2-carbomethoxy-3-aryl-8-bicyclo[3.2.1]octanes: Potent non-nitrogen inhibitors of monoamine transporters

Article abstract of DOI:10.1021/jm000191g

Cocaine is a potent central nervous system stimulant with severe addiction liability. Its reinforcing and stimulant properties derive from inhibition of monoamine transport systems, in particular the dopamine transporter (DAT). This inhibition results in

Full text of DOI:10.1021/jm000191g

2982
J . Med. Chem. 2000, 43, 2982-2991
2-Ca r bom eth oxy-3-a r yl-8-bicyclo[3.2.1]octa n es: P oten t Non -Nitr ogen In h ibitor s
of Mon oa m in e Tr a n sp or ter s
Peter C. Meltzer,*,† Paul Blundell,† Yaw F. Yong,† Zhengming Chen,† Clifford George,‡ Mario D. Gonzalez,† and
Bertha K. Madras§
Organix Inc., 240 Salem Street, Woburn, Massachusetts 01801, Naval Research Laboratory, Washington, D.C. 20375, and
Department of Psychiatry, Harvard Medical School and New England Regional Primate Center,
Southborough, Massachusetts 01772
Received May 2, 2000
Cocaine is a potent central nervous system stimulant with severe addiction liability. Its
reinforcing and stimulant properties derive from inhibition of monoamine transport systems,
in particular the dopamine transporter (DAT). This inhibition results in an increase in synaptic
dopamine with subsequent stimulation of postsynaptic dopamine receptors. A wide variety of
ligands manifest potent inhibition of the DAT, and these ligands include 3-aryltropane as well
as 8-oxa-3-aryltropane analogues of cocaine. There has been considerable effort to determine
structure-activity relationships of cocaine and congeners, and it is becoming clear that these
inhibitors do not all interact with the DAT in the same manner. The functional role of the
8-heteroatom is the focus of this study. We describe the preparation and biology of a series of
2-carbomethoxy-3-arylbicyclo[3.2.1]octane analogues. Results show that methylene substitution
of the amine or ether function of the 8-hetero-2-carbomethoxy-3-arylbicyclo[3.2.1]octanes yields
potent inhibitors of monoamine transport. Therefore neither nitrogen nor oxygen are
prerequisites for binding of tropane-like ligands to monoamine transporters.
In tr od u ction
Cocaine is a potent central nervous system stimulant
with severe addiction liability. Its reinforcing and
stimulant properties are a consequence of its propensity
to inhibit monoamine transport systems, in particular
the dopamine transporter (DAT).1-8 This inhibition
results in an increase in synaptic dopamine levels which
then leads to overstimulation of postsynaptic dopamine
receptors.9 The DAT not only binds the classical nitrogen-
containing 3-aryltropane analogues of cocaine [(1R)-(2â-
carbomethoxy-3â-aryl-8-azabicyclo[3.2.1]octanes; WIN
analogues] (Figure 1)10-14 but also binds 8-oxa ana-
logues (for example O-914) with substantial potency and
selectivity.15-17 There has been considerable effort to
F igu r e 1. Structures of lead bicyclo[3.2.1]octanes.
determine structure-activity relationships (SAR) of
cocaine and congeners.5,6,10-14,17-24 It is becoming clear
Carbon is not a bioisostere for oxygen or nitrogen, and
that these disparate DAT inhibitors do not all interact
with the DAT in the same manner.16,25
therefore the exchange of carbon for an oxygen or
nitrogen atom in a biologically active nucleus is not
generally considered. Notwithstanding, within the phen-
yltropane series of cocaine analogues, we had already
demonstrated that the nitrogen is not essential for
biological activity.16 We had postulated24 that the three-
dimensional topology of the ligand may be more impor-
tant for binding to the biological macromolecule (DAT
or SERT (serotonin transporter)) than the specific
functionality present. Therefore we elected to replace
the heteroatom at position 8 of the tropane nucleus with
a carbon atom that is capable of neither ionic nor
hydrogen bonding and provides nothing other than
maintenance of the overall topological shape. Herein we
describe the preparation and biology of a series of
2-carbomethoxy-3-arylbicyclo[3.2.1]octane analogues
which possess a similar three-dimensional shape to their
8-aza and 8-oxa counterparts but which do not provide
the putative DAT anchor point of position 8. We show
The functional role of the 8-heteroatom in the 8-aza
and 8-oxatropanes16 (Figure 1) is the focus of this study.
The role of these 8-heteroatoms in the tropane system
has been suggested to provide either an ionic bond13
between the protonated amine and the presumed as-
partate residue (Asp79) on the DAT (8-aza)26 or a
hydrogen bond to an as yet unidentified DAT residue
in the case of the 8-oxatropanes.16 To evaluate the
possibility that neither an ionic nor a hydrogen bond is
necessary, we prepared novel bicyclo[3.2.1]octane ana-
logues devoid of an 8-heteroatom, for example, O-1414
(Figure 1).17
* To whom correspondence should be addressed. Tel: 781-932-4142.
Fax: 781-933-6695. E-mail: Meltzer@organixinc.com.
† Organix Inc.
‡ Naval Research Laboratory.
§ Harvard Medical School and New England Regional Primate
Center.
10.1021/jm000191g CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/15/2000

2-Carbomethoxy-3-aryl-8-bicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 2983
Sch em e 1. Synthesis of
2-Carbomethoxy-3-arylbicyclo[3.2.1]octanesa
F igu r e 2. NOE correlations of the epoxide 22.
This compound likely arises from initial isomerization
of the double bond from the 2,3-position to the 3,4-
position and subsequent quenching of the samarium
coordinated intermediate with oxygen present in the
older samarium iodide sample. This compound proved
relatively uninteresting biologically and has not been
pursued further (DAT IC50 ) 1.7 µM). The structure of
this epoxide is clear from mass spectrometry and the
NMR studies discussed below.
The combination of 1H-COSY and direct (HMQC) and
long-range (HMBC) H-C correlation experiments showed
the integrity of the bicyclo[3.2.1]octane skeleton and a
clear mapping of the different substituents present. The
stereochemistry of positions 2-4 was determined by
NOE (Figure 2). Irradiation of H-2′ produced NOE
enhancements in the signals corresponding to H-2 and
H-4, an indication that both of these protons were on
the same face of the molecule as the aromatic ring.
Finally, through-space interactions between H-8b and
H-2 and, to a lesser extent, H-4 indicated that these
protons were on the â-face of the molecule. For that
reason the R-configuration was assigned to both the
2-CO2Me group and the 3,4-epoxide.
a
Reagents: (i) H2SO4; (ii) LDA/THF, CNCOOCH3; (iii) NaN(T-
MS)2, PhNTf2; (iv) ArB(OH)2, Pd2(dba)3; (v) SmI2, CH3OH.
that methylene (-CH2-) substitution of the amine
(-N(CH3)-) or ether (-O-) function of the 8-hetero-2-
carbomethoxy-3-arylbicyclo[3.2.1]octanes results in po-
tent inhibitors of monoamine transport. This calls into
question the dogma that a heteroatom at position 8 is
needed for potent and selective inhibition of the DAT.
Ch em istr y
In each of the four cases 6a -d the corresponding
configurational isomers 7-10 presented as single spots
in all TLC systems evaluated. They therefore proved
extremely difficult to separate, and biological evaluation
was initially conducted on the isomeric mixtures in
order to determine which isomers might warrant labori-
ous separation. The 4-fluorophenyl mixture of isomers
6c and the unsubstituted mixture of isomers 6d both
presented DAT IC50 binding constants of about 0.3-0.8
µM and were therefore set aside. In sharp contrast, the
3-(3,4-dichlorophenyl) 6a and 3-(2-naphthyl) 6b ana-
logues manifested unexpectedly potent binding, and
these two compounds were selected for careful separa-
tion of configurational isomers.
Notwithstanding the great similarity in polarity
between the configurational isomers 7a -10a and 7b-
10b, careful gravity column chromatography on flash
silica provided the pure 2â,3â- (7a ,b), 2R,3â- (8a ,b),
2â,3R- (9a ,b), and 2R,3R- (10a ,b) bicyclo[3.2.1]octanes,
albeit in low yields.
The biological activity determined for these com-
pounds (Table 2) was sufficiently interesting and un-
usual to warrant meticulous and unequivocal structural
assignment. The configuration of each isomer was
determined by NMR studies and was corroborated by
X-ray crystallography. Although proton resonance posi-
tions and multiplicity have been reported for both the
8-aza and 8-oxa analogues, assignments are more dif-
ficult for the carba analogues since the absence of an
8-heteroatom causes the R-protons, H-1 and H-5, to shift
upfield and into the domain of other skeletal protons.
The determination of the relative configuration of
compounds 7a -10a was achieved by a combination of
A general route developed for synthesis of certain
2-carbomethoxy-3-(3,4-dichlorophenyl)bicyclo[3.2.1]-
octanes has been communicated previously from these
laboratories.17 We now report the complete details of
synthesis, separation, and characterization of all four
isomers of the 3-(3,4-dichlorophenyl) and 3-(2-naphthyl)
analogues as well as the 3-(4-fluorophenyl) and the
unsubstituted 3-phenyl carbocycles. The synthetic route
(Scheme 1) provides a racemic mixture of each of the
configurational isomers (7-10), and biological data are
therefore provided for racemates of 7-10.
The ketone 2 was obtained in 77% yield27 upon
treatment of the commercially available 3-chlorobicyclo-
[3.2.1]oct-2-ene, 1, with sulfuric acid. The 2-carbomethoxy
group was then introduced16 by reaction of 2 with
methyl cyanoformate in the presence of lithium diiso-
propylamide to provide the racemic keto ester 3 (83%).
The keto ester 3 exists in equilibrium in three isomeric
forms as evidenced by 1H NMR (2R-carboxy ester, enol-
2-carboxy ester, and 2â-carboxy ester) and was con-
verted as such to the enol triflate 4 (75%) by treatment
with phenylbis(trifluoromethanesulfonyl)amine in the
presence of sodium bis(trimethylsilyl)amide. Suzuki
coupling28,29 of the enol triflate with the appropriate
boronic acids then provided the 2,3-unsaturated ana-
logues 5a -d in 54-75% yield. Reduction of 5a -d with
samarium iodide gave 6a -d (64-84%) as a mixture of
all four isomers 7-10.30
An interesting observation was made in one case
where older samarium iodide was utilized. In addition
to the usual reductive products, treatment of 5c with
reducing agent provided the 3,4-epoxide 22 (Figure 2).

2984 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16
Meltzer et al.
NMR techniques. The 1H NMR spectra were completely
assigned (COSY, HMQC, HMBC). An analysis of the
multiplicity of the key resonances showed familiar
coupling patterns observed previously for the 8-aza and
8-oxa analogues.11,16 The chemical shifts and coupling
constants for selected protons for configurational iso-
mers are presented in Table 1. Compounds 8a and 9a
showed a large coupling (12 Hz) between H-2 and H-3,
typical of a trans-diaxial interaction. This is compatible
with both 2R,3â-substitution in the chair conformation
or 2â,3R-substitution in the boat conformation. In
contrast, coupling constants between H-2 and H-3 in 7a
and 10a were smaller (6 Hz) and characteristic of axial-
equatorial interactions thus indicating 2â,3â-substitu-
tion in the chair conformation or 2R,3R-substitution in
the boat conformation. Finally compounds 9a and 10a
were identified as the 3R-substituted isomers since they
manifested NOE interactions between H-3 and H-8 thus
confirming the through-space proximity of these atoms.
Such proximity is only possible if H-3 is in the â-con-
figuration in a boat conformation. These results not only
provided unequivocal identification of compounds 7a -
10a but also confirmed that, in this series, the 3R-aryl-
substituted analogues adopted the boat conformation for
the six-membered ring, as already shown in the case of
the 8-aza and 8-oxa series.16,31
X-ray structural analyses were conducted on four
configurational racemates: 7a (2â,3â), 8a (2R,3â), 8b
(2R,3â), 10b (2R,3R). The absolute structures were then
correlated with the relevant 1H NMR spectra and all
configurations assigned unambiguously
To probe the dominating significance of the relation-
ship between the C-2 ester and a C-3 aromatic substitu-
ent, the compounds presented in Scheme 2 were pre-
pared by straightforward chemistry. Thus, commercially
available methyl 2-iodobenzoate (16) was coupled with
appropriate arylboronic acids to obtain 17a -d and 21.
Compound 19 was obtained upon benzoylation of 18.
Biology
The affinities of the bicyclo[3.2.1]octane analogues for
the DAT and SERT were determined in competition
studies using [3H]-3â-(4-fluorophenyl)tropane-2â-car-
boxylic acid methyl ester ([3H]WIN 35,428) to label the
DAT6 and [3H]citalopram to label the SERT.15 Each
compound was tested 2-5 times, and each assay was
conducted independently in brain tissue of rhesus or
cynomolgus monkey.
Binding data (IC50) for the bicyclo[3.2.1]octane race-
mates are presented in Table 2. Data for 8-azabicyclo-
[3.2.1]octanes are presented in Table 3. The 1-aryl-2-
carbomethoxy analogues are presented in Table 4.
Studies were conducted in monkey striatum because
these compounds are part of an ongoing investigation
of SARs at the DAT in this tissue.6,11,12,17,19,24 Hence
meaningful comparisons with an extensive database can
be made. IC50 values are reported as the assay concen-
trations of [3H]WIN 35,428 and [3H]citalopram were
below Kd values. Competition studies were conducted
with a fixed concentration of radioligand and a range
of concentrations of the test drug. All drugs inhibited
[3H]WIN 35,428 and [3H]citalopram binding in a con-
centration-dependent manner.
It is clear that certain of the bicyclo[3.2.1]octanes bind
potently and selectively to the DAT versus the SERT

2-Carbomethoxy-3-aryl-8-bicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 2985
Ta ble 2. Inhibition of [3H]WIN 35,428 Binding to the DAT and [3H]Citalopram Binding to the SERT by Bicyclo[3.2.1]octanes in
Cynomolgus Monkey Caudate-Putamen
IC50 (nM)
DAT
SERT
selectivity
SERT/DAT
Ar
no.
compd
[3H]WIN 35,428
[3H]citalopram
3,4-Cl2C6H3
2-naphthyl
4-FC6H4
5a
5b
5c
5d
6c
6d
7a
7b
8a
8b
9a
9b
10a
10b
O-1231
O-1482
O-1436
O-1443
O-1472
O-1488
O-1414
O-1669
O-1415
O-1590
O-1442
O-1670
O-1468
O-1649
7.1
11
5160
1310
35400
>10000
nab
726
119
91
390
3816
335
787
9.6
27
14
12
13
17
C6H5
4-FC6H4 (m)a
C6H5 (m)
>20000
25
3
2
46
67
14
4
3,4-Cl2C6H3
2-naphthyl
3,4-Cl2C6H3
2-naphthyl
3,4-Cl2C6H3
2-naphthyl
3,4-Cl2C6H3
2-naphthyl
33
60
650
807
180
64
na
106
42
25
4
a
b
m ) evaluated as a mixture of all four configurational isomers. na ) not available.
Sch em e 2. Synthesis of Carbomethoxyaryl Analoguesa
Discu ssion
It has long been assumed that for tropanes and
bicyclo[3.2.1]octanes to manifest potent inhibition of the
DAT they should possess substitution at the C-2
position.5,11,32-34 However, although it has often been
presumed that such C-2 substitution should be in the
â-orientation, this proves not to be the case. Indeed,
after careful evaluation of the literature, we were
encouraged to further explore the effect of 2R- versus
2â-substitution upon inhibition of both the DAT and
SERT.
a
Reagents: (i) ArB(OH)2, Pd(Ph3)2Cl2, CsCO3; (ii) C6H5COCl.
The importance of this question resides in the fact
that the dogma of 2â-orientation has guided a consider-
able amount of the work in the tropane area and may
have lead to the abandonment of potentially important
and interesting compounds. In general, 2R-compounds
have not been evaluated even when they have emerged
from the synthetic route utilized to make their 3â-
counterparts.11,20 In the interests of reassessing the
importance of consideration of 2R-substitution, we now
present a summary of relevant SAR.
(Table 2). Analogously to the 8-aza- and 8-oxatropanes,
the most potent carbocycles are those which possess
either a 2-naphthyl group or a 3,4-dichlorophenyl group
at C-3 of the carbocycle. Thus, the 3,4-dichlorophenyl
2,3-unsaturated analogue 5a has an IC50 of 7.1 nM for
the DAT and is extremely selective (SERT: IC50 ) 5160
nM; 726-fold selectivity). This is similar to the potency
(DAT: IC50 ) 1.2 nM) and selectivity (SERT: IC50
)
The assumption that 2R-substitution leads to much
less active DAT inhibitors and therefore potentially less
interesting compounds derives from the early work in
this area. Thus Clarke et al.35 reported that in the
phenyltropanes, moving the C-2 substituent from a C-2â
orientation to a C-2R orientation resulted in loss of
stimulant activity in their locomotor screen.
Later Reith5 reported that moving the C-2 car-
bomethoxy group in cocaine from an axial (â) to an
equatorial (R) position significantly diminished potency
in their behavioral assay. Ritz32 confirmed this in a
ligand binding assay and reported that the potency ratio
between 2R-carbomethoxy-3-phenyltropane (WIN 35,-
140) and 2â-carbomethoxy-3-phenyltropane (WIN 35-
065-2) was 1481, thus rendering the 2R-isomer com-
paratively inactive.
867 nM) exhibited by the 2,3-unsaturated 8-aza ana-
logue 11a . The 2-naphthyl 2,3-unsaturated analogue 5b
is also quite potent (DAT: IC50 ) 11 nM) and selective
(SERT: IC50 ) 1,310). It is notably more selective than
its nitrogen 2,3-unsaturated counterpart 11b (Table 3)
which manifests a SERT IC50 of 109 nM and 38-fold
selectivity. The saturated carbocyclic (Table 2: 7a , 8a ,
9a , 10a ) and 8-aza (Table 3: 12a , 13a , 14a ) 3,4-
dichlorophenyl compounds manifest potencies of 7-42
nM irrespective of the configuration at either C-2 or C-3.
The same is true for the C-3 2-naphthyl carbocyclic
(Table 2: 7b, 8b, 9b, 10b) and 8-aza (Table 3: 12b, 15b)
analogues. In general, the carbocycles in each class are
less potent than their nitrogenous counterparts al-
though both series bind with low nanomolar affinity.

2986 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16
Meltzer et al.
Ta ble 3. Inhibition of [3H]WIN 35,428 Binding to the DAT and [3H]Citalopram Binding to the SERT by Bicyclo[3.2.1]octanes in
Cynomolgus Monkey Caudate-Putamena
IC50 (nM)
DAT
SERT
selectivity
SERT/DAT
Ar
no.
compd
[3H]WIN 35,428
[3H]citalopram
3,4-Cl2C6H3
2-naphthyl
4-FC6H4
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
13c
14a
14b
15a
15b
O-1109
O-1173
O-1104
nab
O-401
O-1229
O-381
na
O-1496
na
O-1492
O-1157
na
1.2
2.9
408
na
1.1
0.49
11
na
2.0
na
633
0.4
na
na
0.57
867
109
7990
na
723
38
20
C6H5
3,4-Cl2C6H3
2-naphthyl
4-FC6H4
2
2
4
15
2.19
160
na
358
na
C6H5
3,4-Cl2C6H3
2-naphthyl
4-FC6H4
3,4-Cl2C6H3
2-naphthyl
3,4-Cl2C6H3
2-naphthyl
179
12200
27
19
68
na
na
5.95
na
O-1228
10
a
b
See ref 11 and references therein for syntheses of these analogues. na ) not available.
Ta ble 4. Inhibition of [3H]WIN 35,428 Binding to the DAT and [3H]Citalopram Binding to the SERT by Biaryl Analogues in
Cynomolgus Monkey Caudate-Putamen
IC50
DAT
SERT
selectivity
SERT/DAT
Ar
no.
compd
[3H]WIN 35,428
[3H]citalopram
2-naphthyla
17a
17b
17c
17d
19
O-1521
O-1567
O-1571
O-1566
O-1574
O-1570
O-1565
145 nM
675 nM
16 µM
>100 µM
548 nM
>100 µM
1 µM
10 µM
46 µM
69
68
2
b
4-ClC6H4
c
4-FC6H4
C6H5
33 µM
d
>70 µM
e
OCOC6H5
COOCH3
e
20
21
>100 µM
>10 µM
C6H4-C6H4-4Br
a
b
Craebe et al. J ustus Liebigs Ann. Chem. 1904, 335; Bradsher et al. J . Am. Chem. Soc. 1940, 62, 3140. Klement et al. Tetrahedron
1996, 52, 7201. c Kelm and Strauss Spectrochim. Acta Part A 1981, 37, 689. Grieve and Hey J . Chem. Soc. 1938,108. e Purchased from
d
Aldrich.
In 19896,18 it was reported that cocaine receptors were
labeled by 2â-carbomethoxy-3â-(4-fluorophenyl)tropane
but not by the 2R-isomer. Neumeyer36 reported (1991)
potent to its 2â-analogue. This work was followed by a
second patent by Moldt et al. (1998)41 in which they
reported that 3â-(3,4-dichlorophenyl)-2R-O-methylal-
doxime tropane inhibits the DAT with an IC50 ) 1.8 nM.
The prototypical tropane WIN 35,42835 has a 2â-
configured carbomethoxy group and manifests an IC50
of about 11 nM with DAT:SERT selectivity of about 15.
We evaluated the 2R-carbomethoxy isomer of WIN 35,-
428 (13c) and found it to possess an IC50 of 633 nM and
DAT:SERT selectivity of 19. It is therefore considerably
weaker than its 3â-counterpart and about as selective.
However, the more potent tropane, 2â-carbomethoxy-
3â-(3,4-dichloro)phenyltropane (12a ), manifests an IC50
of 1.1 nM (selectivity ) 2), and its 2R-carbomethoxy
counterpart 13a is almost as potent with an IC50 for
inhibition of [3H]WIN 35,428 binding of 2.0 nM but has
much enhanced selectivity (179-fold). (Moldt39 had
reported an IC50 ) 16 nM for inhibition of [3H]dopamine
reuptake for this compound.) Likewise, the 2â-car-
[
123I]-2â-carbomethoxy-3â-(4-iodophenyl)tropane as a
SPECT radiotracer for monoamine reuptake sites and
pointed out that the 2R-analogue was effectively 55
times less potent that the 2â-analogue.
Carroll’s report37 on C-2 heterocyclic analogues in
1993 and later in 199638 confirmed this yet again in
that 3â-phenyl-2R-(3′-methyl-1′,2′,4′-oxadiazol-5′-yl)tro-
pane was considerable less potent as an inhibitor of the
DAT than the 2â-analogue.
In contrast, Moldt described39 a series of 2R-substi-
tuted tropanes in 1994 that manifests surprising DAT
potency. In fact, 3â-(3,4-dichlorophenyl)-2R-carbomethoxy
tropane, 13a , reportedly manifested an IC50 ) 16 nM
for inhibition of [3H]dopamine reuptake. Trudell40 then
reported in 1997 that the 2R-homologated ester, 3â-
benzyl-2R-(carbomethoxy)methyltropane, was about equi-

2-Carbomethoxy-3-aryl-8-bicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 2987
bomethoxy-3â-(2-naphthyl) 12b manifests an IC50 ) 0.5
nM (selectivity ) 4), while the 2R-carbomethoxy-3R-(2-
naphthyl) counterpart 15b has IC50 ) 0.57 nM and
selectivity of about 10-fold. Consequently it is not
surprising that in the family of carbocyclic compounds
presented here, similar results are obtained. Thus, while
the 2â-carbomethoxy compound 7a has IC50 ) 9.6 nM
and 9a has IC50 ) 13 nM, the 2R-compounds 8a and
10a manifest IC50’s of 14 and 42 nM, respectively (Table
2). Furthermore, this trend holds for the 3-(2-naphthyl)-
substituted compounds as well. Thus, the 2â-car-
bomethoxy analogues 7b and 9b manifest IC50 values
of 27 (selectivity: 2) and 17 nM (selectivity: 4), respec-
tively, while their 2R-counterparts 8b and 10b have IC50
values of 12 nM (selectivity: 67) and 25 nM (selectiv-
ity: 4), respectively.
remarkably similar to that for the bicyclo[3.2.1]octanes.
Thus the naphthyl compound 17a is more potent (IC50
) 145 nM) than the monochloro 17b (IC50 ) 675 nM),
while the 4-fluoro 17c (IC50 ) 16 µM) and unsubstituted
17d (IC50 ) >100 µM) compounds exhibit very poor
potency (SAR: naphthyl > chloro > fluoro > H). It is
extremely surprising that the naphthyl analogue is as
potent as 145 nM at the DAT. This inhibition is close
to the range of cocaine (IC50 of 90 nM)! In the case where
an intervening ester is introduced between the “skel-
eton” and the aryl group (analogous to cocaine) as in
19, it is remarkable that the IC50 is as potent as 548
nM. Extension of the aromatic system as in 21 and
removal of the aryl ring in 20 lead to a considerable loss
in potency.
Con clu sion
It may therefore be concluded that those 2â-com-
pounds that manifest substantial potency have 2R-
carbomethoxy isomers with similar DAT binding inhi-
bition and often much greater selectivity versus the
SERT. In contrast, the 2R-carbomethoxy analogues of
relatively less potent 2â-carbomethoxy compounds are
themselves not potent. This brings into question the
function of the 2-substituent with respect to its interac-
tion at the acceptor site24 on the DAT or SERT.
The most important conclusion from these studies is
that neither nitrogen nor oxygen are prerequisites for
binding of tropane-like ligands to monoamine transport-
ers. Binding of dopamine, and the tropanes, to the DAT
has been assumed to require the ionic interaction of an
aspartic acid residue (Asp79) with the nitrogenous
ligand.26 Hydrogen bonding has been proposed to ex-
plain the interaction of the 8-oxatropanes with the
DAT.16 Formation of either an ionic bond or a hydrogen
bond is not possible with these carbocyclic compounds,
and yet many bind to both the DAT and SERT with
potency similar to that of their nitrogen- or oxygen-
containing counterparts.
We postulate that there are a number of ligand
acceptor sites within the DAT and that binding at any
one of these acceptor sites can cause inhibition of
dopamine reuptake.16,24,25,42 These three families may
occupy different ligand acceptor sites on the DAT and
SERT and may consequently have different require-
ments for binding. For example, 8-aza compounds may
bind at a site that possesses an acid residue (e.g. Asp79),
while the 8-oxa analogues may bind at a different
acceptor site that can offer hydrogen bonding. The
carbocycles may inhibit monoamine transport by bind-
ing to yet a third acceptor site that relies on neither an
acid residue nor a residue capable of hydrogen donation
to the ligand. This concept is currently under investiga-
tion in our laboratories.
We have previously suggested that tight binding
between the ligand and its biological receptor may
depend more heavily upon the three-dimensional topol-
ogy of the ligand than upon the exact functionality
present.24 For example, the actual substitution of the
8-position is of less consequence than is the volume that
it occupies. Evidence for this is the fact that the
8-position can be changed from nitrogen to oxygen to
carbon with limited effect on affinity. In contrast, the
SAR of DAT inhibition is markedly effected by the
nature of substituents at C-3.11,14,20 Therefore a domi-
nant factor governing interaction of a DAT ligand with
the transporter may be its topology (molecular volume
and shape).24 We have also previously suggested that
subtle topological placement of the 3-aryl substituent
most likely controls not only binding potency but also
selectivity for the DAT versus the SERT.24 This was
evidenced by the fact that compounds in the boat
conformation (3R) are equally potent to, but more
selective than, those in the chair conformation (3â) with
respect to DAT inhibition. This difference in conforma-
tion controls placement of the aromatic ring. Further-
more it appears that the ring conformation may be
further modified by the relationship between the sub-
stituents at C-2 and C-3.
Exp er im en ta l Section
All compounds are racemates (1R/1S). NMR spectra were
recorded in CDCl3 on a J EOL 300 NMR spectrometer operat-
ing at 300.53 MHz for 1H and 75.58 MHz for 13C. TMS was
used as internal standard. Melting points are uncorrected and
were measured on a Gallenkamp melting point apparatus.
Thin-layer chromatography (TLC) was carried out on Baker
Si250F plates. Visualization was accomplished with either UV
exposure or treatment with phosphomolybdic acid (PMA).
Flash chromatography was carried out on Baker silica gel 40
mm. Elemental analyses were performed by Atlantic Microlab,
Atlanta, GA. All reactions were conducted under an inert (N2)
atmosphere. [3H]WIN 35,428 (2â-carbomethoxy-3â-(4-fluo-
rophenyl)-N-[3H]methyltropane, 79.4-87.0 Ci/mmol) and [3H]-
citalopram (86.8 Ci/mmol) were purchased from DuPont-New
England Nuclear (Boston, MA). A Beckman 1801 scintillation
counter was used for scintillation spectrometry. 0.1% Bovine
serum albumin was purchased from Sigma Chemicals. (R)-
(-)-Cocaine hydrochloride for the pharmacological studies was
donated by the National Institute on Drug Abuse (NIDA).
In an effort to further explore the concept of topology
dominating functionality, we prepared and evaluated
the simple molecules 17 and 19 presented in Scheme 2.
The design of these molecules was based upon the
premise that the bicyclo[3.2.1]octane system of the
tropanes, their 8-oxa analogues, and the 8-carba ana-
logues may merely provide a useful skeleton and that
the relative relationship of the C-2 ester and the C-3
aromatic ring may of itself dominate biological activity
with respect to DAT inhibition. From an examination
of the IC50 values (Table 4) obtained for the compounds
modeled on the 3-arylbicyclo[3.2.1]octanes in which the
aryl group is tied directly to the C-3 carbon of the
skeleton, it is clear that the SAR of this small series is

2988 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16
Meltzer et al.
2-Car bom eth oxybicyclo[3.2.1]octan -3-on e (3). To bicyclo-
[3.2.1]octan-3-one, 227 (6.42 g, 51.7 mmol) in THF (75 mL), was
added dropwise at -78 °C lithium diisopropylamide (31 mL,
62 mmol) in THF (125 mL). The mixture was stirred at -78
°C for 1 h and methyl cyanoformate (4.9 mL, 62 mmol) was
added. The cooling bath was removed and the reaction allowed
to warm to room temperature. After stirring for 2 h, saturated
aqueous NaCl (32 mL) was added and about half of THF
removed on a rotary evaporator. The remaining solvent was
extracted with ether (3 × 150 mL) and the dried (Na2SO4)
ether layer concentrated to dryness. The residue was purified
by flash chromatography (eluent: 10% EtOAc/hexanes) to
afford 7.85 g (83%) of 3 as a colorless oil: Rf 0.56 (10% EtOAc/
hexanes); 1H NMR (75:15:10 mixture of 2-en-3-ol, 2R-, and 2â-
carbomethoxy 3-keto tautomers) δ 11.87 (s, 1H), 3.73 (s, 3H),
3.70 (s, 0.6H), 3.69 (s, 0.4H), 3.42 (m, 0.2H), 3.19 (m, 0.13H),
2.93 (m, 1H), 2.81 (m, 0.13H), 2.71 (m, 0.2H), 2.65 (ddd, 0.13H,
J ) 18, 4, 2 Hz), 2.55 (ddd, 1.2H, J ) 18, 4, 2 Hz), 2.41 (m,
1H), 2.34 (m, 0.2H), 2.29 (m, 0.13H), 2.03 (dd, 1H, J ) 18, 2
Hz), 1.65-1.95 (m, 4.4H), 1.30-1.55 (m, 3.6H); 13C NMR (only
the signals corresponding to the 2-en-3-ol tautomer are
reported) δ 172.00, 171.19, 105.38, 51.33, 40.19, 35.92, 35.58,
32.91 (2C), 29.90.
by flash chromatography (eluent: 10% EtOAc/hexanes) to
afford 0.25 g (54%) of 5b as a colorless oil: Rf 0.41 (10% EtOAc/
hexanes); 1H NMR δ 7.83 (m, 3H), 7.62 (d, 1H, J ) 1 Hz), 7.48
(m, 2H), 7.28 (dd, 1H, J ) 9, 2 Hz), 3.44 (s, 3H), 3.14 (bt, 1H,
J ) 5 Hz), 2.84 (ddd, 1H, J ) 19, 4, 1 Hz), 2.53 (m, 1H), 2.38
(bd, 1H, J ) 19 Hz), 1.80-2.20 (m, 4H), 1.60-1.75 (m, 2H);
13C NMR δ 169.17, 143.83, 139.85, 134.55, 133.04, 132.33,
127.76, 127.47, 127.21, 125.83, 125.54 (2), 124.86, 51.04, 44.35,
37.16, 35.54, 34.82, 33.21, 30.60. Anal. (C20H20O2) C, H.
2-Ca r b om et h oxy-3-(4-flu or op h en yl)b icyclo[3.2.1]-2-
octen e (5c). Compound 5c was obtained from with 4-fluo-
rophenylboronic acid as described for 5a : colorless oil (73%);
Rf 0.5 (10% EtOAc/hexanes); 1H NMR δ 6.95-7.10 (m, 4H),
3.46 (s, 3H), 3.00 (t, 1H, J ) 5 Hz), 2.67 (dd, 1H, J ) 19, 4
Hz), 2.46 (m, 1H), 2.20 (bd, 1H, J ) 19 Hz), 1.50-2.05 (m,
6H); 13C NMR δ 169.10, 161.86 (d, J ) 245 Hz), 143.05, 138.32,
134.69, 128.30 (d, J ) 8 Hz), 114.81 (d, J ) 21 Hz), 51.18,
44.53, 37.15, 35.55, 34.86, 33.21, 30.65. Anal. (C16H17O2F) C,
H.
2-Ca r bom eth oxy-3-p h en ylbicyclo[3.2.1]-2-octen e (5d ).
Compound 5d was prepared from with phenylboronic acid as
described for 5a : colorless oil (75%); Rf 0.5 (10% EtOAc/
1
hexanes); H NMR δ 7.27 (m, 3H), 7.08 (m, 2H), 3.43 (s, 3H),
2-Ca r b om et h oxy-3-{[(t r iflu or om et h yl)su lfon yl]oxy}-
bicyclo[3.2.1]-2-octen e (4). To 2-carbomethoxybicyclo[3.2.1]-
octan-3-one, 3 (6.0 g, 3.29 mmol) in THF (120 mL), was added
dropwise at -78 °C sodium bis(trimethylsilyl)amide (1.0 M
solution in THF, 49.4 mL). After stirring for 30 min, N-
phenyltrifluoromethane sulfonimide (17.6 g, 4.94 mmol) was
added in one portion. After 10 min, the cooling bath was
removed and the reaction mixture stirred overnight. Water
(100 mL) was added to the reaction mixture and extracted with
diethyl ether (3 × 150 mL). The dried (Na2SO4) ether layers
were concentrated to dryness on a rotary evaporator. The
residue was purified by flash chromatography (eluent: 20%
EtOAc/hexanes) to afford 7.8 g (75%) of 4 as a colorless oil: Rf
3.00 (bt, 1H, J ) 5), 2.70 (ddd, 1H, J ) 19, 4, 1 Hz), 2.46 (m,
1H), 2.23 (bd, 1H, J ) 19 Hz) 1.80-2.05 (m, 3H), 1.73 (d, 1H,
J ) 11 Hz), 1.50-1.65 (m, 2H); 13C NMR δ 169.31, 144.03,
142.46, 134.28, 127.88, 126.95, 126.61, 51.11, 44.37, 37.17,
35.60, 34.90, 33.26, 30.66. Anal. (C16H18O2) C, H.
2(r,â)-Ca r b om et h oxy-3(r,â)-(4-flu or op h en yl)b icyclo-
[3.2.1]octa n e (6c). Magnesium (47 mg, 1.90 mmol) was added
into 2-carbomethoxy-3-(4-fluorophenyl)bicyclo[3.2.1]-2-octene,
5c (50 mg, 0.19 mmol) in methanol (2 mL). After 1 h, additional
magnesium (47 mg, 1.90 mmol) was added and stirred for 4
h. 1 N HCl (4 mL) was added dropwise and stirred for 1 h.
The reaction mixture was extracted with ether (3 × 20 mL)
and dried over Na2SO4 and the ether layer removed on a rotary
evaporator. The residue was purified by flash chromatography
(eluent: 10% EtOAc/hexanes) to afford 42 mg (84%) of 6c as
1
0.56 (20% EtOAc/hexanes); H NMR δ 3.79 (s, 3H), 3.10 (m,
1H), 2.71 (dd, 1H, J ) 18, 5 Hz), 2.52 (m, 1H), 2.17 (dd, 1H, J
) 18, 2 Hz), 1.75-2.05 (m, 3H), 1.45-1.70 (m, 3H); 13C NMR
δ 164.44, 151.02, 129.04, 118.23 (q, J ) 320 Hz), 52.05, 39.68
(d, J ) 1 Hz), 36.61, 35.34, 34.51, 33.31, 30.01.
a colorless oil: Rf 0.42 (10% EtOAc/hexanes). Anal. (C16H19
-
FO2) C, H.
2(r,â)-C a r b o m e t h o x y -3(r,â)-p h e n y lb ic y c lo [3.2.1]-
octa n e (6d ). Compound 6d was prepared from 5d with
magnesium as described for 6c: colorless oil (48%); Rf 0.42
(10% EtOAc/hexanes). Anal. (C16H20O2) C, H.
2-Ca r bom eth oxy-3-(3,4-d ich lor op h en yl)bicyclo[3.2.1]-
2-octen e (5a ). 2-Carbomethoxy-3-{[(trifluoromethyl)sulfonyl]-
oxy}bicyclo[3.2.1]-2-octene, 4 (2.0 g, 63.6 mmol), 3,4-dichloro-
phenylboronic acid (1.58 g, 82.7 mmol), tris(dibenzylidene-
acetone)dipalladium(0) (0.29 g, 0.32 mmol), Na2CO3 (2 M
solution, 6.4 mL) and diethoxymethane (32 mL) were combined
and refluxed at 95 °C for 4 h. Tris(dibenzylideneacetone)-
dipalladium(0) (1.45 g) was then added in five equal portions
at 4-h intervals. The reaction mixture was cooled to room
temperature, filtered through Celite, and washed with ether
(200 mL). The ether solution was then washed with saturated
aqueous NaCl (100 mL). The dried (Na2SO4) ether layer was
removed on a rotary evaporator. The residue was purified by
flash chromatography (eluent: 10% EtOAc/hexanes) to afford
1.38 g (69%) of 5a as a colorless oil: Rf 0.50 (10% EtOAc/
2â-Ca r b om e t h oxy-3â-(3,4-d ich lor op h e n yl)b icyclo-
[3.2.1]octa n e (7a ), 2r-Ca r bom eth oxy-3â-(3,4-d ich lor o-
ph en yl)bicyclo[3.2.1]octan e (8a), 2â-Car bom eth oxy-3r-(3,4-
d ich lor op h en yl)bicyclo[3.2.1]octa n e (9a ), a n d 2r-Ca r -
bom eth oxy-3r-(3,4-d ich lor op h en yl)bicyclo[3.2.1]octa n e
(10a ). To 2-carbomethoxy-3-(3,4-dichlorophenyl)bicyclo[3.2.1]-
2-octene, 5a (1.38 g, 4.43 mmol) in methanol (50 mL) at -78
°C, was added SmI2 (0.1 M in THF, 237 mL) dropwise via an
addition funnel. After completing the addition, the green
mixture was stirred for 4 h at -78 °C and quenched with TFA
(20 mL) in ether (60 mL). H2O (50 mL) was added and
extracted with ether (3 × 200 mL). The dried (Na2SO4) ether
layer was concentrated to dryness. The residue was purified
by flash chromatography (eluent: 20% EtOAc/hexanes) to
afford a mixture of isomers 6a (1 g, 72%). The isomers were
separated by gravity column chromatography (eluent: 10-
50% toluene/hexanes) to afford 65 mg of 7a as a white solid
(mp 81.1-81.4 °C), 280 mg of 8a as a white solid (mp 65.3-
65.6 °C), 58 mg of 9a as a white solid (mp 82.8-83.3 °C), and
42 mg of 10a as a white solid (mp 83.2-83.8 °C). 7a : 1H NMR
δ 7.31 (d, 1H, J ) 2 Hz), 7.30 (d, 1H, J ) 8 Hz), 7.08 (ddd, 1H,
J ) 8, 2, 1 Hz), 3.44 (s, 3H), 2.98 (ddd, 1H, J ) 13, 6, 6 Hz),
2.84 (dd, 1H, J ) 6, 6 Hz), 2.53 (m, 1H), 2.42 (m, 1H), 2.31
(ddd, 1H, J ) 13, 13, 2 Hz), 1.45-2.00 (m, 5H), 1.85 (bd, 1H,
J ) 12 Hz), 1.28 (ddd, 1H, J ) 12, 6, 6 Hz); 13C NMR δ 173.24,
144.03, 131.86, 129.77, 129.75, 129.63, 126.95, 52.15, 51.05,
1
hexanes); H NMR δ 7.34 (d, 1H, J ) 8 Hz), 7.17 (d, 1H, J )
2 Hz), 6.90 (dd, 1H, J ) 8, 2 Hz) 3.49 (s, 3H), 3.00 (bt, 1H, J
) 5 Hz), 2.64 (ddd, 1H, J ) 19, 4, 2 Hz), 2.44 (m, 1H), 2.14
(dd, 1H, J ) 19, 1 Hz), 1.75-2.05 (m, 3H), 1.45-1.70 (m, 3H);
13C NMR δ 168.54, 142.60, 142.13, 135.55, 132.07, 130.95,
130.00, 128.80, 126.45, 51.48, 44.52, 37.13, 35.65, 34.86, 33.24,
30.76. Anal. (C16H16O2Cl2) C, H, Cl.
2-Car bom eth oxy-3-n aph th ylbicyclo[3.2.1]-2-octen e (5b).
2-Carbomethoxy-3-{[(trifluoromethyl)sulfonyl]oxy}bicyclo[3.2.1]-
2-octene, 4 (0.50 g, 1.60 mmol), 2-naphthaleneboronic acid
(0.36 g, 2.08 mmol), tris(dibenzylideneacetone)dipalladium(0)
(0.07 g, 0.08 mmol), Na2CO3 (2 M solution, 1.6 mL) and
diethoxymethane (8 mL) were combined and refluxed at 95
°C overnight. The reaction mixture was cooled to room
temperature, filtered through Celite and washed with ether
(100 mL). The ether solution was then extracted with satu-
rated aqueous NaCl (50 mL). The dried (Na2SO4) ether layer
was removed on a rotary evaporator. The residue was purified
38.37, 35.91, 34.54, 33.24, 32.95, 29.59, 28.03. Anal. (C16H18
-
Cl2O2) C, H, Cl. 8a : 1H NMR δ 7.31 (d, 1H, J ) 8 Hz), 7.30 (d,
1H, J ) 2 Hz) 7.06 (dd, 1H, J ) 8, 2 Hz), 3.51 (s, 3H), 3.10
(ddd, 1H, J ) 12, 12, 6 Hz), 2.66 (dd, 1H, J ) 12, 2 Hz), 2.48

2-Carbomethoxy-3-aryl-8-bicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 2989
(m, 1H), 2.32 (m, 1H), 1.87 (m, 1H), 1.45-1.80 (m, 7H); 13C
NMR δ 173.94, 144.94, 132.11, 130.18, 129.95, 129.61, 127.18,
52.82, 51.40, 40.83, 39.26, 38.70, 38.28, 34.95, 28.60, 25.14.
Anal. (C16H18Cl2O2) C, H, Cl. 9a : 1H NMR 7.30 (d, 1H, J ) 8
Hz), 7.25 (d, 1H, J ) 2 Hz) 7.01 (dd, 1H, J ) 8, 2 Hz), 3.54 (s,
3H), 3.03 (ddd, 1H, J ) 12, 12, 8 Hz), 2.36 (d, 1H, J ) 12 Hz),
2.30-2.40 (m, 2H), 2.24 (ddd, 1H, J ) 12, 8, 8 Hz), 1.94 (m,
1H), 1.92 (bd, 1H, J ) 12 Hz), 1.74 (m, 1H), 1.56 (m, 1H), 1.44
(m, 1H), 1.20 (dd, 1H, J ) 12, 12 Hz), 1.10 (ddd, 1H, J ) 12,
4, 4 Hz); 13C NMR δ 175.68, 145.19, 132.14, 130.18, 130.05,
129.70, 127.30, 55.93, 51.60, 38.92, 36.99, 36.70, 33.44, 32.89,
31.76, 29.83. Anal. (C16H18Cl2O2) C, H, Cl. 10a : 1H NMR δ
7.31 (dd, 1H, J ) 2, 1 Hz), 7.28 (d, 1H, J ) 8 Hz), 7.07 (ddd,
1H, J ) 8, 2, 1 Hz), 3.45 (s, 3H), 3.31 (dd, 1H, J ) 6, 6 Hz),
3.11 (ddd, 1H, J ) 12, 6, 6 Hz), 2.64 (m, 1H), 2.37 (m, 1H),
2.16 (ddd, 1H, J ) 12, 6, 6 Hz), 1.95 (bdd, 1H, J ) 12, 12 Hz),
1.82 (bd, 1H, J ) 12 Hz), 1.73 (m, 1H), 1.50-1.65 (m, 2H),
1.42 (m, 1H), 1.28 (ddd, 1H, J ) 12, 4, 4 Hz); 13C NMR δ
173.70, 144.18, 131.76, 129.88, 129.61, 129.48, 127.04, 50.89,
50.11, 35.23, 34.49, 34.47, 33.54, 32.31, 32.02, 27.02. Anal.
(C16H18Cl2O2) C, H, Cl.
(m, 1H), 2.40 (m, 1H), 2.29 (ddd, 1H, J ) 12, 7, 7 Hz), 2.20
(ddd, 1H, J ) 12, 12, 2 Hz), 1.89 (bd, 1H, J ) 12 Hz), 1.50-
180 (m, 3H), 1.45 (m, 1H), 1.35 (ddd, 1H, J ) 12, 4, 4 Hz); 13
C
NMR δ 174.35, 141.37, 133.36, 131.88, 127.90, 127.45, 127.29,
126.87, 125.75, 125.72, 125.24, 52.55, 50.96, 38.60, 36.83,
34.85, 33.58, 33.16, 29.92, 28.29. Anal. (C20H22O2) C, H.
2r-Car bom eth oxy-3â-(4-flu or oph en yl)-3r-bicyclo[3.2.1]-
octen e Oxid e (22). Compound 22 was isolated from a complex
mixture obtained by reaction of 5b and an old solution of SmI2
in THF in the conditions described for 6a . Flash chromatog-
raphy (eluent: 0-4% ether/hexanes) afforded 40 mg of 22 as
an oil: Rf 0.2 (5% ether/hexane); 1H NMR δ 7.25(m, 2H), 6.96
(m, 2H), 3.28 (d, 1H, J ) 4 Hz), 3.22 (s, 3H), 3.12 (d, 1H, J )
4 Hz), 2.61 (m, 1H), 2.25-2.45 (m, 2H), 1.60-1.95 (m, 4H),
1.31 (ddd, 1H, J ) 12, 5, 5 Hz); 13C NMR δ 172.21, 161.98 (d,
J ) 246 Hz), 135.90, 128.69 (d, J ) 8 Hz), 114.70 (d, J ) 21
Hz), 63.43, 58.98, 52.53, 51.09, 34.95, 34.36, 30.95, 26.79,
24.27. HRMS: obsd, 277.1242; calcd for C16H18O3F (M + 1),
277.1240.
Meth yl 2-Na p h th a len -2-ylben zoa te (17a ). 2-Iodobenzoic
acid methyl ester, 16 (5.0 g, 18.32 mmol), 2-naphthalenebo-
ronic acid (6.30 g, 36.64 mmol), CsCO3 (11.94 g, 36.64 mmol),
and Pd(Ph3)2Cl2 (1.29 g, 1.83 mmol) in DMF (50 mL) were
heated at 80 °C for 12 h. Water (50 mL) was added and the
water layer was extracted with ether (3 × 50 mL). The ether
layer was removed on a rotary evaporator. The residue was
purified by flash chromatography (20% EtOAc/hexanes) to
afford 2.6 g of 17a as a white powder: mp 60.1-60.4 °C; Rf
0.34 (10% EtOAc/hexanes); 1H NMR δ 7.83-7.93 (m, 5H),
7.25-7.61 (m, 6H), 3.57 (s, 3H). Anal. (C18H14O2) C, H.
4′-Ch lor obiph en yl-2-car boxylic Acid Meth yl Ester (17b).
Compound 17b was prepared from 2-iodobenzoic acid methyl
ester (16) with 4-chlorophenylboronic acid as described for
2â-Car bom eth oxy-3â-n aph th ylbicyclo[3.2.1]octan e (7b),
2r-Ca r bom eth oxy-3â-n a p h th ylbicyclo[3.2.1]octa n e (8b),
2â-Ca r bom eth oxy-3r-n a p h th ylbicyclo[3.21]octa n e (9b),
a n d 2r-Ca r bom eth oxy-3r-n a p h th ylbicyclo[3.2.1]octa n e
(10b ). To 2-carbomethoxy-3-naphthylbicyclo[3.2.1]-2-octene,
5b (0.75 g, 2.57 mmol) in methanol (30 mL) at -78 °C, was
added dropwise SmI2 (0.1 M in THF, 200 mL) via an addition
funnel. After completing the addition, the green mixture was
stirred for 4 h at -78 °C and quenched with TFA (10 mL) in
ether (30 mL). H2O (25 mL) was added and extracted with
ether (3 × 100 mL). The dried (Na2SO4) ether layer was
concentrated to dryness. The residue was purified by flash
chromatography (eluent: 10% EtOAc/hexanes) to afford a
mixture of isomers 6b (0.48 g, 64%). The isomers were
separated by gravity column chromatography (eluent: 40-
80% toluene/hexanes) to afford 20 mg of 7b as a white solid
(mp 78.8-79.1 °C), 30 mg of 8b as a white solid (mp 71.3-
71.7 °C), 50 mg of 9b as a white solid (mp 71.1-71.4 °C), and
10b as a white solid (mp 91.1-91.3 °C). 7b: 1H NMR δ 7.77
(m, 2H), 7.73 (d, 1H, J ) 9 Hz), 7.68 (bs, 1H), 7.41 (m, 3H),
3.32 (s, 3H), 3.22 (ddd, 1H, J ) 12, 6, 6 Hz), 3.00 (dd, 1H, J )
6, 4 Hz), 2.56 (m, 1H), 2.54 (m, 1H), 2.48 (m, 1H), 2.00 (bd,
1H, J ) 12 Hz), 1.92 (m, 1H), 1.55-1.85 (m, 4H), 1.32 (ddd,
1H, J ) 12, 6, 6 Hz); 13C NMR δ 173.76, 141.10, 133.49, 132.16,
127.90, 127.52, 127.42, 126.45, 125.98, 125.75, 125.26, 52.55,
50.96, 38.60, 36.83, 34.85, 33.58, 33.16, 29.92, 28.29. Anal.
(C20H22O2) C, H. 8b: 1H NMR δ 7.76(m, 3H), 7.66 (bd, 1H, J
) 2 Hz), 7.40 (m, 3H), 3.43 (s, 3H), 3.31 (ddd, 1H, J ) 12, 12,
6 Hz), 2.88 (dd, 1H, J ) 12, 2 Hz), 2.51 (m, 1H), 2.35(m, 1H),
2.00 (m, 1H), 1.50-1.85 (m, 7H); 13C NMR δ 174.56, 142.13,
133.66, 132.41, 127.99, 127.77, 127.61, 126.44, 126.12, 125.85,
125.32, 53.14, 51.41, 41.27, 39.60, 39.18, 39.00, 35.33, 28.93,
25.39. Anal. (C20H22O2) C, H. 9b: 1H NMR δ 7.77(m, 3H), 7.63
(bs, 1H), 7.44 (m, 2H), 7.34 (dd, 1H, J ) 9, 2 Hz), 3.48 (s, 3H),
3.26 (ddd, 1H, J ) 11, 11, 7 Hz), 2.58 (d, 1H, J ) 11 Hz) 2.35-
2.45 (m, 2H), 2.32 (ddd, 1H, J ) 12, 7, 7 Hz), 2.05 (bd, 1H, J
) 12 Hz), 1.96 (m, 1H), 1.78 (m, 1H), 1.66 (m, 1H), 1.52 (m,
1H), 1.40 (dd, 1H, J ) 12, 12 Hz), 1.15 (ddd, 1H, J ) 12, 4, 4
Hz); 13C NMR δ 176.34, 142.24, 133.55, 132.32, 128.03, 127.71,
127.61, 126.35, 126.26, 125.90, 125.35, 56.10, 51.58, 39.24,
37.59, 37.25, 33.65, 33.08, 32.07, 30.09. Anal. (C20H22O2) C,
H.
1
17a : colorless oil (56%); Rf 0.52 (EtOAc/hexanes); H NMR δ
7.85 (dd, 1H, J ) 8, 1 Hz), 7.53 (ddd, 1H, J ) 8, 8, 1 Hz), 7.31-
7.44 (m, 4H), 7.21-7.25 (m, 2H), 3.66 (s, 3H). Anal. (C14H11O2-
Cl) C, H, Cl.
4′-Flu or obiph en yl-2-car boxylic Acid Meth yl Ester (17c).
Compound 17c was prepared from 2-iodobenzoic acid methyl
ester 16 with 4-fluorophenylboronic acid as described for 17a :
colorless oil (59%); Rf 0.52 (EtOAc/hexanes); 1H NMR δ 7.82-
7.85 (m, 1H), 7.51 (ddd, 1H, J ) 8, 8, 2 Hz), 7.40 (ddd, 1H, J
) 8, 8, 1 Hz), 7.31-7.34 (m, 1H), 7.23-7.29 (m, 2H), 7.05-
7.12 (m, 2H), 3.65 (s, 3H). Anal. (C14H11O2F) C, H.
2-Ben zoyloxyben zoic Acid Meth yl Ester (19). Benzoyl
chloride (0.12 mL, 1 mmol) was added to 2-hydroxybenzoic acid
methyl ester, 18 (50 mg, 0.33 mmol) in pyridine (2 mL). The
mixture was stirred at 60 °C overnight. Pyridine was removed
on a rotary evaporator. The residue was dissolved in ether (20
mL) and washed with H2O (3 × 10 mL). Ether was removed
on a rotary evaporator. The residue was purified by chroma-
totron (20% EtOAc/hexanes) to afford 60 mg (71%) of 19 as a
white solid: mp 83.8-84 °C; Rf 0.29 (10% EtOAc/hexanes);
1H NMR δ 8.24 (s, 1H), 8.21 (d, 1H, J ) 1 Hz), 8.07 (dd, 1H,
J ) 8, 2 Hz), 7.57-7.66 (m, 2H), 7.49-7.54 (m, 2H), 7.35 (ddd,
1H, J ) 8, 8, 1 Hz), 7.24 (d, 1H, J ) 8 Hz), 3.73 (s, 1H). Anal.
(C15H12O4) C, H.
2-Ca r bom eth oxy-4"-br om o-p-ter p h en yl (21). Compound
21 was prepared from 2-iodobenzoic acid methyl ester (16)
with 4-bromobiphenylboronic acid as described for 17a : mp
114.9-115.6 °C; Rf 0.45 (10% EtOAc/hexanes); 1H NMR δ 7.86
(dd, 1H, J ) 8, 1 Hz), 7.50-7.61 (m, 7H), 7.38-7.46 (m, 4H),
3.69 (s, 3H). Anal. (C20H15O2Br) C, H.
2r-Ca r b om e t h oxy-3r-n a p h t h ylb icyclo[3.2.1]oct a n e
(10b). Compound 5b (200 mg, 0.68 mmol) was hydrogenated
under pressure (50 psi) in the presence of Pd-C (10% w/w 118
mg) in methanol (40 mL) overnight. The resulting mixture was
filtered through Celite and the methanol evaporated. The
crude residue (180 mg) contained a mixture of products and
was purified by gravity column chromatography on flash silica
(eluent: 40-80% toluene/hexanes) to afford 85 mg of a white
solid. Recrystallization from ethanol gave analytically pure
10b (70 mg): mp 91.1-91.3 °C; 1H NMR δ 7.75 (m, 3H), 7.70
(bs, 1H), 7.40 (m, 3H), 3.35-3.45 (m, 2H), 3.36 (s, 3H), 2.70
Tissu e Sou r ces a n d P r ep a r a tion . Brain tissue from adult
male and female cynomolgus monkeys (Macaca fascicularis)
and rhesus monkeys (Macaca mulatta) was stored at -85 °C
in the primate brain bank at the New England Regional
Primate Research Center. The caudate-putamen was dissected
from coronal slices and yielded 1.4 ( 0.4 g of tissue. Mem-
branes were prepared as described previously. Briefly, the
caudate-putamen was homogenized in 10 volumes (w/v) of ice-
cold Tris‚HCl buffer (50 mM, pH 7.4 at 4 °C) and centrifuged
at 3800g for 20 min in the cold. The resulting pellet was
suspended in 40 volumes of buffer, and the entire was

2990 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16
Meltzer et al.
procedure was repeated twice. The membrane suspension (25
mg original wet weight of tissue/mL) was diluted to 12 mL/
mL for [3H]WIN 35,428 or [3H]citalopram assay in buffer just
before assay and was dispersed with a Brinkmann Polytron
homogenizer (setting #5) for 15 s. All experiments were
conducted in triplicate and each experiment was repeated in
each of 2-3 preparations from individual brains.
Ack n ow led gm en t. This work was supported by the
National Institute on Drug Abuse (P.C.M.: DA7-8081,
DA11542; B.K.M.: DA06303, DA11558, DA00304,
RR00168) and by the Office of Naval Research (C.H.G.).
Su p p or tin g In for m a tion Ava ila ble: ORTEP drawings
of 7a , 8a ,b, and 10b, crystal data and refinement parameters,
coordinates, anisotropic temperature factors, distances, and
angles are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
Dop a m in e Tr a n sp or ter Assa y. The DAT was labeled with
[3H]WIN 35,428 ([3H]CFT, (1R)-2â-carbomethoxy-3â-(4-fluo-
rophenyl)-N-[3H]methyltropane, 81-84 Ci/mmol; DuPont-
NEN). The affinity of [3H]WIN 35,428 for the DAT was
determined in experiments by incubating tissue with a fixed
concentration of [3H]WIN 35,428 and a range of concentration
of unlabeled WIN 35,428. The assay tubes received, in Tris‚
HCl buffer (50 mM, pH 7.4 at 0-4 °C; NaCl 100 mM), the
following constituents at a final assay concentration: WIN 35,-
428, 0.2 mL (1 pM - 100 or 300 nM); [3H]WIN 35,428 (0.3
nM); membrane preparation, 0.2 mL (4 mg original wet weight
of tissue/mL). The 2-h incubation (0-4 °C) was initiated by
addition of membranes and terminated by rapid filtration over
Whatman GF/B glass fiber filters presoaked in 0.1% bovine
serum albumin (Sigma Chemical Co.). The filters were washed
twice with 5 mL Tris‚HCl buffer (50 mM) and incubated
overnight at 0-4 °C in scintillation fluor (Beckman Ready-
Value, 5 mL) and radioactivity was measured by liquid
scintillation spectrometry (Beckman 1801). cpm were con-
verted to dpm following determination of counting efficiency
(>45%) of each vial by external standardization. Total binding
was defined as [3H]WIN 35,428 bound in the presence of
ineffective concentrations of unlabeled WIN 35,428 (1 or 10
pM). Nonspecific binding was defined as [3H]WIN 35,428
bound in the presence of an excess (30 µM) of (-)-cocaine.
Specific binding was the difference between the two values.
Competition experiments to determine the affinities of other
drugs at [3H]WIN 35,428 binding sites were conducted using
procedures similar to those outlined above. Stock solutions of
water-soluble drugs were dissolved in water or buffer and stock
solutions of other drugs were made in a range of ethanol/HCl
solutions or other appropriate solvents. Several of the drugs
were sonicated to promote solubility. The stock solutions were
diluted serially in the assay buffer and added (0.2 mL) to the
assay medium as described above. IC50 values were computed
by the EBDA computer program and are the means of
experiments conducted in triplicate.
Refer en ces
(1) Wise, R. A. Catecholamine theories of reward. A critical Review.
Brain Res. 1978, 152, 215-247.
(2) Kennedy, L. T.; Hanbauer, I. Sodium sensitive cocaine binding
to rat striatal membrane: possible relationship to dopamine
uptake sites. J . Neurochem. 1983, 34, 1137-1144.
(3) Ritz, M. C.; Lamb, R. J .; Goldberg, S. R.; Kuhar, M. J . Cocaine
receptors on dopamine transporters are related to self-admin-
istration of cocaine. Science 1987, 237, 1219-1223.
(4) Schoemaker, H.; Pimoule, C.; Arbilla, S.; Scatton, B.; J avoy-Agid,
F.; Langer, S. Z. Sodium dependent [3H]cocaine binding associ-
ated with dopamine uptake sites in the rat striatum and human
putamen decrease after dopaminergic denervation and in Par-
kinson’s disease. Naunyn-Schmiedeberg’s Arch. Pharmacol.
1985, 329, 227-235.
(5) Reith, M. E. A.; Meisler, B. E.; Sershen, H.; Lajtha, A. Structural
requirements for cocaine congeners to interact with dopamine
and serotonin uptake sites in mouse brain and to induce
stereotyped behavior. Biochem. Pharmacol. 1986, 35, 1123-
1129.
(6) Madras, B. K.; Fahey, M. A.; Bergman, J .; Canfield, D. R.;
Spealman, R. D. Effects of cocaine and related drugs in nonhu-
man primates: I. [3H]Cocaine binding sites in caudate-putamen.
J . Pharmacol. Exp. Ther. 1989, 251, 131-141.
(7) Canfield, D. R.; Spealman, R. D.; Kaufman, M. J .; Madras, B.
K. Autoradiographic localization of cocaine binding sites by [3H]-
CFT ([3H]WIN 35,428) in the monkey brain. Synapse 1990, 6,
189-195.
(8) Kuhar, M. J .; Ritz, M. C.; Boja, J . W. The dopamine hypothesis
of the reinforcing properties of cocaine. Trends Neurosci. 1991,
14, 299-302.
(9) Lewis, D. B.; Matecka, D.; Zhang, Y.; Hsin, L.-W.; Dersch, C.
M.; Stafford, D.; Glowa, J . R.; Rothman, R. B.; Rice, K. C.
Oxygenated analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-
[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)pipera-
zines (GBR 12935 and GBR 12909) as potential extended-action
cocaine-abuse therapeutic agens. J . Med. Chem. 1999, 42, 5029-
5042.
(10) Meltzer, P. C.; Liang, A. Y.; Madras, B. K. 2-Carbomethoxy-3-
(diarylmethoxy)-1RH,5RH-tropane analogues: Synthesis and
inhibition of binding at the dopamine transporter and compari-
son with piperazines of the GBR series. J . Med. Chem. 1996,
39, 371-379.
(11) Meltzer, P. C.; Liang, A. Y.; Brownell, A.-L.; Elmaleh, D. R.;
Madras, B. K. Substituted 3-phenyltropane analogues of co-
caine: synthesis, inhibition of binding at cocaine recognition
sites, and Positron Emission Tomography imaging. J . Med.
Chem. 1993, 36, 855-862.
(12) Meltzer, P. C.; Liang, A. Y.; Madras, B. K. The discovery of an
unusually selective and novel cocaine analog: Difluoropine.
Synthesis and inhibition of binding at cocaine recognition sites.
J . Med. Chem. 1994, 37, 2001-2010.
(13) Carroll, F. I.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . Cocaine
receptor: biochemical characterization and structure activity
relationships of cocaine analogues at the dopamine transporter.
J . Med. Chem. 1992, 35, 969-981.
(14) Carroll, F. I.; Mascarella, S. W.; Kuzemko, M. A.; Gao, Y.;
Abraham, P.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . Synthesis,
ligand binding, and QSAR (CoMFA and classical) study of 3â-
(3′-substituted phenyl)-, 3â-(4′-substituted phenyl)-, 3â-(3′,4′-
disubstituted phenyl)tropane-2â-carboxylic acid methyl esters.
J . Med. Chem. 1994, 37, 2865-2873.
(15) Madras, B. K.; Pristupa, Z. B.; Niznik, H. B.; Liang, A. Y.;
Blundell, P.; Gonzalez, M. D.; Meltzer, P. C. Nitrogen-based
drugs are not essential for blockade of monoamine transporters.
Synapse 1996, 24, 340-348.
(16) Meltzer, P. C.; Liang, A. Y.; Blundell, P.; Gonzalez, M. D.; Chen,
Z.; George, C.; Madras, B. K. 2-Carbomethoxy-3-aryl-8-oxabicyclo-
[3.2.1]octanes: Potent non-nitrogen inhibitors of monoamine
transporters. J . Med. Chem. 1997, 40, 2661-2673.
(17) Meltzer, P. C.; Blundell, P.; Chen, Z.; Yong, Y.; Madras, B. K.
Bicyclo[3.2.1]octanes: synthesis and inhibition of binding at the
dopamine and serotonin transporters. Bioorg. Med. Chem. Lett.
1999, 9, 857-862.
Ser oton in Tr a n sp or ter Assa y. The SERT was assayed
in caudate-putamen membranes using conditions similar to
those for the DAT. The affinity of [3H]citalopram (s.a.: 82 Ci/
mmol; DuPont-NEN) for the SERT was determined in experi-
ments by incubating tissue with a fixed concentration of
[3H]citalopram and a range of concentrations of unlabeled
citalopram. The assay tubes received, in Tris‚HCl buffer (50
mM, pH 7.4 at 0-4 °C; NaCl 100 mM), the following constitu-
ents at a final assay concentration: citalopram, 0.2 mL (1 pM
- 100 or 300 nM); [3H]citalopram (1 nM); membrane prepara-
tion, 0.2 mL (4 mg original wet weight of tissue/mL). The 2-h
incubation (0-4 °C) was initiated by addition of membranes
and terminated by rapid filtration over Whatman GF/B glass
fiber filters presoaked in 0.1% poly(ethylenimine). The filters
were washed twice with 5 mL of Tris‚HCl buffer (50 mM) and
incubated overnight at 0-4 °C in scintillation fluor (Beckman
Ready-Value, 5 mL) and radioactivity was measured by liquid
scintillation spectrometry (Beckman 1801). cpm were con-
verted to dpm following determination of counting efficiency
(>45%) of each vial by external standardization. Total binding
was defined as [3H]citalopram bound in the presence of
ineffective concentrations of unlabeled citalopram (1 or 10 pM).
Nonspecific binding was defined as [3H]citalopram bound in
the presence of an excess (10 µM) of fluoxetine. Specific binding
was the difference between the two values. Competition
experiments to determine the affinities of other drugs at [3H]-
citalopram binding sites were conducted using procedures
similar to those outlined above. IC50 values were computed
by the EBDA computer program and are the means of
experiments conducted in triplicate.

2-Carbomethoxy-3-aryl-8-bicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 2991
(18) Madras, B. K.; Spealman, R. D.; Fahey, M. A.; Neumeyer, J . L.;
Saha, J . K.; Milius, R. A. Cocaine receptors labeled by [3H]2â-
carbomethoxy-3â(4-fluorophenyl)tropane. Mol. Pharmacol. 1989,
36, 518-524.
(19) Madras, B. K.; Kamien, J . B.; Fahey, M.; Canfield, D.; Milius,
R. A.; Saha, J . K.; Neumeyer, J . L.; D., S. R. N-Modified
fluorophenyltropane analogues of cocaine with high affinity for
[3H]cocaine receptors. Pharmacol. Biochem. Behav. 1990, 35,
949-953.
(20) Carroll, F. I.; Gao, Y.; Rahman, M. A.; Abraham, P.; Parham,
K.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . Synthesis, ligand
binding, QSAR, and CoMFA study of 3â-(p-substituted phenyl)-
tropane-2â-carboxylic acid methyl esters. J . Med. Chem. 1991,
34, 2719-2725.
(32) Ritz, M. C.; Cone, E. J .; Kuhar, M. J . Cocaine inhibition of ligand
binding at dopamine, norepinephrine and serotonin transport-
ers: A structure-activity study. Life Sci. 1990, 46, 635-645.
(33) Carroll, F. I.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . In
3â-(Substituted phenyl)tropane-2 carboxylic acid ester analogues
of cocaine: Synthesis and biochemical and pharmacological
properties; Kozikowski, A. P., Ed.; Raven Press, Ltd.: New York,
1993; pp 149-166.
(34) Kozikowski, A. P.; Roberti, M.; J ohnson, K. M.; Bergmann, J .
S.; Ball, R. G. SAR of Cocaine: further exploration of structural
variations at the C-2 center provides compounds of subnano-
molar binding potency. Bioorg. Med. Chem. Lett. 1993, 3, 1327-
1332.
(21) Chen, Z.; Izenwasser, S.; Katz, J . L.; Zhu, N.; Klein, C. L.;
Trudell, M. L. Synthesis and dopamine transporter affinity of
2-(methoxycarbonyl)-9-methyl-3-phenyl-9-azabicyclo[3.3.1]-
nonane derivatives. J . Med. Chem. 1996, 39, 4744-4749.
(22) Davies, H. M. L.; Kuhn, L. A.; Thornley, C.; Matasi, J . J .; Sexton,
T.; Childers, S. R. Synthesis of 3â-aryl-8-azabicyclo[3.2.1]octanes
with high binding affinities and selectivities for the serotonin
transporter site. J . Med. Chem. 1996, 39, 2554-2558.
(23) Kozikowski, A. P.; Araldi, G. L.; Ball, R. G. Dipolar cycloaddition
route to diverse analogues of cocaine: the 6- and 7-substituted
3-phenyltropanes. J . Org. Chem. 1997, 62, 503-509.
(24) Meltzer, P. C.; Blundell, P.; Madras, B. K. Structure activity
relationships of inhibition of the dopamine transporter by
3-arylbicyclo[3.2.1]octanes. Med. Chem. Res. 1998, 8, 12-34.
(25) Miller, G. M.; Gracz, I. M.; Goulet, M.; Yang, H.; Meltzer, P. C.;
Hoffman, B. J .; Madras, B. K. Point mutations of the human
dopamine transporter (hDAT) reveal differential binding of an
amine and a non-amine ligand. Soc. Neurosci. Abstr. 1999, in
press.
(26) Kitayama, S.; Shimada, S.; Xu, H.; Markham, L.; Donovan, D.
H.; Uhl, G. R. Dopamine transporter site-directed mutations
differentially alter substrate transport and cocaine binding. Proc.
Natl. Acad. Sci. U.S.A. 1993, 89, 7782-7785.
(27) J efford, C. W.; Gunsher, J .; Hill, D. T.; Brun, P.; Le Gras, J .;
Waegell, B. Bicyclo[3.2.1]octan-3-one. Organic Synthesis;
Wiley: New York, 1988; Coll. Vol. VI, pp 142-145.
(28) Watanabe, T.; Mitaura, N.; Suzuki, A. Synthesis of sterically
hindered biaryls via the palladium-catalyzed cross-coupling
reaction of arylboronic acids or their esters with haloarenes.
Synlett 1992, 207-210.
(29) Oh-e, T.; Miyaura, N.; Suzuki, A. Palladium-catalyzed cross-
coupling reaction of organoboron compounds with organic tri-
flates. J . Org. Chem. 1993, 58, 2201-2208.
(35) Clarke, R. L.; Daum, S. J .; Gambino, A. J .; Aceto, M. D.; Pearl,
J .; Levitt, M.; Cumiskey, W. R.; Bogado, E. F. Compounds
affecting the central nervous system. 4. 3â-Phenyltropane-2-
carboxylic esters and analogues. J . Med. Chem. 1973, 16, 1260-
1267.
(36) Neumeyer, J . L.; Wang, S.; Milius, R. A.; Baldwin, R. M.; Zea-
Ponce, Y.; Hoffer, P. B.; Sybirska, E.; Al-Tikriti, M.; Charney,
D. S.; Malison, R. T.; Laruelle, M.; Innis, R. B.
[
123I]-2â-
Carbomethoxy-3â-(4-iodophenyl)tropane: high-affinity SPECT
radiotracer of monoamine reuptake sites in brain. J . Med. Chem.
1991, 34, 3144-3146.
(37) Carroll, F. I.; Gray, J . L.; Abraham, P.; Kuzemko, M. A.; Lewin,
A. H.; Boja, J . W.; Kuhar, M. J . 3-Aryl-2-(3′-substituted-1′,2′,4′-
oxadiazol-5′-yl)tropane analogues of cocaine: affinities at the
cocaine binding site at the dopamine, serotonin, and norepi-
nephrine transporters. J . Med. Chem. 1993, 36, 2886-2890.
(38) Kotian, P.; Mascarella, S. W.; Abraham, P.; Lewin, A. H.; Boja,
J . W.; Kuhar, M. J .; Carroll, F. I. Synthesis, ligand binding, and
quantitative structure-activity relationship study of 3â-(4′-
substituted phenyl)-2â-heterocyclic tropane: Evidence for an
electrostatic interaction at the 2â-position. J . Med. Chem. 1996,
39, 2753-2763.
(39) Moldt, P.; Scheel-Kruger, J .; J ensen, L. H. 2,3-Trans-substituted
tropane compounds which have useful pharmaceutical utility.
U.S. Patent 5,374,636, 1994.
(40) Lomenzo, S. A.; Izenwasser, S.; Katz, J . L.; Terry, P. D.; Zhu,
N.; Klein, C. L.; Trudell, M. L. Synthesis, structure, dopamine
transporter affinity, and dopamine uptake inhibition of 6-alkyl-
3-benzyl-2-[(methoxycarbonyl)methyl]tropane derivatives. J . Med.
Chem. 1997, 40, 4406-4414.
(41) Moldt, P.; Watjen, F.; Scheel-Kruger, J . Tropane-2-aldoxime
derivatives as neurotransmitter reuptake inhibitors. U.S. Patent
5,736,556, 1998.
(42) Meltzer, P. C.; Blundell, P.; Huang, H.; Liu, S.; Yong, Y. F.;
Madras, B. K. 3-Aryl-2-carbomethoxybicyclo[3.2.1]oct-2-enes
inhibit WIN 35,428 binding potently and selectively at the
dopamine transporter. Bioorg. Med. Chem. 2000, 8, 581-590.
(30) Keverline, K. I.; Abraham, P.; Lewin, A. H.; Carroll, F. I.
Synthesis of the 2â,3R- and 2â,3â-isomers of 3-(p-substituted
phenyl)tropane-2-carboxylic acid methyl esters. Tetrahedron
Lett. 1995, 36, 3099-3102.
(31) Holmquist, C. R.; Keverline-Frantz, K. I.; Abraham, P.; Boja, J .
W.; Kuhar, M. J .; Carroll, F. I. 3R-(4′-Substituted phenyl)-
tropane-2â-carboxylic acid methyl esters: Novel ligands with
high affinity and selectivity at the dopamine transporter. J . Med.
Chem. 1996, 39, 4139-4141.
J M000191G