Novel N-substituted 3α-[bis(4'-fluorophenyl)methoxy]tropane analogues: Selective ligands for the dopamine transporter

Article abstract of DOI:10.1021/jm970525a

A series of N-substituted 3α-[bis(4'-fluorophenyl)methoxy]tropane analogues has been prepared that function as dopamine uptake inhibitors. The N-methylated analogue of this series had a significantly higher affinity for the dopamine transporter than the p

Full text of DOI:10.1021/jm970525a

J . Med. Chem. 1997, 40, 4329-4339
4329
Novel N-Su bstitu ted 3r-[Bis(4′-flu or op h en yl)m eth oxy]tr op a n e An a logu es:
Selective Liga n d s for th e Dop a m in e Tr a n sp or ter
Gregory E. Agoston, J ae H. Wu, Sari Izenwasser, Clifford George,† J onathan Katz, Richard H. Kline, and
Amy Hauck Newman*
Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health,
5500 Nathan Shock Drive, Baltimore, Maryland 21224, and Laboratory for the Structure of Matter,
Naval Research Laboratory, Washington, D.C. 20375-5000
Received August 7, 1997X
A series of N-substituted 3R-[bis(4′-fluorophenyl)methoxy]tropane analogues has been prepared
that function as dopamine uptake inhibitors. The N-methylated analogue of this series had a
significantly higher affinity for the dopamine transporter than the parent compound, N-methyl-
3R-(diphenylmethoxy)tropane (benztropine, Cogentin). Yet like the parent compound, it
retained high affinity for muscarinic receptors. A series of N-substituted compounds were
prepared from nor-3R-[bis(4′-fluorophenyl)methoxy]tropane via acylation followed by hydride
reduction of the amide or by direct alkylation. All compounds containing a basic tropane
nitrogen displaced [3H]WIN 35,428 at the dopamine transporter (Ki range ) 8.5-634 nM) and
blocked dopamine uptake (IC50 range ) 10-371 nM) in rat caudate putamen, whereas ligands
with a nonbasic nitrogen were virtually inactive. None of the compounds demonstrated high
binding affinity at norepinephrine or serotonin transporters. Importantly, a separation of
binding affinities for the dopamine transporter versus muscarinic m1 receptors was achieved
by substitution of the N-methyl group with other N-alkyl or arylalkyl substituents (eg. n-butyl,
allyl, benzyl, 3-phenylpropyl, etc.). Additionally, the most potent and selective analogue in
this series at the dopamine transporter, N-(4′′-phenyl-n-butyl)-3R-[bis(4′-fluorophenyl)methoxy]-
tropane analogue failed to substitute for cocaine in rats trained to discriminate cocaine from
saline. Potentially, new leads toward the development of a pharmacotherapeutic for cocaine
abuse and other disorders affecting the dopamine transporter may be discovered.
In tr od u ction
The cocaine recognition site on the dopamine trans-
porter has been the target for numerous compounds
with structural diversity. The majority of these com-
pounds have been based on cocaine or structural ana-
logues of WIN 35,428.1 These ligands have been
developed as probes to further elucidate the role of the
dopamine transporter in neurological disorders includ-
ing Parkinsonism, schizophrenia, and drug abuse. Co-
caine (1, Figure 1), a prototypic dopamine uptake
inhibitor, is a potent psychomotor stimulant and drug
of abuse. Despite its nonselective binding profile among
monoamine transporters, its mechanism of reinforcing
action appears to be related to the blockade of dopamine
reuptake into presynaptic terminals.2
Until recently, all of the dopamine uptake inhibitors
that have been evaluated behaviorally in animal models
F igu r e 1.
of psychomotor stimulant action demonstrated a cocaine-
like behavioral profile. However, we recently reported3
gence from cocaine and related tropane analogues.3,5 In
combination with the lack of psychomotor stimulant
effects of several of these compounds, a binding domain
on the dopamine transporter, not identical with that of
cocaine, was proposed to exist that may provide a
pharmacological target for a cocaine abuse medical
treatment.3,5
a series of 3R-(diphenylmethoxy)tropane analogues (2)
that were potent inhibitors of dopamine uptake but did
not produce cocaine-like efficacious locomotor stimula-
tion or cocaine-like subjective effects.4 Chemical modi-
fication at the 3-position of the tropane ring, and in
particular the aromatic ring substituents, yielded an
interesting series of compounds that bound with a range
of affinities (Ki range ) 11.8-2000 nM) to the dopamine
transporter. Additionally, the Ki values for binding
were well correlated to their potency for blocking
dopamine uptake.3b Structure-activity relationships
for this series of compounds revealed a striking diver-
The most potent compound in the initial series of
3-substituted tropane analogues was 3R-[bis(4′-fluo-
rophenyl)methoxy]tropane (3). This compound bound
to the dopamine transporter with a Ki value of 11.8 nM
and potently blocked dopamine uptake (IC50 ) 71 nM).3b
Additionally, compound 3 only partially substituted for
cocaine in rats trained to discriminate cocaine from
saline, at doses that were far higher than would be
† Naval Research Laboratory.
X Abstract published in Advance ACS Abstracts, December 1, 1997.
S0022-2623(97)00525-6 This article not subject to U.S. Copyright. Published 1997 by the American Chemical Society

4330 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Agoston et al.
Sch em e 1a
a
(a) RCOOH, DCC, 1-hydroxybenzotriazole hydrate, Et3N, DMF; (b) AlH3, THF; (c) RBr, K2CO3, DMF.
predicted based on its high affinity for the dopamine
transporter.6 In addition, this compound demonstrated
excellent selectivity over the serotonin and norepineph-
rine transporters (200- and 700-fold, respectively).
Despite the selectivity for the dopamine transporter over
the other monoamine transporters, substitution on the
aromatic rings of the 3-position did not significantly
decrease binding affinity at muscarinic receptors.3b
logues were prepared to further develop the structure-
activity relationships and compare them with other
structurally similar analogues at the dopamine trans-
porter. In addition, this study addresses whether di-
verse substitutions at the tropane nitrogen of 3R-[bis-
(4′-fluorophenyl)methoxy]tropane will provide selective
ligands for the dopamine transporter as compared to
muscarinic m1 sites.
The bis(4′-fluorophenyl)methoxy moiety is seen in
another series of potent dopamine uptake inhibitors, e.g.
1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpro-
pyl)piperazine (GBR 12,909, 4). Matecka et al.7 and
Dutta et al.8 recently reported an extensive structure-
activity relationship for a series of heteroaromatic and
piperazine-modified GBR 12,909 analogues. In addition
to the diphenylmethyl ether moiety, 3R-[bis(4′-fluo-
rophenyl)methoxy]tropane also resembles the GBR
series since the tropane ring can be considered a con-
formationally rigid congener of the GBR 12,909 pipera-
zine ring.9 Recently, Meltzer et al. described a series
of N-substituted 2-carbomethoxy-3-(diarylmethoxy)tro-
pane analogues and compared them to other tropane
and piperazine GBR 12,909-like dopamine transporter
ligands. The structure-activity relationships reported
for this series of compounds showed that they are more
GBR-like rather than cocaine-like despite the presence
of a tropane moiety.10 Notably, GBR 12,909 has not
been reported to have high affinity for muscarinic recep-
tors. Since the other terminal nitrogen of the piperazine
ring is substituted with a 3-phenyl-n-propyl group, it
was envisioned that perhaps substituting the N-methyl
group of GBR 12,909-like 3R-[bis(4′-fluorophenyl)-
methoxy]tropane with alkyl or arylalkyl substituents
may result in a compound that retains high affinity for
the dopamine transporter but has decreased muscarinic
receptor binding affinity. Therefore, a series of N-sub-
stituted 3R-[bis(4′-fluorophenyl)methoxy]tropane ana-
Ch em istr y
N-Substituted 3R-[bis(4′-fluorophenyl)methoxy]tro-
pane analogues were prepared by the following methods.
Nor-3R-[bis(4′-fluorophenyl)methoxy]tropane (5) was
prepared by demethylation of compound 3.11 Several
analogues, 7a -e, were prepared using an amidation
method with DCC and 1-hydroxybenzotriazole hydrate
(HOBt) to yield amide 6, which gave amine 7 upon
reduction with allane (Scheme 1). Alternatively, nor-
3R-[bis(4′-fluorophenyl)methoxy]tropane (5) could be
alkylated directly with the appropriate alkyl bromide
in DMF with potassium carbonate (Scheme 1, 8a -h ).12
The acetamide analogue 9, (Scheme 2) was prepared by
nor-3R-[bis(4′-fluorophenyl)methoxy]tropane (5) cou-
pling with acetyl chloride in chloroform and aqueous
bicarbonate under Schotten-Bauman conditions. For-
mamide analogue 10 (Scheme 2) preparation was ac-
complished with ethyl formate and formic acid. Sul-
fonamide analogues 11a ,b were synthesized by coupling
5 and the appropriate sulfonyl chloride in triethylamine
(Scheme 2).13 Finally, the quaternary iodide analogue
12 was prepared by stirring 5 with excess methyl iodide
in ethanol.
Quaternary analogue 12 structure was elucidated by
X-ray crystallography as shown in Figure 2. The bond
distances and angles for the cation for 12 are at expected
values. The 3R-bis(4′-fluorophenyl)methoxy substituent
is axial to the chair-shaped piperidine ring with the

Selective Ligands for the Dopamine Transporter
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4331
Sch em e 2a
caudate putamen. The compounds that demonstrated
moderate to high binding affinity (Ki < 108 nM) to the
dopamine transporter were further tested for binding
to serotonin and norepinephrine transporters, musca-
rinic m1 sites, and for inhibition of dopamine uptake
(Tables 1 and 2).
In general, a large variety of N-substitutions provid-
ing tertiary amines, including alkyl (e.g. n-butyl 8a , allyl
8c, and methyl 3) aromatic (phenylalkyl 7a ,c,d ,e, 8d ,e,
indole-3-ethyl 7b, and cinnamyl 8f), are tolerated at the
dopamine transporter binding site. None of the com-
pounds tested had high affinity for the norepinephrine
and serotonin transporters (Table 2). All compounds
tested inhibited dopamine uptake (Table 1), and their
potencies (IC50 values) significantly correlated with
binding to the dopamine transporter (r2 ) 0.452, p )
0.006).
Ligands containing a nonbasic nitrogen (amides 9, 10
and sulfonamides 11a ,b) did not effectively bind to the
dopamine transporter. This finding is in contrast to
recent reports by Kozikowski13 and Madras14 which
convey a nonbasic tropane nitrogen or non-nitrogen
bridge does not have a detrimental effect on dopamine
transporter affinity. However, our findings are in
agreement with prior studies by Abraham et al. con-
cluding a basic nitrogen is needed for high ligand
affinity to the dopamine transporter.15 One possible
explanation for a basic nitrogen requirement in this
series is that the bioactive form of tropane may be
protonated and interacts with the dopamine transporter
through an ionic attraction. In support of this notion,
the methiodide analogue 12 demonstrated only a 10-
fold decrease in binding affinity as compared to the
parent ligand 3. The modest decrease in binding
affinity might be explained by the addition of the steric
bulk of the additional methyl moiety. Recently, Meltzer
et al. reported on a series of oxytropane analogues of
WIN 35,428 that demonstrated high-affinity binding at
the dopamine transporter and supported the notion that
a basic tropane nitrogen was not necessary.16 However,
when the nitrogen in the tropane ring of the difluoropine
series was replaced with oxygen, a significant decrease
in binding resulted, supporting the findings in our
study. Future molecular modeling studies will address
the issues of sterics and charge of this ligand and its
parent compound.
a
(a) Acetyl chloride, NaHCO3(aq), CHCl3; (b) CH3CH2OCHO,
HCOOH; (c) RSO2Cl, Et3N, -10 °C.
Aromatic substituents and their distance from the
tropane nitrogen can have a significant effect on dopam-
ine transporter binding affinity. For example, as dis-
tance increases between the phenyl ring and tropane
nitrogen (benzyl 8d , 3-phenyl-n-propyl 7a , and 4-phenyl-
n-butyl 7c), a 10-fold increase in binding affinity to the
dopamine transporter (Ki ) 82.2 nM to Ki ) 8.51 nM)
is observed (Figure 3). Methods for obtaining centroid
distances are described in the Experimental Section.
Inhibition of dopamine uptake also follows an analogous
trend (IC50 range ) 285 to 39 nM). The most potent
and selective dopamine transporter ligand in this series
was the N-(4-phenyl-n-butyl) analogue 7c. Also of note,
phenyl ring substitution of the tropane nitrogen does
not appear to have a large effect on dopamine trans-
porter binding affinity as evidenced by a comparison of
ligands 7c and 7d , 7a and 7e. Bulky N-substituted
aromatic substituents (7b, 8h ) retain high binding
affinity to the dopamine transporter as well.
F igu r e 2. Thermal ellipsoid plot drawn from experimental
coordinates for 12.
phenyl groups orientation defined by torsions C3-O1-
C10-C1′ ) -104.9° and C3-O1-C10-C1′′ ) 132.4° as
anticlinal. This places the centroid of the phenyl rings
to N atom distances at 5.96 Å for the C1′ thru C6′
centriod and 7.54 Å for the C1′′ thru C6′′ centroid. The
dihedral angle between the phenyl rings is 79.1°. The
arrangement of 12 is similar to the previously reported
X-ray structure of parent compound 3.3b
Resu lts a n d Discu ssion
All compounds were tested for their displacement of
[3H]WIN 35,428 from the dopamine transporter in rat

4332 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Agoston et al.
Ta ble 1. N-Substituted 3R-[Bis(4′-fluorophenyl)methoxy]tropanes Binding to the Dopamine Transporter and Inhibition of Dopamine
Uptake
compd
no.
R substitution
4′′-phenyl-n-butyl
DAT, Ki, nM (% error)a
[3H]DAUa
7c
5
3
8.51 (14)
11.2 (11)
11.8 (11)b
20.2 (11)
24.6 (8)
39
H
9.7
methyl
4′′-(4′′′-nitrophenyl)-n-butyl
n-butyl
71b
7d
8a
8c
8b
7a
7b
8h
7e
8d
8f
8e
12
8g
10
9
650
370c
14
allyl
29.9 (10)
32.4 (9)
cyclopropylmethyl
3′′-phenyl-n-propyl
indole-3′′-ethyl
2′-{[(4′′-nitrophenyl)phenyl]methoxy}ethyl
3′′-(4′′′-fluorophenyl)-n-propyl
benzyl
cinnamyl
4′′-fluorobenzyl
dimethyl quaternary
2′′-[bis(4′′′-fluorophenyl)methoxy]ethyl
formyl
180
230
1200
NTe
NTe
290
180
200
130
NTe
5400
4600
NTe
NTe
41.9 (11)
44.6 (11)
57.0 (17)
60.7 (12)
82.2 (15)
86.4 (12)
95.6 (10)
108 (12)
634 (23)
2020 (13)
2340 (5)
18%d
acetyl
methylsulfonyl
p-tolylsulfonyl
11b
11a
0%d
a
b
Each Ki value represents data from at least three independent experiments, each performed in triplicate. Data from ref 4. c The
curve is significantly different from linearity; the IC50 value is only an estimate. Percent inhibition at 10 µM. e NT ) not tested.
d
Ta ble 2. N-Substituted 3-[Bis(4′-fluorophenyl)methoxy]tropane
Binding to Norepinephrine and Serotonin Transporters and
Muscarinic m1 Sites
cocaine occurred in the first 30 min after injection. In
contrast, over the first 30 min following injection, 7c
did not significantly increase locomotor activity to values
compd
no.
NET, Ki, 5-HTT, Ki, m1, Ki, nM
greater than obtained after vehicle injection (Figure 4).
In subjects trained to discriminate 10.0 mg/kg cocaine
from vehicle, there was a dose-related increase in the
percentage of responses emitted on the cocaine-ap-
propriate response key as cocaine dose was increased
from 1.0 to 10.0 mg/kg (Figure 5, circles). In contrast,
no dose of 7c produced a level of drug-appropriate
responding that exceeded 10%. This lack of appreciable
cocaine-like discriminative stimulus effects was ob-
tained across a range of doses from those having no
effect on response rates to those decreasing rates to
approximately 31% of control (saline) values. Together
these behavioral results indicate that 7c retained a
novel behavioral spectrum of action compared to that
of other dopamine uptake inhibitors. Further, these
results suggest that N-substitution in general, while
potentially decreasing affinity at muscarinic receptors,
does not render these compounds more similar to
cocaine with regard to their behavioral effects.
R substitution
nMa
NTe
nMa
(% error)
7c
5
3
4′′-phenyl-n-butyl
H
methyl
n-butyl
allyl
cyclopropylmethyl
3′′-phenyl-n-propyl
benzyl
cinnamyl
4′′-fluorobenzyl
NTe
483 (8)
156 (6)
9.00 (10)
251 (5)
126 (6)
136 (8)
136 (9)
773 (7)
238 (9)
611 (7)
29.1 (12)
12,300 (12)
NTe
>8000
>8500b
1330
5920
4790
3520
2080
577
2100
2440b
1730
1450
1190
375
8a
8c
8b
7a
8d
8f
8e
12
10
9
74%b
1490
NTe
60%b
dimethyl quaternary 38%c
79%c
1.6%c
1.3%c
formyl
acetyl
29.4%c
8.5%c
a
Data provided by NOVASCREEN and should be considered
preliminary. Data from ref 4. c Percent inhibition at 10 µM. e NT
) not tested.
b
Thus several members in this series of N-substituted
tropanes have comparable binding profiles for the
dopamine, serotonin, and norepinephrine transporters
as well as for inhibition of dopamine uptake compared
to the parent ligand 3. However, by substituting other
moieties for the methyl group, muscarinic affinity can
be significantly decreased while generally retaining the
other binding characteristics of 3. For example, nor-
ligand 5 has a 17-fold lower affinity for the muscarinic
m1 site compared to 3. Additionally, replacement of the
methyl group for other alkyl groups such as cyclopropyl
methyl (8b), allyl (8c), or n-butyl (8a ) lowers m1 binding
affinity by 14-, 15-, and 28-fold, respectively. Indeed,
the most potent and selective ligand in this series was
the N-(4-phenyl-n-butyl) analogue (7c) which had ap-
proximately the same affinity for the dopamine trans-
porter but was 54-fold lower affinity for the muscarinic
m1 sites compared to the parent ligand 3. This com-
pound was selected for in vivo evaluation.
Su m m a r y a n d Con clu sion s
A series of novel N-substituted 3R-[bis(4′-fluorophen-
yl)methoxy]tropane ligands have been synthesized and
tested for binding to the dopamine, norepinephrine, and
serotonin transporters, muscarinic m1 sites, and inhibi-
tion of dopamine uptake. Further, the most potent and
selective compound in this series, 7c, was evaluated for
cocaine-like behavioral effects. The structure-activity
relationships in this series demonstrate that the 3R-
(diphenylmethoxy)tropanes can tolerate a wide range
of N-substitutions and remain potent and selective
dopamine transporter ligands. This series of compounds
also suggests that a basic tropane nitrogen is required
for high affinity at the dopamine transporter. Impor-
tantly, a separation in the binding affinities of the
dopamine transporter versus muscarinic m1 sites was
achieved by making alkyl and arylalkyl substitutions
at the tropane nitrogen.
Cocaine, as has been demonstrated previously, in-
creased ambulatory activity to greater than 5000 counts
per 10 min at a dose of 20 mg/kg, with a higher dose
producing less stimulation. The maximal activity of
Molecular modeling studies using conformational
molecular field analysis (CoMFA) are being conducted

Selective Ligands for the Dopamine Transporter
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4333
F igu r e 3. Dopamine transporter binding affinities (Ki, nM) related to the distance between the phenyl ring (C1) of N-substitutent
and the tropane nitrogen of ligands 8d , 7a , and 7c.
F igu r e 4. Dose-dependent effects of 7c and cocaine on
locomotor activity in mice. Ordinates: horizontal activity
counts per 10 min. Abscissae: dose of drug in mg/kg, log scale.
Unfilled points above C represent the effects of saline or
propylene glycol vehicle controls. Each point represents the
average effect determined in eight mice, with error bars
representing (1 SEM. For those points that have no error bars
the symbol encompassed the error. The data are from the first
30-min period after drug administration, in which the greatest
stimulant effects were obtained.
F igu r e 5. Effects of 7c and cocaine in rats trained to
discriminate injections of cocaine from saline. Ordinates:
percentage of responses on the cocaine-appropriate lever.
Abscissae: drug dose in mg/kg (log scale). Top panel: percent-
age of responses emitted on the lever on which rats were
trained to respond after injections of cocaine. Bottom panel:
rates at which responses were emitted as a percentage of
response rate after saline administration. Each point repre-
sents the effect in three to six rats. Each point represents the
average effect determined in three to six rats, with error bars
representing (1 SEM. For those points that have no error bars
the symbol encompassed the error.
to design more potent and selective dopamine trans-
porter ligands and to provide insight into the 3R-[bis-
(4′-fluorophenyl)methoxy]tropane-dopamine transporter
binding domain. Currently, several of the N-substituted
analogues are being evaluated behaviorally in animal
models of psychomotor stimulant abuse. These com-
pounds may ultimately yield new leads toward the
development of a therapeutic for cocaine abuse/addic-
tion.
instrument. Samples were dissolved in an appropriate deu-
terated solvent (CDCl3 or CD3OD). Proton chemical shifts are
reported as parts per million (δ) relative to tetramethylsilane
(Me4Si; 0.00 ppm) which was used as an internal standard.
Mass spectra were recorded on a Hewlett-Packard (Palo Alto,
CA) 5971A mass selective ion detector in the electron-impact
mode with sample introduction via a HP-5890 series II, gas
chromatograph fitted with an HP-1 (cross-linked methyl
silicone gum) 25 m × 0.2 mm i.d., 50 µm film thickness.
Ultrapure grade helium was used as the carrier gas at a flow
rate of 1.2 mL/min. The injection port and transfer line
Exp er im en ta l Section
All melting points were determined on a Thomas-Hoover
melting point apparatus and are uncorrected. The 1H NMR
spectra were recorded on a Bruker (Billerica, Mass) AC-300

4334 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Agoston et al.
temperatures were 250 and 280 °C, respectively. The initial
oven temperature was 100 °C, held for 3.0 min, programmed
to 295 °C at 15.0 °C/min, and maintained at 295 °C for 10.0
min. Infrared spectra were recorded in KBr with a Perkin-
Elmer 1600 Series FTIR. Microanalyses were performed by
Atlantic Microlab, Inc. (Norcross, GA) and agree within (0.4%
of calculated values. TLC solvent used was CHCl3/MeOH/NH4-
OH; 90:10:1, unless otherwise indicated. All chemicals and
reagents were purchased from Aldrich Chemical Co. or Lan-
caster Synthesis, Inc. unless otherwise indicated and used
without further purification.
mg, 0.5 mmol, 46% from 5): mp 170-171 °C; 1H NMR (CDCl3)
δ 1.73-2.09 (m, 8H, H-2, 4, 6,7exo, H-CH2), 2.03-2.08 (m, 2H,
H-6,7endo), 2.34 (t, J ) 8 Hz, 2H, H-CH2Ar), 2.63 (t, J ) 8 Hz,
2H, N-CH3), 3.16 (br s, 2H, H-1,5), 3.50-3.55 (m, 1H, H-3eq),
5.36 (s, 1H, H-CAr2), 6.98 (m, 4H, H-Ar), 7.14-7.30 (m, 9H,
H-Ar); 13C NMR (75 MHz, CDCl3) δ 26.0, 30.5, 33.0, 35.6, 52.0,
57.9, 69.0, 79.0, 114.9, 115.2, 125.6, 128.2, 128.2, 128.3, 138.0,
143.0, 160.0, 163.0. Anal. (C29H32NOF2Cl) C, H, N.
N-(In d ole-3′′-eth yl)-3r-[bis(4′-flu or op h en yl)m eth oxy]-
tr op a n e Hyd r och lor id e (7b). 7b was prepared as in 7a
from 5 (660 mg, 2.0 mmol) and indole-3-acetic acid (390 mg,
2.2 mmol). After coupling and reduction, the crude amine was
converted to the HCl salt with a saturated solution of HCl/2-
PrOH. The product was dried under vacuum and recrystal-
lized from hot ethyl actetate to yield 7b (330 mg, 0.60 mmol,
36% from 5): mp > 230 °C; 1H NMR (300 MHz, CDCl3) δ 1.81-
2.02 (m, 6H, H-2,4ax,eq and H-6,7exo), 2.10-2.12 (m, 2H,
H-6,7endo), 2.65-2.71 (m, 2H, H-CH2), 2.92-2.97 (m, 2H,
H-NCH2), 3.32 (br s, 2H, H-1,5), 3.57 (t, J ) 5 Hz, 1H, H-3eq),
5.38 (s, 1H, H-CHAr2), 6.97-7.36 (m, 12H, H-Ar), 7.60 (d, J )
7.6 Hz, 1H, H-indole); 13C NMR (75 MHz, CDCl3) δ 24.5, 26.2,
35.5, 52.9, 58.4, 69.5, 79.5, 111.1, 115.1, 115.4, 118.7, 119.2,
121.4, 121.9, 127.4, 128.3, 128.4, 136.1, 138.6, 160.4, 163.6.
Anal. (C30H31N2OF2Cl‚1/4H2O) C, H, N.
N-(4′′-P h en yl-n -b u t yl)-3r-[b is(4′-flu or op h en yl)m et h -
oxy]tr op a n e Hyd r obr om id e (7c). 7c was prepared as in
7a from 5 (1.30 g, 4.0 mmol) and 4-phenylbutyric acid (730
mg, 4.4 mmol). The crude amine product was converted to
the HBr salt with a saturated solution HBr/methanol and
crystallized using methanol to give 7c (1.4 g, 2.6 mmol, 63%
from 5). 6c: 1H NMR (300 MHz, CDCl3) δ 1.93-2.05 (m, 8H,
H-2,4ax,eq, H-6,7exo, and H-CH2), 2.19-2.40 (m, 2H, H-6,7endo),
2.70 (app t, J ) 7.8, 7.3 Hz, 2H, H-CH2Ar), 3.68 (br t, 1H,
H-3eq), 4.05-4.08, 4.69-4.71 (m, total 2H, H-1,5), 5.42 (s, 1H,
H-CHAr2), 7.01-7.07 (m, 4H, H-Ar), 7.20-7.24 (m, 4H, H-Ar),
7.29-7.34 (m, 5H, H-Ar). 7c: mp 204-205 °C; 1H NMR (300
MHz, CDCl3) δ 1.61 (br s, 4H, H-CH2), 1.80-2.00 (m, 6H,
H-2,4ax,eq and H-6,7exo), 2.00-2.10 (m, 2H, H-6,7endo), 2.35-
2.45 (m, 2H, H-CH2Ar), 2.62 (m, 2H, H-NCH2), 3.20-3.30 (m,
2H, H-1,5), 3.57 (br s, 1H, H-3), 5.40 (s, 1H, H-CHAr2), 6.96-
7.02 (m, 4H, H-Ar), 7.15-7.26 (m, 9H, H-Ar); 13C NMR (75
MHz, CDCl3) δ 25.7, 26.9, 29.1, 35.1, 35.6, 51.8, 58.3, 68.9,
79.8, 115.2, 115.5, 125.6, 128.3, 128.4, 128.4, 138.2, 142.1,
160.5, 163.7. Anal. (C30H34NOF2Br) C, H, N.
Syn th esis. Nor -3r-[bis(4′-flu or op h en yl)m eth oxy]tr o-
p a n e Hyd r och lor id e (5). The hydrochloride salt of com-
pound 33 (10.9 g, 28.7 mmol) was converted to its free base
form by extracting with CHCl3 (3 × 50 mL) from 20% aqueous
NH4OH (100 mL), drying, and evaporating to an oil, which
solidified upon drying. Under an atmosphere of argon, the
crystalline free base was dissolved in 1,2-dichloroethane (100
mL, freshly distilled over P2O5). Anhydrous K2CO3 (15.9 g,
115 mmol) and 1-chloroethyl chloroformate (ACE-Cl, 16.5 g,
115 mmol) were added to the reaction mixture, and it was
warmed and allowed to stir at reflux for 5 h. The mixture
was allowed to cool to room temperature, ACE-Cl (5.0 g, 35
mmol) was added, and the reaction mixture was stirred at
reflux for 3 h. The reaction mixture was allowed to cool to
room temperature, filtered, and washed with methylene
chloride; the excess solvent was removed in vacuo. The residue
was dissolved in MeOH (60 mL) and allowed to stir overnight
at room temperature under an atmosphere of argon. (Note:
if the reaction mixture was allowed to stir at reflux, varying
amounts of nortropine were detected/isolated from the reaction
mixture. After just 2 h of reflux, complete conversion of
product to the undesired cleavage product was obtained. This
cleavage did not appear to occur at ambient temperature). The
product crystallized from methanol and was isolated to give
4.3 g of white crystalline product, as the HCl salt (41%). A
second crop crystallized from acetone to give 5 (total 6.9 g, 21
mmol, 66%): mp 279 °C dec; 1H NMR (300 MHz, CDCl3) δ
1.72-1.92 (m, 6H, H-2,4ax,eq and H-6,7exo), 2.17-2.23 (m, 2H,
H-6,7endo), 3.47 (br s, 2H, H-1,5), 3.60 (br s, 1H, H-3eq), 5.38 (s,
1H, H-CHAr2), 6.97-7.03 (m, 4H, H-ArH), 7.23-7.29 (m, 4H,
H-ArH); 13C NMR (75 MHz, CDCl3) δ 28.3, 35.6, 53.3, 69.1,
79.6, 115.0, 115.3, 128.1, 128.2, 138.2, 160.3, 163.6; EIMS m/z
329 (M+). Anal. (C20H22NOF2Cl) C, H, N.
N-[4′′-(4′′′-Nitr op h en yl)bu tyl]-3r-[bis(4′-flu or op h en yl)-
m eth oxy]tr op a n e Hyd r obr om id e (7d ). 7d was prepared
as in 7b from 5 (2.5 g, 7.6 mmol) and 4-(4-nitrophenyl)butyric
acid (1.9 g, 9.1 mmol). The crude amine product was converted
to the HBr salt with a saturated solution of HBr/methanol and
crystallized using methanol and diethyl ether to give 7d (3.0
g, 5.1 mmol, 67%). 6d : 1H NMR (300 MHz, CDCl3) δ 1.90-
2.10 (m, 8H, H-2,4ax,eq, H-6,7exo, and H-CH2), 2.20-2.41 (m,
4H, H-6,7endo and H-CH2 R to amide carbonyl), 2.81 (app dd, J
) 9, 6.6, 6.4 Hz, 2H, H-CH2Ar), 3.69 (br s, 1H, H-3), 4.11, 4.70
(br s, total 2H, H-1,5), 5.42 (s, 1H, H-CHAr2), 7.01-7.07 (m,
4H, H-Ar), 7.28-7.33 (m, 4H, H-Ar), 7.38 (d, J ) 8.6 Hz, 2H,
H-Ar), 8.18 (d, J ) 8.6 Hz, 2H, H-Ar). 7d : mp 111-115 °C;
1H NMR (300 MHz, CDCl3) δ 1.50-1.70 (m, 2H, H-CH2), 1.72-
1.85 (m, 6H, H-2,4ax,eq and H-6,7exo), 2.05-2.18 (m, 2H,
H-6,7endo), 2.32-2.45 (m, 2H, H-CH2Ar), 2.73 (t, J ) 7.7 Hz,
2H, H-NCH2), 3.13-3.28 (m, 2H, H-1,5), 3.25-3.61 (m, 1H,
H-3eq), 5.36 (s, 1H, H-CHAr2), 7.00-7.06 (m, 4H, H-Ar), 7.28-
7.36 (m, 6H, H-Ar), 8.17 (d, J ) 8.6 Hz, 2H, H-Ar); 13C NMR
(75 MHz, CDCl3) δ 26.0, 27.0, 28.8, 35.6, 35.7, 51.8, 58.1, 69.0,
79.3, 114.9, 115.2, 123.5, 128.2, 128.3, 129.0, 137.0, 146.0,
151.0, 161.0, 163.0. Anal. (C30H33N2O3F2Br‚1/4H2O) C, H, N.
N -[3′′-(4′′′-F lu o r o p h e n y l)p r o p yl]-3r-[b is(4′-flu o r o -
p h en yl)m eth oxy]tr op a n e Hyd r obr om id e (7e). 7e was
prepared as in 7a using 5 (830 mg, 2.5 mmol) and 3-(4′-
fluorophenyl)propionic acid. The crude amine was converted
to the HBr salt with a saturated solution of HBr/methanol and
crystallized using methanol and diethyl ether to give 7e (750
mg, 1.4 mmol, 54%). 6e: 1H NMR (300 MHz, CDCl3) δ 1.81-
1.95 (m, 6H, H-2,4ax,eq and H-6,7endo), 2.19-2.24 (m, 2H, H-CH2
R to amide carbonyl), 2.97 (app q, J ) 7.9, 7.0, 6.5 Hz, 2H,
H-CH2Ar), 3.62 (br s, 1H, H-3eq), 4.06, 4.70 (s, total 2H, H-1,5),
N-(3-P h en ylp r op yl)-3r-[bis(4′-flu or op h en yl)m eth oxy]-
tr op a n e Hyd r och lor id e (7a ). Compound 5 (370 mg, 1.0
mmol) and triethylamine (0.3 mL, 2.2 mmol) were added to a
mixture of hydrocinnamic acid (150 mg, 1.0 mmol), dicyclo-
hexylcarbodiimide (DCC, 250 mg, 1.2 mmol), and 1-hydroxy-
benzotriazole hydrate (HOBT, 180 mg, 1.3 mmol) in 10 mL of
dry DMF. The reaction mixture was allowed to stir for 1 h at
0 °C, under an atmosphere of argon. The reaction mixture
was then allowed to warm to room temperature and to stir
for 48 h. After completion of the reaction (assessed by TLC),
15 mL of H2O was added. The reaction mixture was basified
by adding a few drops of concentrated NH4OH to pH 9. The
organic products were extracted with ether (3 × 30 mL), and
the combined ether fractions were washed with H2O (2 × 25
mL), dried, filtered, and evaporated to an orange oil. A 0.4 g
(10 mmol) portion of LiAlH4 in 20 mL of anhydrous THF was
treated carefully with 0.5 g of 98% sulfuric acid in 1 mL of
anhydrous THF at 0 °C under an atmosphere of argon. After
15 min of stirring at room temperature, a solution of the
intermediate amide in 5 mL of anhydrous THF was added
dropwise to the reaction mixture, under argon. After 2 h of
stirring at room temperature, the reaction mixture was
hydrolyzed by slowly adding 1.6 mL of a 1:1 mixture of THF
and H2O at 0 °C. After 5 min of stirring at room temperature,
the gelatinous product was dissolved in 30 mL of ether, and 2
mL of 15% NaOH was carefully added. After 20 min of stirring
at room temperature, a white precipitate was observed and
separated by suction filtration. The organic filtrate was dried
and evaporated to yield 330 mg (74%) of the crude product as
a light brown oil. The oil was dissolved in a minimal volume
of ether and acidified to pH 2 with a saturated solution of HCl/
2-PrOH. Recrystallization in 2-PrOH/ether yielded 7a (220

Selective Ligands for the Dopamine Transporter
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4335
5.40 (s, 1H, H-CHAr2), 6.95-7.06 (m, 6H, H-Ar), 7.17-7.22
and acidified to pH 2 with a saturated solution of HCl/2-PrOH.
The crystalline product was isolated and recrystallized in
2-PrOH/ether to give 8b (570 mg, 1.4 mmol, 68%): mp 212-
(m, 2H, H-Ar), 7.27-7.31 (m, 4H, H-Ar). 7e: mp 183-185
1
°C; H NMR (300 MHz, CDCl3) 1.80-1.92 (m, 8H, H-2,4ax,eq
,
1
H-6,7exo and H-CH2), 2.11-2.14 (m, 2H, H-6,7endo), 2.39 (br t,
2H, H-NCH2), 2.64 (t, J ) 7.6 Hz, H-CH2Ar), 3.22 (br s, 2H,
H-1,5), 3.58 (br s, 1H, H-3eq), 5.40 (s, 1H, H-CHAr2), 6.96-
7.06 (m, 6H, H-Ar), 7.14-7.19 (m, 2H, H-Ar), 7.28-7.32 (m,
4H, H-Ar); 13C NMR (75 MHz, CDCl3) δ 25.6, 32.5, 51.0, 58.8,
58.9, 68.8, 79.6, 114.8, 115.0, 115.1, 115.3, 128.1, 128.2, 129.5,
213 °C; H NMR (300 MHz, CDCl3) δ 0.076 (app q, J ) 4.9,
5.4 Hz, 2H, H-CH2), 0.45-0.51 (m, 2H, H-CH2), 0.81-0.94 (m,
1H, H-CH), 1.78-1.98 (m, 6H, H-2,4ax,eq and H-6,7exo), 2.03-
2.40 (m, 2H, H-6,7endo), 2.23 (d, J ) 6.4 Hz, 2H, H-NCH2),
3.31-3.34 (m, 2H, H-1,5), 3.54 (t, J ) 5.0 Hz, 1H, H-3), 5.36
(s, 1H, H-CHAr2), 6.96-7.02 (m, 4H, H-Ar), 7.25-7.30 (m, 4H,
H-Ar); EIMS m/z 383 (M+). Anal. (C24H28NOF2Cl) C, H, N.
N-Ben zyl-3r-[bis(4′-flu or oph en yl)m eth oxy]tr opan e Fu -
m a r a te (8d ). Compound 8d was synthesized according to the
procedure described for compound 8c, from 5 (660 mg, 2.0
mmol), and benzyl bromide (380 mg, 2.2 mmol, 0.26 mL). After
extractive workup, evaporation of the solvent resulted in 750
mg of crude product (90%) as a clear oil. A portion of the crude
free base (0.9 mmol) was dissolved in a minimal volume of
2-PrOH and added to a solution of fumaric acid (110 mg, 0.9
mmol) in 2-PrOH. Recrystallization in ethyl acetate gave 8d
(360 mg, 0.7 mmol, 33%): mp 194-195 °C; 1H NMR (300 MHz,
CDCl3) δ 1.78-2.15 (m, 8H, H-2,4ax,eq and H-6,7exo, endo), 3.13
(br s, 2H, H-1,5), 3.52 (s, 2H, H-CH2Ar), 3.56 (t, J ) 5.05 Hz,
1H, H-3), 5.36 (s, 1H, CHAr2), 6.95-7.03 (m, 4H, H-Ar), 7.20-
7.37 (m, 9H, H-Ar); 13C NMR (75 MHz, CDCl3) δ 26.2, 36.3,
56.3, 58.0, 69.7, 79.0, 114.9, 115.2, 126.5, 128.0, 128.2, 128.3,
128.4, 138.0, 140.0, 160.0, 163.0; EIMS m/z 419 (M+). Anal.
(C31H31NO5F2) C, H, N.
N-(4′′-F lu or oben zyl)-3a -[bis(4′-flu or op h en yl)m eth oxy]-
tr op a n e F u m a r a te (8e). Compound 8e was prepared ac-
cording to the procedure described for compound 8c, from 5
(660 mg, 2.0 mmol), using 4-fluorobenzyl chloride (320 mg, 2.2
mmol, 0.3 mL). Evaporation of the solvent resulted in 520
mg of crude product (60%) as a clear oil. The crude free base
was dissolved in a minimal volume of 2-PrOH and added to a
solution of fumaric acid (140 mg, 1.2 mmol) in 2-PrOH.
Recrystallization from 2-PrOH yielded 8e (600 mg, 1.1 mmol,
54%): mp 201 °C; 1H NMR (300 MHz, CDCl3) δ 1.79-1.98 (m,
6H, H-2,4ax,eq and H-6,7exo), 2.08-2.12 (m, 2H, H-6,7endo), 3.10
(br t, 2H, H-1,5), 3.46 (s, 2H, CH2Ar), 3.56 (t, J ) 5.0 Hz, 1H,
H-3), 5.37 (s, 1H, H-CHAr2), 6.95-7.03 (m, 6H, H-Ar), 7.25-
7.34 (m, 6H, H-Ar); 13C NMR (75 MHz, CDCl3) δ 25.5, 35.1,
54.4, 58.4, 68.9, 79.8, 115.2, 115.4, 115.5, 115.7, 128.2, 128.4,
131.4, 131.2, 136.0, 138.1, 160.4, 160.2, 163.7, 164.2, 172.6;
EIMS m/z 437 (M+). Anal. (C31H30NO5F3) C, H, N.
129.5, 137.0, 138.2, 159.8, 160.4, 163.0, 163.7. Anal. (C29H31
NOF3Br) C, H, N.
-
The starting material, 3-(4′-flu or op h en yl)p r op ion ic a cid ,
was prepared by dissolving 4-fluorocinnamyl carboxylic acid
(450 mg, 2.7 mmol) in ethanol (100 mL) in a 250 mL Parr
pressure bottle with Pd on carbon (10%, 20 mg). The vessel
was pressurized to 30 psi and agitated for 18 h. The mixture
was filtered through a Celite pad, and solvent was removed
in vacuo. 3-(4′-Fluorophenyl)propionic acid (490 mg, 2.9 mmol)
was obtained and used without further purification: 1H NMR
(300 MHz, CDCl3) δ 2.70 (app t, J ) 7.8, 7.6 Hz, 2H, H-CH2
R
to carbonyl), 2.98 (t, J ) 7.6 Hz, 2H, H-CH2Ar), 6.98-7.06 (m,
2H, H-Ar), 7.19-7.23 (m, 2H, H-Ar); IR (NaCl plate, neat) 1701
(CO stretch), 2800-3400 (aromatic, aliphatic C-H and O-H
stretch) cm-1
.
N-Allyl-3r-[bis(4′-flu or op h en yl)m eth oxy]tr op a n e Hy-
d r och lor id e (8c). Compound 5 (370 mg, 1.0 mmol) was
converted to its free base form by extracting with CHCl3 (3 ×
10 mL) from 20% NH4OH (20 mL), drying, evaporating, and
dissolving in 3.0 mL of dry DMF. Anhydrous K2CO3 (280 mg,
2.0 mmol) and allyl bromide (100 mL, 1.1 mmol) were added,
and the reaction mixture was allowed to stir at room temper-
ature for 1 h. Inorganics were removed by suction filtration,
the filter pad was washed with ether, and the filtrate was
poured into a separatory funnel. Extraction from H2O (10 mL)
with ether (3 × 10 mL) was followed by washing the combined
organic portions with H2O (1 × 10 mL) and drying. Evapora-
tion of the volatiles resulted in 350 mg of crude product (95%)
as a clear oil. The crude free base was dissolved in a minimal
volume of anhydrous ether and acidified to pH 2 with a
saturated solution of HCl/2-PrOH. Evaporation of the sol-
vent and recrystallization in ether gave 8c (300 mg, 0.8
mmol, 76% from 5): mp 190 °C; 1H NMR (300 MHz, CDCl3) δ
1.73-1.87 (m, 6H, H-2,4ax,eq and H-6,7exo), 1.97-2.05 (m, 2H,
H-6,7endo), 2.90 (d, J ) 6.4 Hz, 2H, H-allylic), 3.11 (br t, 2H,
H-1,5), 5.00-5.10 (m, 2H, H-terminal vinyl), 5.29 (s, 1H,
H-CHAr2), 5.75-5.88 (m, 1H, H-vinyl), 6.88-6.95 (m, 4H,
H-Ar), 7.18-7.23 (m, 4H, H-Ar); EIMS m/z 369 (M+). Anal.
(C23H26NOF2Cl) C, H, N.
N-Bu tyl-3r-[bis(4′-flu or op h en yl)m eth oxy]tr op a n e Hy-
d r och lor id e (8a ). Compound 8a was synthesized according
to the procedure described for compound 8c, from 5 (1.8 g, 5.5
mmol) and 1-bromobutane (0.90 g, 6.6 mmol). The reaction
was allowed to stir at room temperature overnight, under an
atmosphere of argon. After extractive workup, evaporation
of the solvent resulted in 1.9 g of crude product (88%). The
crude free base was dissolved in a minimal volume of ether
and acidified to pH 2 with a saturated solution of HCl/2-PrOH
to give 8a (1.9 g, 4.4 mmol, 81%): mp 180-180.5 °C; 1H NMR
(300 MHz, CDCl3) δ 0.90 (t, J ) 7.2 Hz, 3H, H-CH3), 1.24-
1.36 (m, 2H, H-CH2), 1.39-1.49 (m, 2H, H-CH2) 1.76-1.96 (m,
6H, H-2,4ax,eq and H-6,7exo), 2.03-2.10 (m, 2H, H-6,7endo), 2.28-
2.33 (m, 2H, H-NCH2), 3.17 (br t, 2H, H-1,5), 3.54 (t, J ) 5.0
Hz, 1H, H-3eq), 3.56 (s, 1H, H-CHAr2), 6.95-7.03 (m, 4H, H-Ar),
7.24-7.30 (m, 4H, H-Ar); 13C NMR (75 MHz, CDCl3) δ 16.0,
20.8, 26.1, 30.9, 35.6, 57.8, 70.0, 79.0, 114.9, 115.2, 128.2, 128.3,
138.0, 160.0, 163.0; EIMS m/z 385 (M+). Anal. (C24H30NOF2-
Cl‚1/2H2O) C, H, N.
N -Cin n a m yl-3r-[b is(4′-flu or op h e n yl)m e t h oxy]t r o-
p a n e Hyd r och lor id e (8f). Compound 8f was synthesized
according to the procedure described for compound 8c, from 5
(330 mg, 1.0 mmol), and cinnamyl bromide (220 mg, 1.1 mmol,
0.16 mL). After extractive workup, evaporation of the solvent
resulted in 380 mg of crude product (85%). The crude free
base was dissolved in a minimal volume of ether and acidified
to pH 2 with a saturated solution of HCl/2-PrOH. The solvents
were removed in vacuo, and the product was crystallized from
ether followed by recrystallization from 2-PrOH to give 8f (320
1
mg, 0.7 mmol, 66%): mp 219 °C; H NMR (300 MHz, CDCl3)
δ 1.74-1.87 (m, 6H, H-2,4ax,eq and H-6,7exo), 2.01-2.05 (m, 2H,
H-6,7endo), 3.07 (d, J ) 6.3 Hz, 2H, H-CH2), 3.15 (br t, 2H,
H-1,5), 3.50 (t, J ) 5 Hz, 1H, H-3eq), 5.29 (s, 1H, H-CHAr2),
6.23 (dt, J ) 15.8, 6.5 Hz, 1H, H-vinyl), 6.40 (d, J ) 15.8 Hz,
1H, H-vinyl), 6.89-6.95 (m, 4H, H-Ar), 7.12-7.32 (m, 9H,
H-Ar); IR (KBr) 1501 (ROR), 1602 (aromatic), 2800-3000
(aliphatic C-H stretch) cm-1
N.
. Anal. (C29H30NOF2Cl) C, H,
N-[2′′-[Bis(4′′′-flu or op h en yl)m eth oxy]eth yl]-3r-[bis(4′-
flu or op h en yl)m eth oxy]tr op a n e Hyd r obr om id e (8g). 8g
was prepared as in compound 8c from 5 (340 mg, 1.0 mmol)
and 1-bromo-2-[bis(4′-fluorophenyl)methoxy]ethane (670 mg,
2.1 mmol). The crude product (590 mg) was purified via flash
chromatography (3:1 hexanes/ethyl acetate (trace triethyl-
amine), SiO2, obtain 280 mg, 48%) and converted to the HBr
salt with a saturated solution HBr/methanol. The salt was
crystallized using methanol and diethyl ether to give 8c (240
mg, 0.4 mmol, 35%): mp 200-202 °C; 1H NMR (300 MHz,
CDCl3) δ 1.8-2.0 (m, 6H, H-2,4ax,eq and H-6,7exo), 2.10-2.15
(m, 2H, H-6,7endo), 2.63-2.67 (m, 2H, H-NCH2), 3.22-3.26 (m,
2H, H-1,5), 3.53-3.58 (m, 3H, H-3eq and H-CH2), 5.39 (s, 2H,
N -(C y c lo p r o p y lm e t h y l)-3r-[b is (4′-flu o r o p h e n y l)-
m eth oxy]tr op a n e Hyd r och lor id e (8b). Compound 8b was
synthesized according to the procedure described for compound
8c, from 5 (660 mg, 2.0 mmol), using bromomethyl cyclopro-
pane (300 mg, 2.2 mmol, 0.22 mL). The reaction was allowed
to stir for an additional hour at room temperature under an
atmosphere of argon. After extractive workup, evaporation
of the solvent resulted in 650 mg of crude product (85%). The
crude free base was dissolved in a minimal volume of ether

4336 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Agoston et al.
H-CHAr2), 7.00-7.07 (m, 8H, H-Ar), 7.28-7.33 (m, 8H, H-Ar);
13C NMR (75 MHz, CDCl3) δ 28.2, 35.6, 51.9, 58.8, 68.0, 69.0,
79.2, 82.4, 114.9, 115.0, 115.2, 115.3, 128.1, 128.3, 128.3, 128.5,
137.0, 138.0, 160.3, 160.4, 163.6, 163.7. Anal. (C35H34NO2F4-
Br) C, H, N.
q, J ) 7.4, 6.5, 6.4 Hz, 2H, H-6,7endo) 2.91 (s, 3H, H-CH3), 3.68-
3.70 (m, 1H, H-3eq), 4.25-4.27 (m, 2H, H-1,5), 5.43 (s, 1H,
H-CHAr2), 7.0-7.08 (m, 4H, H-Ar), 7.28, 7.33 (m, 4H, H-Ar);
13C NMR (75 MHz, CDCl3) δ 28.7, 37.3, 40.1, 55.8, 60.1, 79.7,
115.1, 115.4, 128.1, 128.2, 137.0, 160.0, 163.0. Anal. (C21H23
NO3SF2) C, H, N.
-
N-[2′′-[(4′′′-Nitr op h en yl)p h en ylm eth oxy]eth yl]-3r-[bis-
(4′-flu or op h en yl)m eth oxy]tr op a n e Hyd r obr om id e (8h ).
8h was prepared as in 8c from 5 (290 mg, 2.5 mmol) and
1-bromo-2-[(4′-nitrophenyl)phenyl]ethane (1.04 g, 3.09 mmol).
The crude product was converted to the HBr salt with a
saturated solution of HBr/methanol and crystallized in metha-
N-(p-Tolylsu lfon yl)-3r-[bis(4′-flu or op h en yl)m eth oxy]-
tr op a n e (11a ). 11a was prepared as in 11b from 2 (370 mg,
1.1 mmol) and p-toluenesulfonyl chloride (220 mg, 1.1 mmol)
except the reaction was only stirred for 1 h. After purification
via column chromatography, 11a was obtained as a white
1
1
nol to give 8h (850 mg, 1.3 mmol, 63%): mp 129-133 °C; H
powder (400 mg, 0.8 mmol, 74%): mp 165-168 °C; H NMR
NMR (300 MHz, CDCl3) δ 1.76-1.89 (m, 6H, H-2,4ax,eq and
H-6,7exo), 2.09 (d, J ) 7.1 Hz, H-6,7endo,major) and 2.18 (d, J )
7.4 Hz, H-6,7endo,minor), 2.64 (t, J ) 6.2 Hz, 2H, H-NCH2), 3.20
(br s, 2H, H-1,5), 3.48-3.57 (m, 3H, H-3eq and H-CH2), 5.36
(s, 1H, H-CHAr(Ar-NO2)), 5.46 (s, 1H, H-CHAr2), 6.96-7.02
(m, 4H, H-Ar), 7.25-7.33, (m, 9H, H-Ar), 7.52 (d, J )9 Hz,
2H, H-Ar), 8.16 (d, J ) 8.7 Hz, 2H, H-Ar); 13C NMR (75 MHz,
CDCl3) δ 26.2 (major) and 29.0 (minor), 51.9, 54.0, 58.9, 69.0,
69.3, 79.2, 82.9, 115.0, 115.2, 123.5, 126.9, 127.3, 128.0, 128.1,
128.3, 128.6, 138.0, 141.0, 147.0, 149.0, 160.0, 163.0. Anal.
(C35H35N2O4F2Br‚3/4H2O) C, H, N.
N-Acetyl-3r-[bis(4′-flu or op h en yl)m eth oxy]tr op a n e (9).
Compound 5 (1.3 g, 3.4 mmol) was converted to the free base
form as described for compound 3 and dissolved in 50 mL of
methylene chloride. An aqueous solution of NaHCO3 (1.0 g
in 14 mL of H2O) was added followed by a solution of acetyl
chloride (400 mg, 5.1 mmol) in methylene chloride (4 mL), at
0 °C. The biphasic reaction mixture was allowed to warm to
room temperature and stir for 3 h. The reaction mixture was
then poured into a separatory funnel, the organic layer was
removed, and the aqueous layer was washed with CHCl3 (2 ×
20 mL). The combined organic fraction was dried and evapo-
rated to an oil. Purification using flash column chromatog-
raphy (EtOAc) gave compound 9 as a pure clear oil (640 mg,
1.7 mmol, 51%). 9: 1H NMR (300 MHz, CDCl3) δ 1.82-2.03
(m, 9H, H-2,4ax,eq, H-6,7exo and H-COCH3), 2.15-2.30 (m, 2H,
H-6,7endo), 3.66 (app br t, J ) 4.41, 3.68 Hz, 1H, H-3eq), 4.07-
4.09, 4.64-4.66 (m, total 2H, H-1,5), 5.39 (s, 1H, H-CHAr2),
6.98-7.03 (m, 4H, H-Ar), 7.25-7.30 (m, 4H, H-Ar); 13C NMR
(75 MHz, CDCl3) δ 21.3, 27.2 and 28.7, 35.1 and 37.1, 50.4
and 54.5, 69.7, 79.8, 115.1, 115.1, 115.4, 128.0, 128.2, 128.2,
128.3, 133.0, 160.0, 163.0, 166.0; IR (neat) 1631 cm-1; EIMS
m/z 371 (M+). Anal. (C22H23NO2F2) C, H, N.
N-For m yl-3r-[bis(4′-flu or oph en yl)m eth oxy]tr opan e (10).
Compound 3 (740 mg, 2.0 mmol) was converted to the free base
as described for compound 5 and dissolved in ethyl formate (9
mL, 111 mmol, freshly distilled over P2O5). Formic acid (6 mL,
100%, Fluka) was added, and the reaction mixture was allowed
to stir, under an atmosphere of argon, overnight. Removal of
volatiles, in vacuo, followed by purification through a short
silica gel column with ethyl acetate resulted in 400 mg (56%)
of the product as a white solid which recrystallized from ethyl
acetate/hexane to give 10 as shiny white crystals (300 mg, 0.8
mmol, 42%), mp 117-118 °C. 10: 1H NMR (300 MHz, CDCl3)
δ 1.83-2.10 (m, 6H, H-2,4ax,eq and H-6,7exo), 2.22-2.30 (m, 2H,
H-6,7endo), 3.67-3.72 (m, 1H, H-5), 4.00-4.07 (m, 1H, H-1),
4.55-4.62 (m, 1H, H-3), 5.40 (s, 1H, H-CHAr2), 7.02-7.10 (m,
4H, H-Ar, 7.25-7.30 (m, 4H, H-Ar), 8.10 (s, 1H, H-CHO); EIMS
m/z 357 (M+). Anal. (C21H21NO2F2) C, H, N.
N-(Meth ylsu lfon yl)-3r-[bis(4′-flu or op h en yl)m eth oxy]-
tr op a n e (11b). Compound 2 (790 mg, 2.4 mmol) was con-
verted to the free base form as described for 5 and dissolved
in anhydrous triethylamine (18 mL), cooled to -10 °C, and
stirred for 20 min. Methanesulfonyl chloride (300 mg, 2.6
mmol) was added dropwise, and the mixture was stirred for 1
h at -10 °C and then 14 h at room temperature, after which,
another 1.1 equiv of methanesulfonyl chloride was added to
the mixture and stirred for an additional 3 h. A white solid
formed during the course of the reaction that over time turned
to a brown gum. Triethylamine was removed under vacuum,
and the resulting residue was purified via flash chromatog-
raphy (SiO2, methylene chloride) to give 11b as a white powder
(300 mg, 0.7 mmol, 31%): mp 109-112 °C; 1H NMR (300 MHz,
CDCl3) δ 2.02-2.06 (m, 6H, H-2,4ax,eq and H-6,7exo), 2.31 (app
(300 MHz, CDCl3) δ 1.48-1.54 (m, 2H, H-6,7endo), 1.96-2.07
(m, 6H, H-2,4ax,eq and H-6,7exo), 2.45 (s, 3H, H-CH3Ar), 3.66
(br s, 1H, H-3eq), 4.25 (br s, 2H, H-1,5), 5.37 (s, 1H, H-CHAr2),
6.98-7.04 (m, 4H, H-Ar), 7.23-7.30 (m, 6H, H-Ar), 7.77 (d,
J ) 8.2 Hz, 2H, H-Ar); 13C NMR (75 MHz, CDCl3) δ 22.0, 28.1,
37.5, 55.9, 68.0, 79.0, 115.1, 115.3, 127.2, 128.0, 128.2, 129.4,
137.0, 138.0, 143.0, 160.0, 161.0, 163.0. Anal. (C27H27NO3-
SF2) C, H, N.
N-Meth yl-3r-[bis(4′-flu or oph en yl)m eth oxy]tr opan e Me-
th iod id e (12). Compound 5 (760 mg, 2.0 mmol) was converted
to the free base as described for 3 and was dissolved in 10 mL
of absolute ethanol. Under an atmosphere of argon, io-
domethane (2.0 mL, 32 mmol, passed through a small column
of anhydrous potassium carbonate) was added, and the reac-
tion mixture was allowed to stir at reflux for 1 h. The reaction
mixture was allowed to cool and stir overnight at room
temperature. The resulting crystalline product was isolated
by filtration and washed with ethyl ether to give 12 as white
1
crystals (720 mg, 1.8 mmol, 91%): mp 248 °C; H NMR (300
MHz, CDCl3/CD3OD (1 mL/1 drop)) δ 2.11 (s, 2H, H-6,7endo),
2.16 (s, 2H, H-6,7exo), 2.33-2.39 (m, 2H, H-2,4), 2.46-2.49 (m,
2H, H-2,4), 3.25 (s, 3H, H-NCH3), 3.30 (s, 3H, H-NCH3), 3.78
(t, J ) 5.9 Hz, 1H, H-3eq), 4.11 (br s, 2H, H-1,5), 5.45 (s, 1H,
H-CHAr2), 7.00-7.06 (m, 4H, H-Ar), 7.24-7.32 (m, 4H, H-Ar);
13C NMR (75 MHz, CDCl3/CD3OD (1 mL/1 drop)) δ 25.1, 32.2,
44.6, 51.0, 64.5, 67.9, 80.2, 115.3, 115.6, 128.1, 128.2, 137.0,
160.0, 163.0. Anal. (C22H26NOF2I) C, H, N.
Molecu la r Mod elin g Meth od s. Molecular modeling stud-
ies were performed using the SYBYL17 software package
(Tripos, version 6.3, R4000) installed on a Silicon Graphics
IRIS Indigo XZ workstation running IRIX 5.3. The chemical
structures were drawn using the SKETCH option. Optimized
geometries and partial charges were obtained using the AM118
model Hamiltonian as implemented in the MOPAC19 program
(version 6.0) using the PRECISE convergence criteria. Cen-
troids were defined perpendicular to the surface of the
aromatic rings contained in the N-substituents. The distance
from the bridge N to the centroid dummy atom was measured
using the MEASURE DISTANCE command.
Sin gle-Cr ysta l X-r a y An a lysis of 12. A clear rectangular
0.18 × 0.18 × 0.44 mm crystal recrystallized from EtOH,
C
22H26OF2N•+I-, FW ) 485.34, was selected for data collection.
Data were collected on a computer controlled diffractometer
with an incident beam graphite monochromator (Siemens P4
with Cu KR radiation, l ) 1.541 78 Å, T ) 295 K). A least-
squares refinement using 28 centered reflections within 14 <
2q < 60° gave the monoclinic P21/c cell, a ) 16.755(2) Å, b )
10.660(1) Å, c ) 12.958(1) Å, with V ) 2151.7(4) Å3, Z ) 4,
and dcalc ) 1.498 g/cm3. A total of 3283 reflections were
measured in the q/2q mode to 2qmax ) 116.5°, of which there
were 3014 independent reflections. Corrections were applied
for Lorentz and polarization effects. A face indexed numerical
absorption correction was applied, m ) 11.93 mm-1, and max
and min transmissions were 0.74 and 0.28, respectively. The
structure was solved by direct methods with the aid of the
program SHELXTL.20 The full-matrix least-squares refine-
2
ment on Fo varied 245 parameters including the coordinates
and anisotropic thermal parameters for all non-hydrogen
atoms. H atoms were included using a riding model [coordi-
nate shifts of C applied to attached H atoms, C-H distances
set to 0.96 Å, H angles idealized, Uiso(H) were set to 1.2 Ueq
-
(C) or, if methyl, 1.5 Ueq(C)]. The final R values for the 2396
observed reflections with Fo > 4sFo were R1 ) 0.041, and wR2

Selective Ligands for the Dopamine Transporter
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4337
) 0.11 for all data.21 The final difference Fourier excursions
placed in scintillation vials to which 1 mL of methanol and 2
mL of 0.2 M HCl were added to extract the accumulated [3H]-
dopamine. Radioactivity was determined by liquid scintilla-
tion spectrometry at an efficiency of approximately 30%. The
reported values represent specific uptake from which nonspe-
cific binding to filters was subtracted. Uptake data were
analyzed using standard analysis of variance and linear
regression techniques. IC50 values were calculated using the
linear portion of the concentration-response curve (linear
regression p < 0.05).
Mu sca r in ic m 1 Bin d in g Assa y. Whole frozen rat brains
excluding cerebellum (Taconic, Germantown, NY) were thawed
in ice-cold buffer (10 mM Tris-HCl, 320 mM sucrose, pH 7.4)
and homogenized with a Brinkman polytron in a volume of
10 mL/g of tissue. The homogenate was centrifuged at 1000g
for 10 min at 4 °C. The resulting supernatant was then
centrifuged at 10000g for 20 min at 4 °C. The resulting pellet
was resuspended in a volume of 1.53 mL/g in 10 mM Tris
buffer (pH 7.4).
Assays were conducted in binding buffer (10 mM Tris-HCl,
5 mM MgCl2). The total volume in each tube was 0.5 mL, and
the final concentration of membrane after all additions was
approximately 200-300 mg of protein/sample. Triplicate
samples of membrane suspension were preincubated for 5 min
in the presence or absence of the compound being tested. [3H]-
Pirenzepine (specific activity 73.9 Ci/mmol, from New England
Nuclear, Boston, MA, final concentration 3 nM) was added,
and the incubation was continued for 1 h at 37 °C. The
incubation was terminated by the addition of 5 mL of ice-cold
buffer (10 mM Tris-HCl, pH 7.4) and rapid filtration through
Whatman GF/B glass fiber filter paper (presoaked in 0.5%
polyethylenimine in water to reduce nonspecific binding) using
a Brandel Cell Harvester (Gaithersburg, MD). The filters were
washed with two additional 5 mL washes and transferred to
scintillation vials. Absolute ethanol (0.5 mL) and Beckman
Ready Value Scintillation Cocktail (2.75 mL) were added to
the vials which were counted the next day at an efficiency of
about 36%. Under these assay conditions, an average experi-
ment yielded approximately 15000 dpm total binding per
sample and approximately 900 dpm nonspecific binding,
defined as binding in the presence of 10 µM QNB (quinuclidi-
nyl benzilate). Each compound was tested with concentrations
ranging from 0.01 nM to 100 µM for competition against
binding of [3H]pirenzepine, in at least three independent
experiments, each performed in triplicate.
Serotonin (5-HTT) and norepinephrine transporter (NET
binding data were provided by NOVASCREEN, Hanover, MD).
The radiolabeled ligands used and the methods were from the
following published procedures: 5-HTT, [3H]citalopram (spe-
cific activity 70-87 Ci/mmol, final ligand concentration 0.7
nM);24 NET, [3H]desmethylimipramine (specific activity 40-
70 Ci/mmol, final ligand concentration 3.0 nM).25
Locom otor Activity. Ambulatory activity of male Swiss
Webster mice (Taconic Farms) were studied in 40 cm3 clear
acrylic chambers. The acrylic chambers were placed inside
monitors (Omnitech Electronics, Columbus, OH) that were
equipped with light sensitive detectors, spaced 2.5 cm apart
along two perpendicular walls. Mounted on the opposing walls
were infrared light sources that were directed at the detectors.
One count of horizontal activity was registered each time the
subject interrupted a single beam. Mice were injected with
cocaine or 7c and immediately placed in the apparatus for 60
min, with horizontal activity counts collected each 10 min.
Intraperitoneal (ip) injections were administered in volumes
of 1 mL/100 g. Each dose was studied in eight mice, and mice
were used only once. Vehicle was saline (cocaine) or 50%
propylene glycol (7c).
The data from the 60-min observation period were analyzed
and those from the 30-min period in which maximal stimula-
tion of activity was observed were selected for presentation.
Each dose-effect curve was analyzed using standard analysis
of variance (ANOVA) and post-hoc testing to determine
significance of effects at individual doses.
Coca in e Discr im in a tion . Male Sprague-Dawley rats
(Charles River, Wilmington, MA) weighing 310-385 g were
individually housed with free access to water under a 12 h
were 0.70 and -0.68 e Å-3
.
P h a r m a cology. Dop a m in e Tr a n sp or ter Bin d in g As-
sa y. Male Sprague-Dawley rats (200-250 g, Taconic, Ger-
mantown, NY) were decapitated and their brains removed to
an ice-cooled dish for dissection of the caudate putamen. The
tissue was homogenized in 30 volumes ice-cold modified Krebs-
HEPES buffer (15 mM HEPES, 127 mM NaCl, 5 mM KCl,
1.2 mM MgSO4, 2.5 mM CaCl2, 1.3 mM NaH2PO4, 10 mM
D-glucose, pH adjusted to 7.4) using a Brinkman polytron and
centrifuged at 20000g for 10 min at 4 °C. The resulting pellet
was then washed two more times by resuspension in ice-cold
buffer and centrifugation at 20000g for 10 min at 4 °C. Fresh
homogenates were used in all experiments.
Binding assays were conducted in modified Krebs-HEPES
buffer on ice. The total volume in each tube was 0.5 mL, and
the final concentration of membrane after all additions was
0.5% (w/v), corresponding to 200-300 mg of protein/sample.
Triplicate samples of membrane suspension were preincubated
for 5 min in the presence or absence of the compound being
tested. [3H]WIN 35,428 [2-â-carbomethoxy-3-â-(4-fluorophen-
yl)tropane-1,5-naphthalenedisulfonate; specific activity 82.4
Ci/mmol, from New England Nuclear, Boston, MA, final
concentration 1.5 nM] was added, and the incubation was
continued for 1 h on ice. The incubation was terminated by
the addition of 3 mL of ice-cold buffer and rapid filtration
through Whatman GF/B glass fiber filter paper (presoaked in
0.1% BSA in water to reduce nonspecific binding) using a
Brandel Cell Harvester (Gaithersburg, MD). The filters were
washed with three additional 3 mL washes and transferred
to scintillation vials. Absolute ethanol (0.5 mL) and Beckman
Ready Value Scintillation Cocktail (2.75 mL) were added to
the vials which were counted the next day at an efficiency of
about 36%. Under these assay conditions, an average experi-
ment yielded approximately 6000 dpm total binding per
sample and approximately 250 dpm nonspecific binding,
defined as binding in the presence of 100 µM cocaine. Each
compound was tested with concentrations ranging from 0.01
nM to 100 µM for competition against binding of [3H]WIN 35,-
428, in three independent experiments, each performed in
triplicate.
In both saturation and competition experiments, two com-
ponents of [3H]WIN 35,428 binding were apparent. Analysis
of the data utilizing the LIGAND program revealed a high
affinity component with a KD of 7 ( 5 nM and a Bmax of 445 (
338 fmol/mg of protein and a low-affinity component with a
KD of 126 ( 115 nM and a Bmax of 1995 ( 559 fmol/mg of
protein.
Saturation and displacement data were analyzed by the use
of the nonlinear least squares curve-fitting computer program
LIGAND.22 Data from replicate experiments were modeled
together to produce a set of parameter estimates and the
associated standard errors of these estimates. In each case,
the model reported fit significantly better than all others
according to the F test at p < 0.05. The Ki values reported
are the dissociation constants derived for the unlabeled
ligands.
[3H]Dop a m in e Up t a k e Assa y. Rats were sacrificed by
decapitation and their brains removed to an ice-cooled dish
for dissection of the caudate putamen. [3H]Dopamine uptake
was measured in a chopped tissue preparation as described
previously.23 Briefly, the tissue was chopped into 225 µm slices
on a McIllwain tissue slicer with two successive cuts at an
angle of 90°. The strips of tissue were suspended in oxygen-
ated modified Krebs-HEPES buffer (see above), which was
pregassed with 95% O2/5% CO2 and warmed to 37 °C. After
rinsing, aliquots of tissue slice suspensions were incubated in
buffer in glass test tubes at 37 °C to which either the drug
being tested or no drug was added, as appropriate. After a 5
min incubation period in the presence of drug, [3H]dopamine
(final concentration 15 nM, specific activity 50 Ci/mmol, from
Amersham Corp, Arlington Heights, IL) was added to each
tube. After 5 min the incubation was terminated by the
addition of 2 mL of ice-cold buffer to each tube and filtration
under reduced pressure over glass fiber filters (presoaked in
0.1% polyethylenimine in water). The filters were rinsed and

4338 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Agoston et al.
light/dark cycle (lights on 07.00 h). The rats had not been
tested previously. All testing was between 14 and 15.00 h.
Rats were fed 15 g standard lab chow daily at least 30 min
after testing.
Animal Resources, National Research Council, Depart-
ment of Health, Education and Welfare, Publication
(NIH) 85-23, revised 1985. Radiolabeled ligand binding
experiments for the norepinephrine and serotonin trans-
porters were provided by NOVASCREEN under the
NIMH contract.
Rats were tested in two-lever operant-conditioning chambers
(modified Med Associates, model ENV 007, St. Albans, VT)
housed within light- and sound-attenuating enclosures with
white noise present throughout testing. Ambient illumination
was by a lamp in the top center of the front panel. Levers
were set 17 cm apart, with a pair of red lamps above the left
lever and a pair of white lamps above the right. A force of 0.4
N through 1 mm was required to register a lever press;
reinforced presses activated an audible click and dispensed
one 45 mg pellet (BioServe, Frenchtown, NJ ) into the centrally
located food tray.
Su p p or tin g In for m a tion Ava ila ble: X-ray unit cell,
torsion angle list, crystal data, refinement parameters, atomic
coordinates and isotropic displacement parameters, bond
angles and lengths, anistropic displacement parameters, and
hydrogen coordinates and isotropic displacement parameters
for 12 (7 pages). Ordering information is given on any current
masthead page.
Rats were initially trained to press both levers under a fixed-
ratio 20-response schedule of food reinforcement. Following
ip cocaine injection, responses on only one lever were rein-
forced; following saline, responses on the other lever were
reinforced. The assignment of cocaine- and saline-appropriate
levers was counterbalanced across rats. Immediately after
injection, rats were placed inside the experimental chambers
and a 5 min time-out period was initiated, during which all
lamps were extinguished and responding was not reinforced.
All lamps were then illuminated and responses on the ap-
propriate lever were reinforced. Responses on the inappropri-
ate lever reset the FR 20 response requirement on the
appropriate lever. Each food presentation was followed by a
20 s time-out period during which all lamps were off, and
responding had no scheduled consequences. Sessions ended
after 20 food presentations or 15 min, whichever occurred first.
Training sessions for which cocaine (C) and saline (S) injections
were administered were ordered in an SCCS sequence, with
test sessions conducted after consecutive SC or CS training
sessions.
Test sessions were conducted if the subject attained criterion
performance on both of the immediately preceding saline and
cocaine training sessions. The criteria were at least 85%
appropriate responding overall, and during the first FR of the
session. Test sessions were identical with training sessions,
with the exception that 20 consecutive responses on either
lever were reinforced. Before test sessions, different doses of
cocaine or doses of 7c were administered. Vehicles were the
same as those used in assessing effects on locomotor activity.
On-line experimental control and data collection were by
PC MS-DOS computers operating Med Associates software
(Med Associates, St. Albans, VT). For each rat, the overall
response rate and the percentage of responses occurring on
the cocaine-appropriate lever were calculated. The mean
values were calculated for each measure at each drug dose
tested. Data from any rat which failed to respond at a rate
exceeding 0.02 responses per second was not included in the
calculation of mean cocaine-appropriate responding at that
dose. If less than three rats met the response rate require-
ment, no mean value was calculated for percentage of cocaine-
appropriate responding at that dose.
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Ack n ow led gm en t. G.E.A. was fully and J .H.W. was
partially supported by an NIH IRTA fellowship. R.H.K.
was supported by a NIDA-sponsored National Research
Council Fellowship. Single-crystal X-ray analysis of 12
was funded in part by the Office of Naval Research and
NIDA contract DA09045. We thank Brett Heller, Phyllis
Terry, Richard Loeloff, Bettye Campbell, and Robert
Mitkus for expert technical assistance. Animals used
in this study were maintained in facilities fully ac-
credited by the American Association for the Accredita-
tion of Laboratory Animal Care (AAALAC), and all
experimentation was conducted according to the guide-
lines of the Institutional Care and Use Committee of
the Division of Intramural Research, National Institute
on Drug Abuse, NIH, and the Guide for Care and Use
of Laboratory Animals of the Institute of Laboratory

Selective Ligands for the Dopamine Transporter
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4339
(21) R1 ) ∑||Fo| - |Fc||/∑|Fo|. wR2 ) [∑(wD2)/∑[w(Fo2)2]]1/2, where D
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