Synthesis and transporter binding properties of bridged piperazine analogues of 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909)

Article abstract of DOI:10.1021/jm000300r

A series of analogues related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) and 1-{2-[bis(4-fiuorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine(3) (GBR 12935 and GBR 12909, respectively), in which the piperazine moiety was replaced

Full text of DOI:10.1021/jm000300r

4840
J . Med. Chem. 2000, 43, 4840-4849
Syn th esis a n d Tr a n sp or ter Bin d in g P r op er ties of Br id ged P ip er a zin 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)
Ying Zhang,#,† Richard B. Rothman,‡ Christina M. Dersch,‡ Brian R. de Costa,#,§ Arthur E. J acobson,# and
Kenner C. Rice*,#
Laboratory of Medicinal Chemistry, Building 8, Room B1-22, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, and Clinical Psychopharmacology Section,
National Institute on Drug Abuse, Addiction Research Center, Baltimore, Maryland 21224
Received J uly 18, 2000
A series of analogues related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2)
and 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (3) (GBR 12935 and
GBR 12909, respectively), in which the piperazine moiety was replaced by bridged piperazines
for structural rigidity, has been designed, synthesized, and evaluated for their ability to bind
3
to the dopamine transporter (DAT) and to inhibit the uptake of H-labeled dopamine (DA).
The binding data indicated that compounds 7 and 11, the N-methyl- and N-propylphenyl-3,8-
diaza[3.2.1]bicyclooctane analogues of 3, showed high affinity for the DAT (IC50 ) 8.0 and 8.2
nM, respectively), and 7 had high selectivity at the DAT relative to the serotonin transporter
(SERT) (88- and 93-fold for binding and reuptake, respectively). They also displayed linear
activity in DA uptake inhibition, possessing a similar binding and reuptake inhibition profile
to 3. The N-indolylmethyl analogue 16 showed the highest affinity (IC50 ) 1.4 nM) of the series,
with a 6-fold increase over its corresponding N-phenypropyl derivative 11. Interestingly, this
compound exhibited a high ratio (29-fold) of IC50 for the inhibition of DA reuptake versus binding
to the DAT. Replacing the piperazine moiety of 2 and 3 with (1S,4S)-2,5-diazabicyclo[2.2.1]-
heptane resulted in compounds 23-26, which showed moderate to poor affinity (IC50 ) 127-
1170 nM) for the DAT. Substitution of the homopiperazine moiety of 4 with a more rigid 3,9-
diazabicyclo[4.2.1]nonane gave compounds 28-33. However, the binding data showed that
compound 32 displayed a 10-fold decrease in affinity at the DAT and a 100-fold decrease in
selectivity at the DAT relative to the SERT compared to its corresponding homopiperazine
compound 4.
In tr od u ction
Cocaine inhibits the presynaptic reuptake of neu-
rotransmitters such as dopamine (DA), serotonin (5-HT),
and norepinephrine (NE). However, evidence suggests
that its binding to the dopamine transporter (DAT) and
subsequent inhibition of DA reuptake may be respon-
sible for its reinforcing property and locomotor activ-
ity.7-11 Further evidence supporting this DAT hypoth-
esis has emerged from recent studies on knockout mice
lacking the DAT gene. Treatment of homozygote mice
with high doses of cocaine resulted in no increase of loco-
motor activity, suggesting that the DAT is the molecular
target of cocaine responsible for its abuse potential.12
Cocaine (1) is one of the most powerfully addictive
drugs known, exerting its effect by acting directly on
the reward or pleasure centers of the brain.1 Cocaine
abuse has imposed a great burden on public health and
public safety worldwide, by playing an important role
in the rapid spread of acquired immune deficiency
syndrome (AIDS) and drug-resistant tuberculosis and
in drug-related violent and nonviolent crimes.2,3 Al-
though smoking cocaine base (crack) and other forms
of its abuse appear to have stabilized at a high level,
various forms of cardiovascular, respiratory, and neu-
rological morbidity and mortality continue to present a
formidable public health problem.4-6 Therefore, study
of the mechanism of action of cocaine with the goals of
development of strategies for the treatment and preven-
tion of cocaine abuse has become a major goal of the
National Institute on Drug Abuse through the Medica-
tions Development Program and numerous groups
worldwide.
However, several lines of evidence suggest that the
strategy of developing selective and high-affinity DA
uptake inhibitors for the treatment of cocaine abuse may
be misplaced. Recent studies showed that DAT knockout
mice self-administer cocaine13 and demonstrate cocaine
conditioned place preference,14 indicating that in the
absence of the DAT, cocaine can still establish reward-
ing effects. Although these data suggest that the DAT
is not critical for mediating cocaine reward, the data
do not rule out a role for mesolimbic DA as a mediator
of cocaine reward. Since DA is a substrate of the NE
transporter,15 DA could be accumulated by NE nerves.
This has been shown to occur in both the medial frontal
cortex16 and nucleus accumbens, but not in the striatum
* Corresponding author address: LMC, NIDDK, NIH; Bldg. 8, Rm.
B1-23; 8 Center Dr., MSC 0815; Bethesda, MD 20902-0815. Tel: 301-
496-11856. Fax: 301-402-0589. E-mail: kr21f@nih.gov.
#
National Institute of Diabetes and Digestive and Kidney Diseases.
‡ National Institute on Drug Abuse.
† Present address: ArQule, Inc., 200 Boston Ave., Suite 1000,
Medford, MA 02155.
§ Present address: Hospital of St. Raphael, 1450 Chapel St., New
Haven, CT 06511.
10.1021/jm000300r This article not subject to U.S. Copyright. Published 2000 by the American Chemical Society
Published on Web 11/18/2000

Binding Properties of Bridged Piperazine Analogues
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25 4841
of rats,17 which lacks noradrenergic innervation.18 The
inability of cocaine to elevate extracellular DA in the
striatum of DAT knockout mice13 is consistent with the
lack of NE transporters in this brain region. Thus, in
the absence of the DAT, it is reasonable to assume that
some of the extracellular DA in the nucleus accumbens
would be accumulated by NE nerves. Since cocaine is a
potent inhibitor of the NE transporter,19 administration
of cocaine would block DA accumulation and increase
extracellular DA, triggering the cocaine reward.
Ch a r t 1
Second, although, as noted above, the evidence that
DA mediates the reinforcing effect of cocaine in rodent
models is overwhelming, published data strongly sug-
gest that DA is not the sole mediator of the acute
euphoric effects of cocaine in humans. These data, as
reviewed in detail elsewhere,20-23 include the observa-
tions: (1) that DA receptor antagonists do not block the
subjective effects of cocaine20,24 or amphetamine,25,26 (2)
that administration of pharmacologically active doses
of bromocriptine did not produce or block cocaine-like
subjective effects,27 and (3) that inhibition of DA syn-
thesis by R-methyparatyrosine failed to significantly
block cocaine-induced subjective effects.28 Third, other
studies indicate that cocaine withdrawal causes a dual
neurochemical deficit of dopaminergic and serotonergic
function and that pharmacotherapy for cocaine depen-
dence will have to normalize both deficits.29,30
decreases cocaine-maintained responding without af-
fecting food-maintained responding in rhesus mon-
keys.38,39 It has also been reported that 3 attenuates
cocaine-induced activation of mesolimbic DA neurons,
as measured by in vivo microdialysis.40 Recently, a
behavioral study of rhesus monkeys administered the
decanoate ester of a racemic benzylic hydroxyl deriva-
tive of 3 (3a ) was carried out.41 The benzylic hydroxyl
derivative 3a was selected for conversion to the de-
canoate ester prodrug after preliminary in vivo and in
vitro studies revealed its profile to be similar to that of
3.41 Preliminary data showed that a single treatment
with this prodrug 3a as an extended action formulation
resulted in a sustained and selective effect on cocaine-
maintained responding for almost 30 days without
affecting the normal food-seeking behavior of rhesus
monkeys. Later studies with the enantiomers of 3a
showed that these compounds were nearly equipotent,
but twice as potent as 3 in preventing cocaine-main-
tained responding in rhesus monkeys.42 Given the
promising neurochemical and behavioral properties of
3, this compound and its analogues have been identified
as novel compounds potentially useful for the pharma-
cotherapy of cocaine abuse in humans.
An early SAR study on 2, replacing the piperazine
moiety with homopiperazine, resulted in the identifica-
tion of LR 1111 (4, Chart 1) as a highly selective DA
uptake inhibitor. This compound has been reported to
show similar binding affinity to 2 for the DAT but with
greater than 4000-fold selectivity for inhibition of [3H]-
DA uptake relative to [3H]5-HT uptake.43 Other studies
have also shown that modifying the central piperazine
ring of the GBR molecule significantly alters the affinity
and selectivity of the analogues at the DAT site.44,45 We
have utilized these findings in the development of a new
series of GBR-related ligands, in which the piperazine
fragment was replaced by a bridged piperazine or
bridged homopiperazine moiety (Chart 2), and we report
Viewed collectively, these data indicate the need to
further test the clinical relevance of the DA hypothesis
of cocaine reward. One approach to test the DA hypoth-
esis is to develop appropriate pharmacological tools such
as high-affinity slowly dissociating DAT ligands with
low intrinsic activity.31,32 The DA hypothesis predicts
that such an agent would have efficacy in treating
cocaine addiction. The present study focuses not on the
ultimate goal of testing the clinical relevance of the DA
hypothesis but rather on developing potential medica-
tions with which to test the hypothesis.
One of the approaches to develop a potential thera-
peutic agent for the treatment of cocaine abuse proposed
by Rothman et al. in 1991 is to develop an agent which
binds with high affinity to and dissociates slowly from
the DAT.33 This strategy assumes that if the dissociation
rate of such a ligand from the transporter is slow
enough, the agent will behave as a noncompetitive
inhibitor, creating an insurmountable inhibition of the
effects of cocaine mediated via elevation of extracellular
DA. Such an agent may also provide cocaine addicts
with some relief from cocaine craving, thereby reducing
cocaine self-administration behavior.33 Aryl-1,4-dialk-
(en)ylpiperazines including: GBR 12935 (1-[2-(diphen-
ylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine) (2), GBR
12909 (1-{2-[bis(4-fluorophenyl)]methoxy]ethyl}-4-(3-
phenylpropyl)piperazine) (3), and GBR 12783 (1-[2-
(diphenylmethoxyl)ethyl]-4-(3-phenyl-2-propenyl)piper-
azine) (Chart 1), were among the first agents charac-
terized as high-affinity and selective inhibitors of DA
reuptake.34,35 GBR 12909 (3) produces only a modest
increase in extracellular DA levels;36,37 however, it
attenuates the ability of cocaine to increase extracellular
DA levels in rat caudate.33 It binds tightly to the DAT
but is less efficient than cocaine in increasing DA-
mediated motoric behaviors.32 It has been shown in
cocaine and food self-administration studies that 3

4842 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25
Zhang et al.
Ch a r t 2
Sch em e 2. Synthesis of Bridged Piperazine GBR
Derivativesa
a
(a) 2,2,2-Trichloroethyl chloroformate, toluene, reflux; (b) Zn,
acetic acid, rt; (c) hydrocinnamoyl chloride, methylene chloride,
rt; (d) 1.0 M AlH3 in THF, rt.
Sch em e 1. Synthesis of N-Methyl Bridged Piperazine
GBR Analoguesa
2,4-dione according to the literature method with
modifications.47-49 The imide was reduced by 0.5 M
aluminum hydride in THF at 0 °C to afford the diamine,
which was then followed by an N-debenzylation using
catalytic hydrogenation to afford 5 in 54% yield. N-
Alkylation of 5 with 2-(diphenylmethoxy)ethyl chloride
or 2-[bis(4-fluorophenyl)methoxy]ethyl chloride, pre-
pared as previously described,34 afforded N-methyl
analogues 6 and 7 (Scheme 1).
N-Demethylation of 6 and 7 was then carried out
under mild reaction conditions50 (method A, Scheme 2).
Compounds 6 and 7 were converted into carbamates
with 2,2,2-trichloroethyl chloroformate in toluene, fol-
lowed by a treatment with zinc powder in acetic acid at
room temperature to give 8 and 9, respectively. The
obtained N-demethylated compounds 8 and 9 were
acylated with hydrocinnamoyl chloride in dichlorometh-
ane, and the resulting amides underwent alane reduc-
tion (method C) to afford the target amines 10 and 11.
N-Acylation of 9 with indole-2-carboxylic acid, 2-furyl-
acrylic acid, 3-(2-thienyl)acrylic acid, or trans-3-(3-
pyridyl)acrylic acid, followed by alane reduction at 0 °C,
afforded the unsaturated final products 16-19 respec-
tively (Scheme 3, methods B and C).
a
(a) 0.5 M AlH3 in THF, 0 °C; (b) H2, ethanol, 10% Pd/C; (c)
K2CO3, toluene, reflux.
The synthesis of 23 and 24 (Scheme 4) proceeded from
the N-alkylation of the commercially available (1S,4S)-
N-t-Boc-2,5-diazabicyclo[2.2.1]heptane with diarylmeth-
oxyethyl iodide (method D) to form 21 and 22, followed
by a reduction of the N-Boc protecting group with 1.0
M lithium aluminum hydride (LAH) in THF. Deprotec-
tion of N-Boc in 88% of formic acid at room temperature,
followed by N-alkylation with 1-iodo-3-phenylpropane
in THF, gave the desired compounds 25 and 26.
The bridged homopiperazine 9-methyl-3,9-diazabicyclo-
[4.2.1]nonane (27) was prepared according to the lit-
erature method in two steps with minor modifications.51
Treatment of 3-tropinone with hydrazoic acid gave the
bicyclic lactam, which was then reduced with lithium
aluminum hydride under refluxing conditions for 2 days
to afford 27 in 73% overall yield (Scheme 5). This
N-methyl bridged homopiperazine was then alkylated
here the binding affinity of these novel ligands for the
DAT and serotonin transporter (SERT) and their ability
to inhibit the reuptake of DA and 5-HT. Additionally,
an earlier study on 3 showed that modification of the
phenylpropyl “tail” portion of the molecule by incorpora-
tion of a heteroaromatic moiety resulted in an increase
of the binding affinity and selectivity at DAT binding
site.46 Therefore, it was also our intention to synthesize
a series of bridged piperazine derivatives of 3 with a
heteroaromatic “tail” (Chart 2) in order to evaluate their
biological activities.
Ch em istr y
The bridged piperazine 8-methyl-3,8-diaza[3.2.1]-
bicyclooctane (5) was prepared (Scheme 1) in two steps
from 3-benzyl-8-methyl-3,8-diaza[3.2.1]bicyclooctane-

Binding Properties of Bridged Piperazine Analogues
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25 4843
Sch em e 3. Synthesis of Bridged Piperazine GBR
Sch em e 4. Synthesis of One-Carbon Bridged
(1S,4S)-Piperazine GBR Derivativesa
Derivatives with Heterocyclic Aromatic Taila
a
(a) NaI, acetone, reflux overnight; (b) K2CO3, THF, reflux; (c)
1 M LiAlH4 in THF, reflux; (d) 88% formic acid, rt; (e) 1-iodo-3-
phenylpropane, K2CO3, THF, reflux.
a
(a) Carboxylic acid, EDCI, methylene chloride, rt; (b) 1.0 M
AlH3 in THF, 0 °C for 2 min.
Sch em e 5. Synthesis of Racemic Bridged
Homopiperazine GBR Derivativesa
with diarylmethoxyethyl iodide to give the N-methyl
compounds 28 and 29 (method D). N-Demethylation of
28 and 29 (method A) resulted in 30 and 31, followed
by N-alkylation with 1-iodo-3-phenylpropane in THF
(method D) to afford the target compounds 32 and 33
(Scheme 5).
All final products were purified and crystallized as
salts with organic or inorganic acids as listed in Table
1.
Resu lts a n d Discu ssion
The bridged piperazine series of compounds were
designed to introduce some rigidity to the piperazine
ring of the analogues of 3 and to force these analogues
to adopt a conformation similar to cocaine. Replacement
of the C-3 carbon in the tropane skeleton of cocaine with
a basic nitrogen results in the analogues 6, 7, 10, and
11 with a two-carbon bridge in the piperazine ring, as
shown in Scheme 1. The binding data in Table 2
indicated that both 7 and 11, the compounds with
p-fluoro substitution in the aromatic region, showed
high activity in DA reuptake inhibition with high
affinity for the DAT. Compound 7 possessed an affinity
of 8.0 nM at DAT binding and 9.6 nM in DA reuptake
inhibition. It exhibits an 88-fold selectivity for the DAT
relative to the SERT, as well as a 93-fold selectivity at
reuptake inhibition for DA relative to 5-HT. Replacing
the phenylpropyl side chain of the bridged piperazine
derivative 11 with a heteroaromatic “tail” resulted in
compounds 16-19. An earlier study by Matecka et al.
showed that the binding affinity of the corresponding
unbridged series of compounds benefited from the
a
(a) Concd H2SO4, NaN3, -5 to 50 °C; (b) 1 M LiAlH4 in THF,
reflux 2 days; (c) K2CO3, THF, reflux; (d) 2,2,2-trichloroethyl
chloroformate, K2CO3, toluene; (e) Zn, acetic acid, rt; (f) 1-iodo-3-
phenylpropane, K2CO3, THF, reflux.
incorporation of a heteroaromatic moiety such as furan
or thiophene into the N-phenylpropyl side chain.46 We
observed the same effects in our bridged series (Table
2) in that compounds containing indole, furan, and

4844 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25
Ta ble 1. Physical Properties of the Ligands
Zhang et al.
The design of compounds 23-26 was intended to
provide some view into the geometry of the piperazine
moiety of GBR analogues upon binding. Although a
variety of studies have been carried out in the modifica-
tion of both N- and N′-substitution of the piperazine
ring, studies on the piperazine moiety itself have
remained minimal. Among the few, a study by Matecka
et al.44 showed that the (()-2,5-dimethylpiperazine
derivative of 3 had a comparable affinity to 3 (GBR
12909) for the DAT labeled by [125I]RTI-55. In addition,
the compound exhibited enantioselectivity at the DAT
as well as DA uptake inhibition in favor of the 2S,5R
absolute configuration [IC50(DAT) ) 2.9 nM].44 In our
bridged piperazine series, the methylene group locks the
six-membered ring into a more rigid geometry with the
bridge heads existing in an S,S configuration. The
binding data of compounds 23-26 (Table 2) showed that
these compounds displayed only moderate affinity for
DAT binding as well as moderate inhibitory activity for
DA reuptake. Within this series, compound 26 possesses
the closest structural similarity to the Matecka et al.
compound, the 2,5-dimethylpiperazine derivative of 3.44
Interestingly, 26 exhibited a binding affinity of 127 nM
for the DAT and 203 nM for the SERT, similar to the
binding property of the (2R,5S)-(+)-dimethylpiperazine
derivative [IC50(DAT labeled by [125I]RTI-55) ) 99 nM,
IC50(SERT labeled by [125I]RTI-55) ) 298 nM] in Mate-
cka’s series, while the corresponding 2S,5R compound
showed high affinity and selectivity at the DAT.44 This
suggests that the 2S,5R absolute configuration is one
of the important criteria for the interaction of the GBR
type of compounds with the binding domain of the DAT
site. The increased bulk of the bridged piperazines and
their increased molecular volume did not prevent bind-
ing.
mp
CI-MS
no.a
salt
HBr
solvent
ethanol
(°C)
(m/z)
analysisb
6
7
221-2 336 C22H28N2O‚2HBr
154-5 372 22H26N2OF2‚2C2H2O4
oxalate acetone
C
10 oxalate acetone
11 oxalate acetone
16 oxalate acetone
17 oxalate acetone
143-4 440 C30H36N2O‚2C2H2O4
155-6 476 C30H34N2OF2‚2C2H2O4
203-4 487 C30H31N3OF2‚C2H2O4
195-6 478 C28H30N2O2F2‚2C2H2O4
‚0.5H2O
18 oxalate acetone
19 oxalate acetone
194-5 494
C28H30N2OF2S‚2C2H2O4
151-3 489 C29H31N3OF2‚2C2H2O4
‚1.25H2O
23 oxalate ethanol
24 oxalate ethanol
160-1 322
C21H26N2O‚2C2H2O4
167-9 358 C21H24N2OF2‚2C2H2O4
‚0.5H2O
25 oxalate methanol 188-9 426
C29H34N2O‚2C2H2O4
26 oxalate methanol 185-6 462 C29H32N2OF2‚2C2H2O4
28 HClc
29 HClc
30 HClc
32 HClc
33 HClc
ether
ether
ether
ether
ether
70d
81d
93d
85d
67d
350 C23H30N2O‚2HCl‚H2O
386 C23H28N2OF2‚2HCl‚0.5H2O
336 C22H28N2O‚2HCl‚0.25H2O
454 C31H38N2O‚2HCl‚0.5H2O
490 C31H36N2OF2‚2HCl‚H2O
a
The 1H NMR data for the free base of these compounds are
b
shown in the Experimental Section. Elemental compositions (%)
were found to be within (0.4% of the theoretical values of C, H,
c
and N. HCl salt was tritiated from ether. dSoftening point.
thiophene moieties showed low-nanomolar affinity at
the DAT binding, while the pyridine-containing ana-
logue exhibited a slightly lower affinity. The indole-
containing compound 16 displayed the highest affinity
(IC50 ) 1.4 nM) for DAT binding, a 6-fold increase over
the corresponding phenylpropyl derivative 11, while
retaining high binding selectivity (74-fold) over the
SERT. However, it is interesting to note that this
compound displayed a relatively lower activity (IC50
)
40 nM) in DA reuptake inhibition and exhibited a high
ratio (29-fold) of IC50 for the inhibition of DA reuptake
versus binding to the DAT. Recently, attention has been
drawn toward the design of compounds that show high
affinity for the DAT and relatively low inhibitory
activity for DA reuptake as potential therapeutic agents
for cocaine abuse.52-54 It has been proposed that such a
compound could be an effective therapeutic agent
because it would serve to block cocaine from binding to
the transporter while not interfering with DA transport.
Although the biological significance of such an agent has
not been fully studied, the development of novel agents
such as 16 will allow further functional studies to be
performed to test this hypothesis.
In summary, we have synthesized a series of novel
bridged piperazine analogues corresponding to the un-
bridged compounds 2 and 3. The preliminary binding
study showed that compound 16, a bridged piperazine
derivative with an N-indolylmethyl, displayed high
binding affinity and selectivity for the DAT. Compounds
such as 2 and 3 usually show a linear correlation
between the binding affinity and reuptake inhibition
activity (by IC50 value). However, 16 was 29-fold (by IC50
value) less active in DA reuptake inhibition. The
interesting binding profile of 16 will lead to further
investigation of its behavioral profile.
As mentioned earlier, modification of 2 by replace-
ment of the piperazine with a homopiperazine moiety
resulted in 4, a compound that exhibited a similar
binding profile as 2 for the DAT while having a much
higher selectivity (4000-fold) at the DAT relative to the
SERT. Therefore, it was of interest to prepare a group
of bridged homopiperazine compounds to compare their
binding properties with 4. The binding data in Table 2
show that among this series (28-33), compound 32
displayed the highest affinity for the DAT (IC50 ) 32
nM), a 10-fold decrease in affinity versus 4. This
compound differs from 4 only by a two-carbon bridge
over C-2 and C-7. However it shows a 100-fold decrease
in selectivity versus 4 at the DAT relative to SERT. The
nor-compound 30 showed the lowest affinity of the series
with IC50 ) 0.4 µM, indicating that a tertiary amine
center may be important for high-affinity binding at the
DAT.
Exp er im en ta l Section
Ch em ica l Meth od s. Melting points were determined on a
Mel-Temp II capillary apparatus and are reported uncorrected.
Elemental analyses were obtained from Atlantic Microlabs,
Atlanta, GA, and were determined to be within (0.4% of the
theoretical values for carbon, hydrogen, and nitrogen. CI-MS
(chemical ionization mass spectra) was performed using a
Finnigan 1015 mass spectrometer. 1H NMR spectra were
obtained on
a Varian XL-300 spectrometer using CDCl3
solutions of free bases. All the chemical shifts reported are
relative to a tetramethylsilane (TMS) internal reference in
ppm on the δ scale. Thin-layer chromatography (TLC) was
performed on Analtech GHLF silica gel plates (250 microns)
with a solvent system of 90:9:1 CHCl3/MeOH/concentrated
NH4OH unless otherwise indicated. No attempt was made to
optimize the reaction yields reported. The physical properties
of the ligands synthesized are given in Table 1.
Meth od A: N-Dem eth yla tion . A solution of the N-methyl
compound, 1.2 equiv of 2,2,2-trichloroethyl chloroformate, and

Binding Properties of Bridged Piperazine Analogues
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25 4845
Ta ble 2. Binding Affinities at the DAT and SERT Labeled with [125I]RTI-55 and DA and 5-HT Reuptake Inhibition of GBR
Analogues
binding IC50 ((SEM, nM)
reuptake ((SEM, nM)
[3H]DA [3H]5-HT
5-HT/DA ratio
no.
DAT
5-HT
binding
reuptake
6
7
111 ( 6
8.0 ( 0.2
18 ( 1
6400 ( 600
705 ( 24
740 ( 19
277 ( 7
1140 ( 190
9.6 ( 0.2
24 ( 1
13700 ( 930
898 ( 51
1390 ( 70
506 ( 20
645 ( 27
299 ( 8
58
88
42
34
74
27
12
33
29
14
3
12
93
58
27
16
13
10
40
33
17
5
1.5
6.6
47
15
26
44
46
10
11
16
17
18
19
23
24
25
26
28
29
30
32
33
8.2 ( 0.2
1.4 ( 0.1
5.5 ( 0.4
4.0 ( 0.2
12 ( 0.5
1170 ( 30
121 ( 4
223 ( 8
127 ( 3
307 ( 19
89 ( 4
19 ( 1
104 ( 4
40 ( 7
146 ( 4
46 ( 1
24 ( 1
28 ( 1
268 ( 8
395 ( 23
33 ( 5 (µM)
1697 ( 108
720 ( 38
203 ( 33
17 ( 2 (µM)
1903 ( 71
6060 ( 230
1320 ( 40
843 ( 25
126 ( 5
24 ( 2
968 ( 30
28 ( 1 (µM)
2150 ( 70
912 ( 34
173 ( 7
6154 ( 375
1667 ( 117
3960 ( 120
2300 ( 100
2080 ( 130
73 ( 2
830 ( 37
125 ( 10
198 ( 15
113 ( 6
928 ( 48
36 ( 2
1.6
56
21
14
41
6.5
25
431 ( 12
32 ( 1
130 ( 6
3.7 ( 0.4
260 ( 8
87 ( 8
47 ( 1
7.3 ( 0.2
3 (GBR 12909)a
a
Data from ref 46.
1.5 equiv of K2CO3 in dry toluene (10 mmol of N-methyl
compound in 100 mL of solvent) was heated at reflux over-
night. The light brown colored solution was washed with
water, extracted with 15% aqueous citric acid solution twice,
washed with water and brine, dried over Na2SO4 and evapo-
rated to give a dark brown colored oil. The oil was dissolved
in CH2Cl2 and filtered through a silica gel plug to remove polar,
colored impurities, and a light yellow oil was collected after
evaporation of the filtrate. To the obtained oil in acetic acid
(10 mmol of carbamate in 100 mL of 99.7% HOAc) was added
zinc powder (50 mmol), and the suspension was allowed to stir
at room temperature vigorously until TLC showed the disap-
pearance of the carbamate. The solvent was evaporated on a
rotavapor with an equal volume of toluene, and the residue
was dissolved in methylene chloride. The solution containing
a small amount of zinc powder was extracted three times with
15% aqueous citric acid. The combined aqueous layer was
washed once with CH2Cl2, basified with concentrated NH4OH,
and extracted three times with CH2Cl2. The organic layer was
washed with water, brine, dried over Na2SO4, and evaporated
to give the N-demethylated product as light yellow oil.
Meth od B: N-Acyla tion . A solution of the carboxylic acid
and dimethylaminopropylethylcarbodiimide (EDCI) in CH2Cl2
was allowed to stir at room temperature for 5 min before a
solution of the amino compound in CH2Cl2 was added. The
mole ratio of amine to acid to EDCI was approximately 1:1.25:
1.5. The reaction mixture was stirred at room temperature,
overnight, at which time TLC showed the completion of the
reaction. The mixture was then washed with saturated aque-
ous NaHCO3 twice, water once, brine once and dried over Na2-
SO4. A yellow oil was obtained after the solution was evapo-
rated. The crude product was then purified on a silica gel
column with 15:1 CHCl3/MeOH to give the desired amide as
light yellow oil.
Meth od C: Am id e Red u ction . A solution of the amide in
the minimum amount of THF was added dropwise to a stirred,
freshly prepared solution of 1 M AlH3 in THF.55 The molar
ratio of amide to AlH3 was about 1:5. The reaction mixture
was stirred at room temperature or in an ice water bath until
TLC showed the disappearance of the amide (<0.5 h). The
mixture was then poured slowly into a 15% aqueous NaOH
solution in an ice-water bath. The layers were separated and
the aqueous layer was extracted with CH2Cl2 three times. The
combined organic layer was then washed with water and brine,
dried over Na2SO4, and evaporated to give the corresponding
amino compound in free base form. The crude product was
then purified through crystallization of the salt in a specified
solvent (Table 1). Column chromatography was performed
(with 150:10:1 CHCl3/MeOH/concentrated NH4OH) prior to
salt formation if necessary.
Meth od D: N-Alk yla tion . A solution of amine, alkyl
iodide, and K2CO3 in THF was heated at reflux overnight,
when TLC showed the completion of the reaction. The molar
ratio of amine to alkyl iodide and K2CO3 was about 1:1.5:2.
THF was then evaporated, and the mixture was dissolved in
CH2Cl2, washed with water and brine, and dried over Na2SO4.
The solution was evaporated to give the desired crude product,
which was purified by salt formation or column chromatog-
raphy prior to salt formation.
8-Meth yl-3,8-d ia za bicyclo[3.2.1]octa n e (5). Prepared ac-
cording to the literature method with some modification.47-49
A solution of 20.0 g (82 mmol) of 3-benzyl-8-methyl-3,8-diaza-
[3.2.1]bicyclooctane-2,4-dione in 60 mL of anhydrous THF was
added to 200 mL of 0.5 M freshly prepared AlH3 in THF while
cooling in an ice water bath. The mixture was allowed to stir
at 0 °C until TLC showed the disappearance of imide. The
reaction was quenched by pouring the mixture into 300 mL of
ice cold 15% aqueous NaOH solution. The layers were sepa-
rated and the aqueous phase was extracted with ethyl acetate
several times. The combined organic layer was washed with
water once, brine once and dried over Na2SO4. Evaporation of
the solution gave 11.5 g of 3-benzyl-8-methyl-3,8-diazabicyclo-
[3.2.1]octane as a yellow oil in 65% yield: CI-MS 217 (M + 1).
To a solution of 3.8 g of 3-benzyl-8-methyl-3,8-diazabicyclo-
[3.2.1]octane in 100 mL of ethanol was added 1.9 g of 10% Pd/C
under Ar, and the mixture was hydrogenated on a Parr
reduction apparatus. The catalyst was filtered off through
Celite after TLC showed the completion of the reaction, and
the product in EtOH was converted to its HCl salt by
treatment with 20 mL of 4 M HCl in methanol. White crystals
were collected after vacuum filtration (1.9 g, 54% overall yield,
reduction and salt formation).
3-{2-[Bis(4-flu or op h en yl)m eth oxy]eth yl}-8-m eth yl-3,8-
d ia za bicyclo[3.2.1]octa n e (7). To a suspension of 0.79 g (4.0
mmol) of 5 (HCl salt) and 0.80 g of triethylamine in 20 mL of
toluene were added 2.24 g (2 equiv) of 2-[bis(4-fluorophenyl)-
methoxy]ethyl chloride and 1 g of K2CO3. The mixture was
heated at reflux for 2 days, when TLC showed only a small
amount of starting piperazine 5. The reaction solution was
washed with water, then extracted with 15% aqueous citric
acid solution until TLC showed no product present in the
organic layer. The extracts were combined and basified with
concentrated NH4OH to pH 9. The cloudy solution was then
extracted with CH2Cl2 three times. The organic layer was
washed with water, brine, dried over Na2SO4, and evaporated
to give 0.40 g of product as a light brown colored oil, which
was converted to its oxalic acid salt in acetone to give 0.50 g
of light yellow colored solid: CI-MS (NH3) m/z 373 (M + 1);
1H NMR (CDCl3) δ 7.28 (m, 4H, ArH), 7.01 (t, J ) 8.8 Hz, 4H,
ArH), 5.34 (s, 1H, ArCHAr), 3.49 (t, J ) 5.9 Hz, 2H, OCH2),

4846 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25
Zhang et al.
3.06 (brs, 2H, NCH), 2.60 (t, J ) 5.8 Hz, 4H, NCH2), 2.38 (d,
J ) 10.5 Hz, 2H, NCH2), 2.27 (s, 3H, NCH3), 1.76-1.92 (m,
4H).
(CDCl3) δ 7.84 (d, J ) 14.7 Hz, 1H, olefinic H), 7.27 (m, 6H,
ArH), 7.01 (m, 4H, ArH) 6.55 (d, J ) 14.7 Hz, 2H, ArH +
olefinic H), 5.31 (s, 1H, ArCHAr), 4.73 (d, J ) 5.1 Hz, 1H,
NCH), 4.30 (brs, 1H, NCH), 3.51 (t, J ) 5.4 Hz, 2H, OCH2),
2.75 (m, 2H, NCH2) 2.65 (t, J ) 5.9 Hz, 2H, NCH2), 2.44 (m,
2H, NCH2), 1.91 (m, 4H).
1-(3-{2-[B i s (4-flu o r o p h e n y l)m e t h o x y ]e t h y l}-3,8-
d ia za bicyclo[3.2.1]oct-8-yl)-3-p yr id in -3-ylp r op en on e (15).
Synthesized from 9 with trans-3-(3-pyridyl)acrylic acid accord-
ing to method B. The compound was purified by column
chromatography using 30:1 CH2Cl2:MeOH and was obtained
as a yellow oil: CI-MS(NH3) m/z 490 (M + 1); 1H NMR (CDCl3)
δ 8.77 (s, 1H, ArH), 8.58 (d, J ) 4.0 Hz, 1H, ArH), 7.83 (dt, J
) 7.8 Hz, J ) 1.9 Hz, 1H, ArH), 7.77 (d, J ) 15.6 Hz, 1H,
olefinic H), 7.27 (m, 5H, ArH), 7.01 (m, 4H, ArH), 6.89 (d, J )
15.6 Hz, 1H, olefinic H), 5.31 (s, 1H, ArCHAr), 4.75 (d, J )
5.9 Hz, 1H, NCH), 4.32 (brs, 1H, NCH), 3.51 (t, J ) 5.9 Hz,
2H, OCH2), 2.79 (m, 2H, NCH2) 2.65 (t, J ) 5.9 Hz, 2H, NCH2),
2.44 (m, 2H, NCH2), 1.94 (m, 4H).
3-[2-(Dip h en ylm et h oxy)et h yl]-8-m et h yl-3,8-d ia za b i-
cyclo[3.2.1]octa n e (6). Synthesized by N-alkylation of 5 with
2-[diphenylmethoxy]ethyl chloride according to the method
described above for 7. The obtained product was further
purified by preparing its HBr salt in ethanol resulting an off-
white colored solid that was collected after vacuum filtration:
CI-MS (NH3) m/z 337 (M + 1); 1H NMR (CDCl3) δ 7.34 (m,
10H, ArH), 5.38 (s, 1H, ArCHAr), 3.54 (t, J ) 5.9 Hz, 2H,
OCH2), 3.14 (brs, 2H, NCH), 2.65 (m, 4H, NCH2), 2.54 (d, J )
10.8 Hz, 2H, NCH2), 2.34 (s, 3H, NCH3), 1.87 (m, 4H).
3-{2-[Bis(4-flu or op h e n yl)m e t h oxy]e t h yl}-3,8-d ia za -
bicyclo[3.2.1]octa n e (9). Prepared from N-demethylation of
1
7 according to method A: CI-MS (NH3) m/z 359 (M + 1); H
NMR (CDCl3) δ 7.28 (dd, J ) 8.6 Hz, J ) 3.0 Hz, 4H, ArH),
7.01 (t, J ) 8.7 Hz, 4H, ArH), 5.34 (s, 1H, ArCHAr), 3.50 (t, J
) 5.9 Hz, 2H, OCH2), 3.42 (brs, 2H, NCH) 2.67 (dd, J ) 11.0
Hz, J ) 1.6 Hz, 2H, NCH2), 2.59 (t, J ) 5.9 Hz, 2H, NCH2),
2.26 (d, J ) 10.8 Hz, 2H, NCH2), 1.69-1.89 (m, 4H).
3-{2-[Bis(4-flu or op h en yl)m eth oxy]eth yl}-8-(1H-in d ol-
2-ylm et h yl)-3,8-d ia za bicyclo[3.2.1]oct a n e (16). Synthe-
sized from 12 according to method C: CI-MS(NH3) m/z 488
(M + 1); 1H NMR (CDCl3) δ 7.54 (d, J ) 7.8 Hz, 1H, ArH),
7.37 (d, J ) 7.8 Hz, 1H, ArH), 7.27 (dd, J ) 8.7 Hz, J ) 3.0
Hz, 4H, ArH), 7.16 (t, J ) 7.4 Hz, 1H, ArH), 7.10 (t, J ) 7.4
Hz, 1H, ArH), 7.01 (t, J ) 8.9 Hz, 4H, ArH), 6.30 (s, 1H, ArH),
5.34 (s, 1H, ArCHAr), 3.67 (s, 2H, ArCH2N), 3.50 (t, J ) 5.9
Hz, 2H, OCH2), 3.11 (bs, 2H, NCH) 2.62 (t, J ) 5.9 Hz, 2H,
NCH2), 2.61 (s, 2H, NCH2), 2.38 (m, 2H, NCH2), 1.83 (m, 4H).
3-{2-[Bis(4-flu or op h en yl)m eth oxy]eth yl}-8-(3-fu r a n -2-
ylallyl)-3,8-diazabicyclo[3.2.1]octan e (17). Synthesized from
3-[2-(Dip h en ylm eth oxy)eth yl]-8-(3-p h en ylp r op yl)-3,8-
d ia za [3.2.1]bicycloocta n e (10). N-Demethylation of 6 ac-
cording to method A afforded 3-[2-(diphenylmethoxy)ethyl]-
3,8-diazabicyclo[3.2.1]octane (8) in 77% yield. To a solution of
300 mg (0.93 mmol) of 8 in 10 mL of CH2Cl2 was added 160
µL of hydrocinnamoyl chloride, and the mixture was allowed
to stir at room temperature for 0.5 h, when TLC showed the
completion of the reaction. The reaction mixture was washed
with 10% aqueous NaOH, water, brine, dried over Na2SO4, and
evaporated to give a product mixture as a light yellow oil. The
oil was purified on a preparative TLC plate with 100:10:1
CHCl3/MeOH/concentrated NH4OH to give 339 mg of the
amide in 80% yield: CI-MS(NH3) m/z 455 (M + 1). This amide
then underwent an alane reduction according to method C to
give the desired compound 10: CI-MS (NH3) m/z 441 (M + 1);
1H NMR (CDCl3) δ 7.34 (m, 15H, ArH), 5.39 (s, 1H, ArCHAr),
3.53 (t, J ) 5.9 Hz, 2H, OCH2), 3.12 (brs, 2H, NCH), 2.62 (m,
6H, NCH2 + ArCH2), 2.35 (m, 4H, NCH2), 1.78 (m, 6H).
3-{2-[Bis-(4-flu or op h en yl)m eth oxy]eth yl}-8-(3-p h en yl-
p r op yl)-3,8-d ia za bicyclo[3.2.1]octa n e (11). Synthesized ac-
cording to the same procedure as 10: CI-MS (NH3) m/z 477
1
13 according to method C: CI-MS (NH3) m/z 465 (M + 1); H
NMR (CDCl3) δ 7.27 (m, 5H, ArH + olefinic H), 7.01 (t, J )
8.9 Hz, 4H, ArH), 6.21-6.37 (m, 4H, ArH + olefinic H), 5.35
(s, 1H, ArCHAr), 3.50 (t, J ) 5.9 Hz, 2H, OCH2), 3.21 (brs,
2H, NCH), 3.13 (d, J ) 6.0 Hz, 2H, NCH2), 2.62 (m, 4H, NCH2),
2.42 (m, 2H, NCH2), 1.83 (m, 4H).
3-{2-[Bis(4-flu or oph en yl)m eth oxy]eth yl}-8-(3-th ioph en -
2-yla llyl)-3,8-d ia za bicyclo[3.2.1]octa n e (18). Synthesized
from 14 according to method C: CI-MS (NH3) m/z 481 (M +
1
1); H NMR (CDCl3) δ 7.27 (m, 5H, ArH), 7.14 (m, 1H, ArH),
7.01 (m, 5H, ArH) 6.63 (d, J ) 15.6 Hz, 1H, olefinic H), 6.15
(dt, J ) 15.6 Hz, J ) 6.8 Hz, 1H, olefinic H), 5.35 (s, 1H,
ArCHAr), 3.50 (t, J ) 5.9 Hz, 2H, OCH2), 3.21 (brs, 2H, NCH),
3.11 (d, J ) 6.8 Hz, 2H, NCH2), 2.62 (m, 4H, NCH2), 2.41 (t, J
) 10.7 Hz, 2H, NCH2), 1.83 (m, 4H).
1
(M + 1); H NMR (CDCl3) δ 7.15-7.29 (m, 9H, ArH), 7.00 (t,
J ) 8.7 Hz, 4H, ArH), 5.34 (s, 1H, ArCHAr), 3.48 (t, J ) 5.9
Hz, 2H, OCH2), 3.18 (brs, 2H, NCH) 2.61 (m, 6H, NCH2
ArCH2), 2.40 (m, 4H, NCH2), 1.78 (m, 6H).
+
(3-{2-[Bis(4-flu or op h en yl)m et h oxy]et h yl}-3,8-d ia za -
bicyclo[3.2.1]oct-8-yl)(1H-in d ol-2-yl)m eth a n on e (12). Syn-
thesized from acylation of 9 with indole-2-carboxylic acid
according to method B: mp 56 °C; CI-MS (NH3) m/z 502 (M +
3-{2-[Bis(4-flu or op h en yl)m eth oxy]eth yl}-8-(3-p yr id in -
3-yla llyl)-3,8-d ia za bicyclo[3.2.1]octa n e (19). Synthesized
from 15 according to method C: CI-MS (NH3) m/z 476 (M +
1
1); H NMR (CDCl3) δ 8.58 (d, J ) 2.0 Hz, 1H, ArH), 8.47 (d,
1
1); H NMR (CDCl3) δ 7.66 (d, J ) 7.8 Hz, 1H, ArH), 7.44 (d,
J ) 4.9 Hz, 1H, ArH), 7.73 (d, J ) 7.8 Hz, 1H, ArH), 7.27 (m,
5H, ArH), 7.01 (t, J ) 8.8 Hz, 4H, ArH) 6.48 (m, 2H, olefinic
H), 5.34 (s, 1H, ArCHAr), 3.50 (t, J ) 5.9 Hz, 2H, OCH2), 3.22
(m, 4H, NCH2), 2.64 (m, 4H, NCH2), 2.47 (m, 2H, NCH2), 1.87
(m, 4H).
2-[Bis(4-flu or op h en yl)m eth oxy]eth yl Iod id e (20). So-
dium iodide (4.5 g,1.5 equiv) was added to a solution of 5.65 g
(20 mmol) 2-[bis(4-fluorophenyl)methoxy]ethyl chloride in 50
mL of acetone, and the reaction mixture was heated at reflux
overnight. The yellow solution with white precipitate was
evaporated and suspended in dry chloroform. The solution was
filtered through Celite and the filtrate was then evaporated
to give 7.36 g of 20 as a brown colored oil in 94% yield: 1H
NMR (CDCl3) δ 7.30 (m, 4H, ArH), 7.02 (t, J ) 8.7 Hz, 4H,
ArH), 5.39 (s, 1H, ArCHAr), 3.69 (t, J ) 6.6 Hz, 2H, OCH2),
3.30 (t, J ) 6.7 Hz, 2H, ICH2).
(1S,4S)-2-[2-(Dip h e n ylm e t h oxy)e t h yl]-5-m e t h yl-2,5-
d ia za bicyclo[2.2.1]h ep ta n e (23). Alkylation of (1S,4S)-N-t-
Boc-2,5-diazabicyclo[2.2.1]heptane with 2-(diphenylmethoxy)-
ethyl iodide was carried out according to method D and gave
(1S,4S)-2-[2-(diphenylmethoxy)ethyl]-5-t-Boc-2,5-diazabicyclo-
[2.2.1]heptane (21) in 98% yield: CI-MS (NH3) m/z 409 (M +
1). A solution of 1.00 g (2.5 mmol) of 21 in 10 mL of anhydrous
THF was then added slowly via an addition funnel to a
J ) 7.8 Hz, 1H, ArH), 7.29 (m, 6H, ArH), 7.15 (t, J ) 6.9 Hz,
1H, ArH) 7.01 (t, J ) 8.7 Hz, 4H, ArH), 6.81 (s, 1H, ArH),
5.33 (s, 1H, ArCHAr), 4.86 (brs, 2H, NCH), 3.55 (t, J ) 5.9
Hz, 2H, OCH2), 2.84 (brs, 2H, NCH2) 2.70 (t, J ) 5.9 Hz, 2H,
NCH2), 2.59 (bs, 2H, NCH2), 2.00 (m, 4H).
1-(3-{2-[Bis(4-flu or op h e n yl)m e t h oxy]e t h yl}-3,8-d i-
azabicyclo[3.2.1]oct-8-yl)-3-fu r an -2-ylpr open on e (13). Syn-
thesized from acylation of 9 with 2-furylacrylic acid according
to method B. The compound was purified by column chroma-
tography using 100:1 CHCl3:MeOH and was obtained as a light
yellow oil: CI-MS (NH3) m/z 479 (M + 1); 1H NMR (CDCl3) δ
7.46 (d, J ) 14.7 Hz, 1H, olefinic H), 7.27 (m, 5H, ArH), 7.01
(t, J ) 9.2 Hz, 4H, ArH) 6.66 (d, J ) 15.6 Hz, 1H, olefinic H),
6.55 (1H, ArH), 6.47 (m, 1H, ArH), 5.31 (s, 1H, ArCHAr), 4.73
(d, J ) 6.0 Hz, 1H, NCH), 4.34 (brs,1H, NCH), 3.51 (t, J ) 5.9
Hz, 2H, OCH2), 2.76 (m, 2H, NCH2) 2.65 (t, J ) 5.4 Hz, 2H,
NCH2), 2.43 (m, 2H, NCH2), 1.91 (m, 4H).
1-(3-{2-[B i s (4-flu o r o p h e n y l)m e t h o x y ]e t h y l}-3,8-
diazabicyclo[3.2.1]oct-8-yl)-3-th ioph en -2-ylpr open on e (14).
Synthesized from acylation of 9 with 3-(2-thienyl)acrylic acid
according to method B. The compound was purified by column
chromatography using 100:1 CHCl3:MeOH and was obtained
as a colorless oil: CI-MS (NH3) m/z 495 (M + 1); 1H NMR

Binding Properties of Bridged Piperazine Analogues
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25 4847
refluxing solution of 1.0 M LiAlH4 in THF, and the solution
was allowed to reflux for another 2 h, when TLC showed the
completion of the reaction. After the mixture was allowed to
cool to room temperature, the reaction was quenched by
addition of 40 mL brine and 5 g of sodium potassium tartrate.
The layers were separated and the aqueous layer was ex-
tracted with chloroform. The combined organic layer was
washed with water, brine, dried over Na2SO4, and evaporated
to give 0.70 g of 23 as a light yellow colored oil in 90% yield.
The compound was purified via salt formation with oxalic acid
in ethanol to give 0.90 g of first crop as a white solid: CI-MS
(NH3) m/z 323 (M + 1); 1H NMR (CDCl3) δ 7.33 (m, 10H, ArH),
5.37 (s, 1H, ArCHAr), 3.55 (t, J ) 6.3 Hz, 2H, OCH2), 3.35
(brs, 1H, NCH), 3.17 (bs, 1H, NCH), 2.82 (m, 6H, NCH2), 2.38
(s, 3H, NCH3), 1.71 (m, 2H).
4H, NCH2), 2.42 (s, 3H, NCH3), 1.80-2.20 (m, 4H), 1.61 (m,
2H).
(()-3-[2-(Diph en ylm eth oxy)eth yl]-3,9-diazabicyclo[4.2.1]-
n on a n e (30). Synthesized from 3-[2-(diphenylmethoxy)eth-
yl]-3,9-diazabicyclo[4.2.1]nonane (28) according to method A:
CI-MS (NH3) m/z 337 (M + 1); 1H NMR (CDCl3) δ 7.31 (m,
10H, ArH), 5.36 (s, 1H, ArCHAr), 3.68 (t, J ) 7.3 Hz, 1H,
NCH), 3.53 (t, J ) 5.9 Hz, 3H, NCH + OCH2), 2.77 (t, J ) 5.9
Hz, 2H, NCH2), 2.66 (dd, J ) 7.8 Hz, J ) 2.9 Hz, 2H, NCH2),
2.59 (brs, 2H, NCH2), 1.67 (m, 6H).
(()-3-{2-[Bis(4-flu or op h e n yl)m e t h oxy]e t h yl}-3,9-d i-
a za bicyclo[4.2.1]n on a n e (31). Synthesized from 3-{2-[bis-
(4-fluorophenyl)methoxy]ethyl}-9-methyl-3,9-diazabicyclo[4.2.1]-
nonane (29) according to method A: CI-MS (NH3) m/z 373 (M
1
+ 1); H NMR (CDCl3) δ 7.29 (m, 4H, ArH), 7.01 (t, J ) 8.8
Hz, 4H, ArH), 5.33 (s, 1H, ArCHAr), 3.66 (t, J ) 7.3 Hz, 1H,
NCH), 3.54 (d, J ) 7.8 Hz, 1H, NCH), 3.49 (t, J ) 5.9 Hz, 2H,
OCH2), 2.75 (t, J ) 5.9 Hz, 2H, NCH2), 2.63 (m, 2H, NCH2),
2.56 (d, J ) 2.9 Hz, 2H, NCH2), 1.65 (m, 6H).
(()-3-[2-(Dip h en ylm eth oxy)eth yl]-9-(3-p h en ylp r op yl)-
3,9-d ia za bicyclo[4.2.1]n on a n e (32). Prepared from 3-[2-
(diphenylmethoxy)ethyl]-9-methyl-3,9-diazabicyclo[4.2.1]-
nonane (30) according to method D: CI-MS (NH3) m/z 455 (M
+ 1); 1H NMR (CDCl3) δ 7.33 (m, 15H, ArH), 5.37 (s, 1H,
ArCHAr), 3.51 (t, J ) 5.9 Hz, 2H, OCH2), 3.32 (t, J ) 7.5 Hz,
1H, NCH), 3.22 (d, J ) 7.5 Hz, 1H, NCH), 2.73 (t, J ) 6.5 Hz,
2H, NCH2), 2.63 (m, 8H, NCH2 + ArCH2), 1.43-2.06 (m, 8H).
(()-3-{2-[B is (4-flu o r o p h e n y l)m e t h o x y ]e t h y l}-9-(3-
p h en ylp r op yl)-3,9-d ia za bicyclo[4.2.1]n on a n e (33). Pre-
pared by N-demethylation of 3-{2-[bis(4-fluorophenyl)methoxy]-
ethyl}-9-methyl-3,9-diazabicyclo[4.2.1]nonane (29) according
to method A, followed by an N-alkylation according to method
D: CI-MS (NH3) m/z 490 (M + 1); 1H NMR (CDCl3) δ 7.27 (m,
9H, ArH), 7.01 (t, J ) 8.8 Hz, 4H, ArH), 5.33 (s, 1H, ArCHAr),
3.47 (t, J ) 5.9 Hz, 2H, OCH2), 3.34 (t, J ) 7.3 Hz, 1H, NCH),
3.23 (d, J ) 7.8 Hz, 1H, NCH), 2.72 (t, J ) 5.9 Hz, 2H, NCH2),
2.63 (m, 8H, NCH2 + ArCH2), 1.40-2.08 (m, 8H).
Biologica l Meth od s. Binding assays for the DAT and
SERT followed published procedures46 and used 0.01 nM [125I]-
RTI-55 (s.a. ) 2200 Ci/mmol). Briefly, 12 × 75 mm polystyrene
test tubes were prefilled with 100 µL of drug, 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/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),
EDTA (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(ethylenimine).
The [3H]DA and [3H]5-HT uptake assays also proceeded
according to published procedures.46 Briefly, synaptosomes
were prepared by homogenization of rat caudate (for [3H]DA
reuptake) or whole rat brain minus cerebellum (for [3H]5-HT
reuptake) in ice-cold 10% sucrose, using a Potter-Elvehjem
homogenizer. After a 1000g centrifugation for 10 min at 4 °C,
the supernatants were retained on ice. The uptake assays were
initiated by the addition of 100 µL of synaptosomes to 12 ×
75 mm polystyrene test tubes prefilled with 750 µL of [3H]DA
or [3H]5-HT (final concentration of 5 nM and 2 nM, respec-
tively) in a Krebs-phosphate buffer (pH 7.4), which contained
ascorbic acid (1 mg/mL) and pargyline (50 µM) (buffer), 100
µL of test drugs made up in buffer, and 50 µL of buffer. The
nonspecific uptake of each [3H]ligand was measured by
incubations in the presence of 1 µM 3 ([3H]DA) and 10 µM
fluoxetine ([3H]5-HT). The incubations were terminated after
20 min ([3H]DA) or 30 min ([3H]5-HT) incubation at 25 °C by
adding 4 mL of wash buffer (10 mM Tris-HCl, pH 7.4,
containing 0.9% NaCl at 25 °C) followed by rapid filtration
over Whatman GF/B filters and one additional wash cycle. The
Krebs-phosphate buffer contained 154.5 mM NaCl, 2.9 mM
(1S,4S)-3-{2-[Bis(4-flu or oph en yl)m eth oxy]eth yl]-5-m eth -
yl-2,5-diazabicyclo[2.2.1]h eptan e (24). Alkylation of (1S,4S)-
N-t-Boc-2,5-diazabicyclo[2.2.1]heptane with 2-(bis(4-fluoror-
phenyl)methoxy)ethyl iodide according to method D gave 3-[2-
[bis(4-fluorophenyl)methoxy]ethyl]-8-(1S,4S)-N-t-Boc-2,5-
diazabicyclo[2.2.1]heptane (22) in 91% yield: CI-MS(NH3) m/z
445 (M + 1). LAH reduction on 22 was then carried out
according to the same procedure used for 23 to afford 24 as a
light yellow oil in 95% yield. The oil was purified via salt
formation with oxalic acid in ethanol to give the first crop as
a white solid in 90% yield: CI-MS (NH3) m/z 359 (M + 1); 1H
NMR (CDCl3) δ 7.27 (dd, J ) 8.8 Hz, J ) 3.0 Hz, 4H, ArH),
7.03 (t, J ) 8.8 Hz, 4H, ArH), 5.33 (s, 1H, ArCHAr), 3.51 (t, J
) 5.9 Hz, 2H, OCH2), 3.33 (brs, 1H, NCH), 3.17 (bs, 1H, NCH),
2.55-2.85 (m, 6H, NCH2), 2.37 (s, 3H, NCH3), 1.70 (dd, J )
9.7 Hz, J ) 6.9 Hz, 2H).
(1S,4S)-2-[2-(Dip h en ylm eth oxy)eth yl]-5-(3-p h en ylp r o-
p yl)-2,5-d ia za bicyclo[2.2.1]h ep ta n e (25). (1S,4S)-2-[2-(Di-
phenylmethoxy)ethyl]-5-N-t-Boc-2,5-diazabicyclo[2.2.1]heptane
(21) was deprotected in 88% aqueous formic acid solution at
room temperature. After TLC showed the completion of the
reaction, the solution was extracted with CH2Cl2. The com-
bined organic layer was washed with water, brine, dried over
Na2SO4, and evaporated to give a light brown oil. The oil was
directly carried on to the N-alkylation step with 1-iodo-3-
phenylpropane without purification according to method D.
The crude product 25 was purified by salt formation with oxalic
acid in methanol to give the first crop as white solid: CI-MS
(NH3) m/z 427 (M + 1); 1H NMR (CDCl3) δ 7.33 (m, 15H, ArH),
5.37 (s, 1H, ArCHAr), 3.55 (t, J ) 6.3 Hz, 2H, OCH2), 3.35 (s,
1H, NCH), 3.29 (s, 1H, NCH), 2.49-2.87 (m, 10H, NCH2
ArCH2), 1.77 (tt, J ) 7.8 Hz, 2H), 1.70 (s, 2H).
+
(1S,4S)-2-{2-[Bis(4-flu or op h en yl)m eth oxy]eth yl}-5-(3-
p h en ylp r op yl)-2,5-d ia za bicyclo[2.2.1]h ep ta n e (26). Syn-
thesized from (1S,4S)-{2-[bis(4-fluorophenyl)methoxy]ethyl}-
5-N-t-Boc-2,5-diazabicyclo[2.2.1]heptane (22) according to the
procedure for 25: CI-MS (NH3) m/z 463 (M + 1); 1H NMR
(CDCl3) δ 7.28 (m, 9H, ArH), 7.01 (t, J ) 8.8 Hz, 4H, ArH),
5.33 (s, 1H, ArCHAr), 3.50 (t, J ) 5.9 Hz, 2H, OCH2), 3.31
(brs, 1H, NCH), 3.27 (bs, 1H, NCH), 2.43-2.87 (m, 10H, NCH2
+ ArCH2), 1.77 (tt, J ) 7.8 Hz, 2H), 1.68 (s, 2H).
(()-3-[2-(Dip h e n ylm e t h oxy)e t h yl]-9-m e t h yl-3,9-d i-
a za bicyclo[4.2.1]n on a n e (28). Synthesized by N-alkylation
of (()-9-methyl-3,9-diazabicyclo[4.2.1]nonane (27)51 with 2-(di-
phenylmethoxy)ethyl iodide according to method D: CI-MS
(NH3) m/z 351 (M + 1); 1H NMR (CDCl3) δ 7.34 (m, 10H, ArH),
5.37 (s, 1H, ArCHAr), 3.52 (t, J ) 5.9 Hz, 2H, OCH2), 3.21 (t,
J ) 7.8 Hz, 1H, NCH), 3.09 (d, J ) 8.8 Hz, 1H, NCH), 2.73 (t,
J ) 5.9 Hz, 2H, NCH2), 2.59 (m, 4H, NCH2), 2.42 (s, 3H,
NCH3), 1.38-2.17 (m, 6H).
(()-3-{2-[Bis(4-flu or op h en yl)m eth oxy]eth yl}-9-m eth yl-
3,9-d ia za bicyclo[4.2.1]n on a n e (29). Synthesized by N-alky-
lation of 9-methyl-3,9-diazabicyclo[4.2.1]nonane (27) with
2-[bis(4-fluorophenyl)methoxy]ethyl iodide according to method
D: CI-MS (NH3) m/z 387 (M + 1); 1H NMR (CDCl3) δ 7.28 (m,
4H, ArH), 7.01 (t, J ) 8.8 Hz, 4H, ArH), 5.33 (s, 1H, ArCHAr),
3.48 (t, J ) 5.9 Hz, 2H, OCH2), 3.21 (t, J ) 7.5 Hz, 1H, NCH),
3.10 (m, 1H, NCH), 2.77 (t, J ) 5.9 Hz, 2H, NCH2), 2.59 (m,

4848 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25
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Ack n ow led gm en t. The authors offer their sincere
appreciation to Noel Whittaker and Wesley White, LAC,
NIDDK, for performing mass spectral analyses of all the
compounds in this paper and acknowledge Dr. A.
Thurkauf of Neurogen Corp. for providing 3-benzyl-8-
methyl-3,8-diaza[3.2.1]bicyclooctane-2,4-dione. Y. Zhang
acknowledges the NIDDK Intramural Research Train-
ing Award Program for financial support. We also thank
the National Institute on Drug Abuse for partial support
of this research.
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