m in e Tr a n sp or ter
Thomas Prisinzano,† Elisabeth Greiner,† Edward M. J ohnson II,† Christina M. Dersch,‡ J amila Marcus,‡
J ohn S. Partilla,‡ Richard B. Rothman,‡ Arthur E. J acobson,† and Kenner C. Rice*,†
Laboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, and
Clinical Psychopharmacology Section, Intramural Research Program, NIDA, NIH, Baltimore, Maryland 21224
Received J une 21, 2002
A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethylpiperidines were examined for their ability
to bind to the dopamine transporter (DAT), the norepinephrine transporter, and the serotonin
transporter (SERT). In particular, the role of the N-substituent on affinity and selectivity for
the DAT was probed. 4-[2-[Bis(4-fluorophenyl)methoxy]ethyl-1-(2-naphthylmethyl)piperidine
was found to possess subnanomolar affinity (Ki ) 0.7 nM) and good selectivity for the DAT
(SERT/DAT ) 323).
In tr od u ction
Cocaine is a widely abused drug, and its abuse has
had great effects on public health, through the spread
of human immunodeficiency virus (HIV), hepatitis, and
tuberculosis.1-9 Unfortunately, there are no U.S. Food
and Drug Administration (FDA)-approved therapeutic
agents available for the treatment of cocaine abuse or
for the prevention of relapse.10 Among the various
agents tested clinically, the best results appear to have
been achieved with dextroamphetamine,11 supporting
the hypothesis that agonist substitution therapy is a
reasonable approach to developing pharmacotherapies
for cocaine dependence.
On a molecular level, cocaine inhibits the reuptake
of dopamine (DA), serotonin (5-HT), and norepinephrine
(NE). Evidence suggests, however, that its binding to
the dopamine transporter (DAT) and subsequent inhibi-
tion of DA reuptake may be responsible for its reinforc-
ing properties and a good target for the design of an
agonist substitution type medication for cocaine
abuse.12-16
Our approach to developing this type of potential
therapeutic for cocaine abuse is to find a competitive
inhibitor of the DAT that dissociates very slowly.17 1-[2-
[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)-
piperazine (GBR 12909) (1, Figure 1) was among the
first agents to be characterized as a high-affinity and
selective inhibitor of DA reuptake.18,19 Studies with
rhesus monkeys have shown that in cocaine and food
self-administration studies, 1 decreases cocaine-main-
tained responding without affecting food-maintained
responding.20,21 Given the promising properties of 1 and
its analogues, these compounds have been identified as
novel agents for the potential pharmacotherapy of
cocaine abuse in humans.
F igu r e 1. Structure of 1-{2-[bis-(4-fluoro-phenyl)methoxy]-
ethyl}-4-(3-phenylpropyl)piperazine analogues.
The binding of these agents at the transporter for
norepinephrine (NET) is a possible source of sympatho-
mimetic side effects. In our continuing efforts to develop
new agents that might reduce cocaine self-administra-
tion, we are attempting to find more selective and high-
affinity DAT inhibitors.20-26 Our efforts were focused
on analogues, where a piperidine ring was substituted
for the piperazine ring in 1. Several piperidine ana-
logues have been prepared.27 Compound 2 was reported
to have good affinity for the DAT but was not very
selective.27 Previous reports have shown that modifica-
tion of this compound may lead to analogues with
enhanced selectivity for the DAT over the serotonin
transporter (SERT).28,29
Ch em istr y
The N-substituted piperidines were synthesized from
the commercially available 4-piperidineethanol (Scheme
1). The reaction of 4-piperidineethanol with hydrocin-
namoyl chloride, followed by reduction of the corre-
sponding amide with LAH, and ether formation using
4,4′-difluorobenzhydrol in toluene under azeotropic
distillation conditions gave 2 in good yield.27 Alternately,
a three step sequence of N-protection, ether formation,
and N-deprotection afforded 5.27,30 The coupling of
piperidine 5 with trans-cinnamic acid using 1-[3-(di-
methylamino)propyl]-3-ethylcarbodiimide hydrochloride
(EDCI), followed by reduction of the corresponding
amide with AlH3, afforded alkene 4.31,32
* To whom correspondence should be addressed. Tel: 301-496-1856.
Fax: 301-402-0589. E-mail: kr21f@nih.gov.
† National Institutes of Health.
‡ Addiction Research Center.
10.1021/jm020264r This article not subject to U.S. Copyright. Published 2002 by the American Chemical Society
Published on Web 08/17/2002

4372 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Brief Articles
Sch em e 1a
Ta ble 1. Binding Affinities at the DAT and SERT Labeled
with [125I]RTI-55 of 2, 4, and 6-13 (Ki ( SD, nM)
compdsa
DATb
SERTb
SERT/DAT
1
2
4
6
7
8
9
10
11
12
13
3.7 ( 0.4
1.1 ( 0.1
126 ( 27
68 ( 8
34
65
104
41
35
31
0.45 ( 0.03
0.99 ( 0.07
1.3 ( 0.1
47 ( 2
41 ( 6
45 ( 5
5.3 ( 0.4
164 ( 26
85 ( 10
246 ( 33
88 ( 10
370 ( 27
229 ( 21
1.01 ( 0.18
1.61 ( 0.15
0.73 ( 0.07
16 ( 1
84
153
121
23
0.71 ( 0.06
323
a
a
b
Reagents: (a) Hydrocinnamoyl chloride, NEt3, CH2Cl2. (b)
Prepared and tested as oxalate salt. Values determined as
in ref 23 using [125I]RTI-55 as radioligand for the DAT and SERT.
LAH, THF. (c) 4,4-Difluorobenzhydrol, p-TsOH‚H2O, toluene. (d)
Benzoyl chloride, NEt3, CH2Cl2. (e) NaOH, EtOH. (f) trans-
Cinnamic acid, EDCI, CH2Cl2. (g) LAH, H2SO4, THF.
On the basis of this observation and our previous
discovery that 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-
4-(3-phenylallyl)piperazine (GBR 13069, 3) also had
higher affinity for the DAT than 1,23 we thought it might
be of great interest to prepare 4. Although it was
prepared previously, we thought it possible that 4 might
have greater affinity for the DAT in our assay. We found
that 4 had higher affinity for the DAT (Ki ) 0.45 nM)
than 2 (Ki ) 1.1 nM). This result, however, was also in
contrast to previous findings where the affinity of 4 was
reported to be 41.4 nM.32 In an attempt to better
understand these results, we evaluated several ad-
ditional analogues with N-substituents that had been
previously investigated in the piperazine series.22 In
particular, we chose to examine N-substituents in the
piperidine series that displayed high affinity (Ki e 10
nM) in the piperazine series, such as a 3-furan-2-ylallyl
and a 3-thiophen-2-ylallyl substituent, as well as several
others.22 It was hoped that these specific alterations
might provide an explanation for the mode of binding
of the two series relative to one another.
Sch em e 2a
The binding results showed that the replacement of
the phenyl ring in 4 with a 2-furyl, 6, or 2-thienyl, 7,
group resulted in a decrease in affinity for the DAT as
compared to 4. These compounds were similar to 4 in
their affinity for the SERT.
a
Reagents: (a) Appropriate acid, EDCI, CH2Cl2. (b) LAH,
H2SO4, THF. (c) Phenylacetylene, (CH2O)n, CuSO4, THF. (d)
1-Chloromethylnaphthalene, K2CO3, DMF.
The role of the trans-alkene in 4 was then tested. The
introduction of an alkyne, i.e., 8, decreased affinity for
the DAT (10-fold) as compared to 4. This seemed to
indicate that a trans-alkene was favored over a linear
conformation, i.e., 8. Furthermore, the trans-alkene in
4 was then incorporated into several heterocycles, 9-11.
These modifications decreased affinity for the DAT and
the SERT as compared to 4. We noted that the intro-
duction of an indole moiety, 11, was optimal for affinity
(Ki ) 0.73 nM) among the heterocycles, 9-11. However,
the benzothiophene analogue, 10, had the best selectiv-
ity over the SERT (153-fold).
In an attempt to further investigate the binding
region of the N-substituent, we synthesized two naph-
thalene isomers. 1-Naphthylmethyl analogue 12 had the
least affinity for the DAT (Ki ) 16 nM) and the SERT
(Ki ) 370 nM) of this series of ligands. Remarkably,
2-naphthylmethyl analogue, 13, was found to have
subnanomolar affinity (Ki ) 0.71 nM) for the DAT and
the best selectivity over the SERT (323-fold) of the
compounds examined.
Targets 6, 7, 9-11, and 13 were prepared from 5
using a procedure similar to the preparation of 4
(Scheme 2). The coupling of 5 with the appropriate acid
using EDCI followed by reduction of the corresponding
amide with AlH3 gave 6, 7, 9-11, and 13.33,34 A modified
Mannich reaction using 5, phenylacetylene, and para-
formaldehyde gave 8. The treatment of 5 with 1-chloro-
methylnaphthalene under basic conditions afforded 12.
Resu lts a n d Discu ssion
We resynthesized 2 to compare (Table 1) its binding
affinities with those of our new analogues. It was hoped
that the introduction of different functional groups into
the N-alkyl group of 2 would give us a compound with
high affinity and better selectivity than 1. These ana-
logues might represent a second generation cocaine
abuse treatment agent.
We found that the affinity of 2 in our binding assay
(Table 1) was higher than previously reported.27 It had
higher affinity (Ki ) 1.1 nM) for the DAT and greater
selectivity over the SERT (68-fold) than 1. This might
be due to the use of [125I]RTI-55 to label a site on the
DAT rather than the formerly used27 [3H]WIN 35,428.
The functional binding assays (Table 2) were carried
out for two of the most interesting ligands, 10 and 13.

Brief Articles
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4373
Ta ble 2. Reuptake Inhibition Studies of 1, 10, and 13 (IC50
SD, nM)
(
triethylamine (11.7 g, 116.1 mmol) in dry CH2Cl2 (400 mL) at
0 °C. The mixture was stirred at room temperature overnight,
washed successively with H2O (3 × 100 mL), 2 N HCl (3 ×
100 mL), and saturated NaCl (2 × 200 mL), and dried (Na2-
SO4). Removal of the solvent under reduced pressure afforded
a crude oil that was used without further purification. A
mixture of crude oil, p-toluenesulfonic acid monohydrate (13.8
g, 72.6 mmol), and 4,4-difluorobenzhydrol (26.8 g, 121.9 mmol)
in dry toluene (800 mL) was heated at reflux under azeotropic
distillation conditions overnight. The solvent was removed
under reduced pressure, and EtOAc (600 mL) was added. The
EtOAc portion was washed with H2O (3 × 100 mL) and
saturated NaCl (2 × 100 mL) and dried (Na2SO4). Removal of
the solvent under reduced pressure afforded a crude oil that
solidified upon addition of hexane. A solution of the crude solid,
NaOH (21.2 g, 529 mmol), H2O (50 mL), and absolute EtOH
(500 mL) was heated at reflux for 36 h. The solvent was
removed under reduced pressure, and H2O (300 mL) was added
to the residue. The mixture was extracted with CH2Cl2 (3 ×
100 mL). The combined CH2Cl2 portion was washed with
saturated NaCl (2 × 100 mL) and dried (Na2SO4). Removal of
the solvent under reduced pressure afforded a crude oil that
was dissolved in dry acetone. Oxalic acid (1.1 equiv) was added,
and precipitate was collected and dried to afford 36.1 g (74%)
compdsa
DAb
5-HTb
NEb
5-HT/DA NE/DA
1
10
13
4.3 ( 0.3
73 ( 2
79 ( 5
17
87
38
18
22
13
11.9 ( 1.0 1037 ( 92 260 ( 21
7.2 ( 0.4
277 ( 15
93 ( 8
a
b
Prepared and tested as oxalate salt. Values determined as
in ref 23b.
These compounds were chosen because they had the
best selectivity over the SERT in this series. The uptake
assay showed that both 10 and 13 had slightly lower
potency than 1 in inhibiting DA uptake. However, both
had increased selectivity over inhibiting 5-HT uptake
as compared to 1, and 10 showed the desired increase
in selectivity over NE.
In comparison with the piperazine series, the piperi-
dine analogues generally had higher affinity for both
the DAT and the SERT.22 In agreement with the
piperazine series,22 2-furyl analogue 6 (Ki ) 0.99 nM)
had slightly higher affinity for the DAT than the
2-thienyl analogue 7 (Ki ) 1.3 nM). Compounds 9 and
10 had higher affinity and better selectivity than the
corresponding piperazine analogues. Compound 11 was
nearly identical to its piperazine counterpart. The only
difference was a slightly higher affinity for the SERT
that was responsible for a lower selectivity. Compounds
12 and 13 showed very different results. In the pipera-
zine series, the 2-naphthylmethyl derivative had lower
affinity for the DAT than the 1-naphthylmethyl deriva-
tive. It was thought that if the piperidine series was
binding in an identical manner to the piperazine series,
then compound 12 would have higher affinity than 13
for the DAT. Interestingly, 13 had subnanomolar affin-
ity for the DAT and the best selectivity over the SERT
in this series of ligands. Apparently, an extended
conformation is preferred in the piperidine series. It also
appears that previous piperazine structure-activity
relationships (SAR) may not be applicable to the pip-
eridine series, suggesting that these two series are not
binding in an identical manner at the DAT.
1
of 5 as a white solid; mp 146-148 °C. H NMR (DMSO-d6): δ
7.1-7.4 (m, 8H, aromatic); 5.5 (s, 1H, CH-O); 3.9 (bs, NH);
3.1-3.4 (m, 4H); 2.5-2.9 (m, 5H); 1.1-2.0 (m, 5H).
4-{2-[Bis-(4-flu or op h en yl)m eth oxy]eth yl}-1-(3-p h en yl-
a llyl)p ip er id in e Oxa la te (4). A solution of the free base of 5
(1.5 g, 4.5 mmol), trans-cinnamic acid (0.7 g, 4.5 mmol), and
EDCI (0.9 g, 5.0 mmol) in dry CH2Cl2 (25 mL) was stirred at
room temperature overnight. The solvent was removed under
reduced pressure, and the ethyl acetate (125 mL) was added
to the residue. The ethyl acetate solution was washed succes-
sively with 1 N 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 2.0 g (96%) of
the corresponding amide as an oil that was used without
further characterization. A 100% amount of H2SO4 (d ) 1.84)
(1.1 g, 11.0 mmol) was added cautiously to a suspension of
LAH (0.8 g, 22 mmol) in dry tetrahydrofuran (THF, 100 mmol)
at 0 °C. After the addition was complete, 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 10% NaOH (150
mL) was added cautiously. The layers separated, and the
aqueous layer was extracted with ethyl acetate (2 × 100 mL).
The combined organic portion was 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 dissolved in dry acetone. Oxalic acid (1.1 equiv) was added,
and the solvent was removed under reduced pressure. Anhy-
drous Et2O was added, and the precipitate was collected and
dried to afford 1.6 g (67%) of 4 as a white solid; mp 158-160
°C (literature2 162.7-163.5 °C). Anal. (C29H31F2NO‚C2H2O4‚
0.5H2O): C, H, N.
Con clu sion s
A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethylpi-
peridines were synthesized and evaluated. Several
ligands were identified with subnanomolar affinity to
DAT. The 2-naphthyl derivative (13) was more than
300-fold selective for DAT over the SERT, and in
reuptake inhibition studies, the benzothiophene com-
pound 10 was found to have somewhat better selectivity
for DAT over the NET than 1. This study indicates that
previous SAR seen in the GBR-12909 piperazine series
do not hold for the corresponding piperidine series.
Further exploration of this is currently underway.
4-{2-[Bis-(4-flu or op h en yl)m eth oxy]eth yl}-1-(3-p h en yl-
p r op -2-yn yl)p ip er id in e Oxa la te (8). A mixture of the free
base of 5 (1.5 g, 4.7 mmol), phenylacetylene (0.7 g, 7.1 mmol),
CuSO4 (0.8 g, 4.7 mmol), and paraformaldehyde (0.4 g, 14.1
mmol) in dry THF (45 mL) was heated at reflux for 2 h. Et2O
(100 mL) was added, and the mixture was filtered through a
pad of Celite. The filtrate was evaporated to dryness under
reduced pressure, and the residue was dissolved in CH2Cl2 (100
mL). The CH2Cl2 portion was washed with H2O (5 × 50 mL)
and saturated NaCl (2 × 50 mL) and dried (Na2SO4). The
solvent was removed under reduced pressure affording a crude
oil that was dissolved in anhydrous Et2O. Oxalic acid (1.1
equiv) was added, and the precipitate was collected, washed
with cold absolute EtOH (20 mL), and dried to afford 2.0 g
(80%) of 8 as a white solid; mp 134-136 °C. 1H NMR (DMSO-
d6): δ 7.1-7.6 (m, 13H, aromatic); 5.5 (s, 1H, CH-O); 4.0 (s,
2H, NCH2); 3.1-3.4 (m, 4H); 2.5-2.9 (m, 5H); 1.0-2.0 (m, 5H).
Anal. (C29H29F2NO‚C2H2O4): C, H, N.
Exp er im en ta l Section
Unless otherwise indicated, all reagents were purchased
from commercial suppliers and were used without further
purification. The instrumentation used has been previously
noted.26
4-{2-[Bis-(4-flu or oph en yl)m eth oxy]eth yl}piper idin e Ox-
a la te (5). A solution of benzoyl chloride (16.3 g, 116.1 mmol)
in dry CH2Cl2 (200 mL) was added in a dropwise manner to a
solution of 4-piperidineethanol (15.0 g, 116.1 mmol) and

4374 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Brief Articles
of Dopamine Uptake. Eur. J . Med. Chem. 1980, 15, 363-370.
(19) Andersen, P. H. The Dopamine Uptake Inhibitor GBR 12909:
Selectivity and Molecular Mechanism of Action. Eur. J . Phar-
macol. 1989, 166, 493-504.
(20) 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. Comparison with
Other Drugs and Repeated Administrations. Exp. Clin. Psy-
chopharmacol. 1995, 3, 232-239.
(21) 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-hydroxy-3-phenylpropyl)piperazi-
nyl Decanoate, a Long-Acting Ester Derivative of GBR 12909.
J . Med. Chem. 1996, 39, 4689-4691.
(22) Matecka, D.; Lewis, D. B.; 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-phenyl-
propyl)piperazines (GBR 12935 and GBR 12909) as High-Affinity
Dopamine Reuptake Inhibitors J . Med. Chem. 1997, 40, 705-
716.
(23) 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-(Diphenyl)methoxy]ethyl- and
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl-4-(3-phenylpropyl)pip-
erazines (GBR 12935 and GBR 12909) as Potential Extended-
Action Cocaine-Abuse Therapeutic Agents. J . Med. Chem. 1999,
42, 5029-5042. (b) Rothman, R. B.; Lewis, B.; Dersch, C. M.;
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,
LR1111, Which is Over 4, 000-Fold Selective for the Dopamine
Transporter, Relative to Serotonin and Norepinephrine Trans-
porters. Synapse 1993, 14, 34-39.
(24) Zhang, Y.; Rothman, R. B.; Dersch, C. M.; de Costa, B. R.;
J acobson, A. E.; Rice, K. C. Synthesis and Transporter Binding
Properties of Bridged Piperazine Analogues of 1-{2-[Bis(4-
fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR
12909). J . Med. Chem. 2000, 43, 4840-4849.
4-{2-[Bis-(4-flu or op h en yl)m et h oxy]et h yl}-1-n a p h t h a -
len -1-ylm eth ylp ip er id in e Oxa la te (12). A suspension of 5
(1.0 g, 2.4 mmol), K2CO3 (1.0 g, 7.2 mmol), a catalytic amount
of NaI, and 1-chloromethylnaphthalene (0.5 g, 2.6 mmol) in
dimethylformamide (DMF, 30 mL) was stirred at 100 °C
overnight. The mixture was poured into H2O (200 mL) and
extracted with ethyl acetate (3 × 60 mL). The combined ethyl
acetate portion was washed with H2O (2 × 75 mL) and
saturated NaCl (2 × 75 mL) and dried (Na2SO4). Removal of
the solvent under reduced pressure afforded a residue that
was dissolved in anhydrous Et2O. Oxalic acid (1.1 equiv) was
added, and the precipitate was collected, recrystallized from
absolute EtOH, and dried to afford 0.9 g (67%) of 12 as a white
solid; mp 176-178 °C. 1H NMR (DMSO-d6): δ 7.1-8.4 (m,
15H, aromatic); 5.5 (s, 1H, CH-O); 4.5 (s, 2H, ArCH2-); 3.1-
3.4 (m, 4H); 2.5-2.9 (m, 5H); 1.1-2.0 (m, 5H). Anal. (C31H31F2-
NO‚C2H2O4): C, H, N.
Ack n ow led gm en t. We (LMC, NIDDK) thank the
National Institute on Drug Abuse, NIH, for partial
support of this work.
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