Synthesis and Monoamine Transporter Binding of 2-(Diarylmethoxymethyl)-3β-aryltropane Derivatives

Article abstract of DOI:10.1021/jm030430a

3β-Aryltropane analogues wherein the 2-position was substituted with various diarylmethoxyalkyl groups were synthesized and evaluated for binding at the dopamine transporter (DAT), serotonin transporter (SERT), norepinephrine transporter (NET), and muscar

Full text of DOI:10.1021/jm030430a

1676
J . Med. Chem. 2004, 47, 1676-1682
Syn th esis a n d Mon oa m in e Tr a n sp or ter Bin d in g of
2-(Dia r ylm eth oxym eth yl)-3â-a r yltr op a n e Der iva tives
Lifen Xu,† Santosh S. Kulkarni,§ Sari Izenwasser,‡ J onathan L. Katz,§ Theresa Kopajtic,§ Stacey A. Lomenzo,†
Amy Hauck Newman,§ and Mark L. Trudell*,†
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148,
Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Miami, Florida 33136,
and Medications Discovery Research Branch, National Institute on Drug Abuse, Intramural Research Program,
5500 Nathan Shock Drive, Baltimore, Maryland 21224
Received September 4, 2003
3â-Aryltropane analogues wherein the 2-position was substituted with various diarylmethoxy-
alkyl groups were synthesized and evaluated for binding at the dopamine transporter (DAT),
serotonin transporter (SERT), norepinephrine transporter (NET), and muscarinic (M1) receptors.
The 2â-analogues 9a -i generally demonstrated high to moderate binding affinities (Ki ) 34-
112 nM) at the DAT with good selectivity over SERT, NET, and M1 receptors. Alternatively,
the 2R-isomers 10a -i were 10-fold less potent at the DAT with poor selectivity over SERT.
These SAR studies provide further evidence for the varied binding requirements of structurally
diverse tropane-based ligands and support future studies to elucidate DAT binding requirements
in relation to cocaine-like behavioral endpoints.
In tr od u ction
Cocaine (1) is a powerful psychostimulant and drug
of abuse that inhibits dopamine reuptake by binding to
the dopamine transporter (DAT). The 2-substituted
3-aryltropanes [e.g., [3H]WIN 35,428 (2)] have been
studied extensively as cocaine congeners and developed
as tools to explore the DAT.1-23 This broad class of
compounds has provided significant insight into the
nature of the DAT pharmacophore and the pharmaco-
logical actions associated with cocaine abuse. It has been
well established for the 2-substituted 3-aryltropanes
that â-stereochemistry at the 2-position and a 4-sub-
stituted or 3,4-disubstituted aryl group (e.g., tolyl,
4-chlorophenyl, or 3,4-dichlorophenyl, respectively) at
the 3â-position of the tropane ring affords compounds
that exhibit high-affinity binding at the DAT. However,
a variety of functional groups and substituents (alkyl,
vinyl, aryl, alcohol, and ester groups) are well tolerated
at the 2-position with little variation in pharmacological
activity. Recently we reported on the DAT binding
affinity and dopamine uptake inhibition of a series of
novel 2-substituted 3â-tolyltropane derivatives.23 The
2â-(R)-(hydroxymethyltolyl)-3â-tolyltropane (3) exhib-
ited an unexpectedly high dopamine uptake inhibition
(DUI)/DAT affinity ratio (10:1), suggesting that this
compound was not as potent in inhibiting dopamine
uptake as its DAT binding affinity may have predicted.
Nevertheless, the behavioral profile of 3 did not vary
significantly from cocaine, and thus, further investiga-
tion of the effects of alkylaryl substituents at the
2-position seemed warranted.
In another class of DAT inhibitors, the diarylmethoxy
moiety when attached to the tropane ring system has
produced benztropine analogues with unique pharma-
cological profiles (e.g., 3′-chlorobenztropine and difluoro-
pine).24-27 In addition, the diarylmethoxy group has
been established as an important structural feature of
the DAT selective ligand GBR 12909 and related GBR/
tropane hybrid analogues.28-33 Therefore, it was of
interest to investigate the effects of the diarylmethoxy
group at the 2-position for a series of 3â-aryltropanes.
Herein, we describe the synthesis, DAT, serotonin
(SERT), norepinephrine transporter (NET), and mus-
carinic M1 receptor binding affinities for a series
of 2-(diarylmethoxyalkyl)-3â-aryltropanes. In addition,
CoMFA studies were performed in an attempt to cor-
relate chemical structures and DAT binding activity.
Resu lts a n d Discu ssion
Ch em istr y. The syntheses of the 2-substituted 3â-
aryltropane derivatives were completed in a straight-
forward fashion from anhydroecgonine methyl ester (4)
(Scheme 1).34 The reaction of an arylmagnesium bro-
mide with anhydroecgonine methyl ester in dichloro-
methane furnished a mixture of 2â-carbomethoxy-3â-
aryltropane (5) and 2R-carbomethoxy-3â-aryltropane
* To whom correspondence should be addressed. Phone: (504)-280-
7337. Fax: (504) 280-6860. E-mail: mtrudell@uno.edu.
† University of New Orleans.
§ National Institute on Drug Abuse, Intramural Research Program.
‡ University of Miami School of Medicine.
10.1021/jm030430a CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/02/2004

Aryltropane Derivatives
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7 1677
Sch em e 1a
Sch em e 2
All of the 2-substituted 3â-aryltropanes displaced
[3H]WIN 35,428 from caudate putamen membranes
with relatively high affinity (Ki) ranging from 34 nM
(9a ) to 112 nM (9e). In general, the 2â-isomers (9) were
10-fold more potent than the corresponding 2R-isomers
(10) at DAT. Among the 2â-isomers (9), the selectivity
(SERT/DAT) for DAT was significant and ranged from
6.1 (9f) to 2.5 (9i). However, there was less difference
between the DAT and the SERT affinities for the 2R-
isomers (10). The 2R-isomers (10) generally exhibited,
if any, only a slight preference for the DAT (SERT/DAT
from 0.8 to 2.8). The 2â-[(4-chlorophenyl)phenylmethoxy-
methyl]-3â-(4-chlorophenyl)tropane (9f) was the most
selective analogue of the series (SERT/DAT ) 6.1),
though its DAT binding affinity (Ki ) 76 nM) was 2-fold
lower than the most potent analogue (9a ), which had a
more modest selectivity (SERT/DAT ) 3.6). All of the
2-substituted 3â-aryltropanes (9 and 10) exhibited low
binding affinities at NET (g684 nM) and muscarinic
(M1) receptors (>9 µM).
The substituents (CH3, F, Cl) on the 3â-aryl ring had
little effect; however, the stereochemistry at the 2-posi-
tion had a profound effect on DAT affinity. Similar to
most 2-substituted 3â-aryltropanes, the 2â-isomers (9)
were significantly more potent at the DAT than the
corresponding 2R-isomers (10). Despite the bulky di-
arylmethoxy group of 9, the binding affinities at DAT
were not significantly affected. This further demon-
strates the ability of the DAT to tolerate a wide variety
of functionality and steric bulk at the 2â-position.16,23
The particular substituents on the diarylmethoxy moi-
ety appeared to have only a subtle effect on DAT affinity
for the 2â-isomers (9). It is noteworthy that the di-
phenylmethoxy derivatives (9a , 9b, and 9c) were always
slightly more potent than the bis(4-fluorophenyl)-
methoxy derivatives (9g, 9h , and 9i). This is consistent
with the SAR of the diarylmethoxy moiety of GBR-
related compounds. However, the high SERT/DAT
selectivity often observed for GBR-related compounds
was not observed for any of the 2â-isomers 9.
a
Reagents: (i) p-R-C6H4MgBr, CH2Cl2, -78 °C, then TFA; (ii)
LiAlH4, Et2O; (iii) (p-X-C6H4)(p-Y-C6H4)CHCl, 160 °C.
(6).34 Separation of the isomers by flash column chro-
matography and independent reduction of each isomer
with lithium aluminum hydride furnished the alcohols
7 and 8, respectively, in excellent yield (>90%). The
alcohols 7 and 8 were then converted into the diaryl-
methoxymethyl-3â-aryltropanes 9 and 10 using a modi-
fied melt procedure with the corresponding benzhydryl
chloride. The 2â-isomers 9 were obtained in yields
ranging from 50% to 86%, while the 2R-isomers 10 were
furnished in yields ranging from 32% to 66%. The
stereochemistry of the 2â-derivatives 7a (R ) CH3), 9g,
and 9i was unequivocally established by X-ray crystal-
lography.35
The 2â-three-carbon-chain homologues 12a -c were
synthesized from the alcohol 1116 (Scheme 2). The
diarylmethoxy group was attached in a fashion similar
to that described above to afford the 2â-three-carbon-
chain homologues 12a -c in good yields (66-85%).
Biology. DAT binding affinities were determined for
the 2-substituted 3â-aryltropanes 9, 10, and 12 by their
ability to displace bound [3H]WIN 35,428 (2) from rat
caudate-putamen tissue.36 The Ki values that are re-
ported in Table 1 are inhibition constants derived for
the unlabeled ligands. The binding affinities of the
2-substituted 3â-aryltropanes were also determined at
SERT by inhibition of [3H]citalopram and at NET by
inhibition of [3H]nisoxetine in assays previously de-
scribed.23 In addition, because of the structural similar-
ity of 9, 10, and 12 to benztropine, muscarinic receptor
(M1) binding affinities were also determined using a
[3H]pirenzepine binding assay.27
The three-carbon-chain homologues 12a -c exhibited
a slightly different pharmacological profile than the
corresponding congeners (9). The unsubstituted homo-
logue 12a and the (4-chlorophenyl)phenylmethoxy ho-

1678 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7
Xu et al.
Ta ble 1. Dopamine, Serotonin, Norepinephrine Transporter, and Muscarinic Receptor Binding Affinities of
2-(Diarylmethoxymethyl)-3â-aryltropanes and 2â-[3-(Diarylmethoxy)propyl]-3â-aryltropanes
[3H]WIN 35,428 (DAT)
[3H]citalopram (SERT)
[3H]nisoxetine (NET)
[3H]pirenzepine (M1)
compda
R
X
Y
Ki (nM)b
Ki (nM)b
Ki (nM)b
Ki (nM)b
9a
9b
9c
9d
9e
9f
9g
9h
CH3
F
Cl
CH3
F
Cl
CH3
F
Cl
CH3
Cl
CH3
Cl
H
H
H
Cl
Cl
Cl
F
H
H
H
H
H
H
F
34 ( 2
121 ( 19
684 ( 100
10600 ( 1100
49 ( 12
52 ( 2.1
80 ( 9
147 ( 8
443 ( 60
1190 ( 72
4400 ( 238
11000 ( 1290
31600 ( 4300
112 ( 11
76 ( 7
62 ( 7
462 ( 36
233 ( 24
2056 ( 236
1830 ( 177
39900 ( 5050
15500 ( 1400
F
F
F
F
63 ( 13
99 ( 18
455 ( 36
478 ( 72
937 ( 84
553 ( 106
690 ( 76
250 ( 40
139 ( 15
261 ( 19
60 ( 7
9i
245 ( 16
530 ( 72
408 ( 16
1001 ( 109
1293 ( 40
786 ( 67
724 ( 100
61 ( 9
2890 ( 222
2609 ( 195
3998 ( 256
22500 ( 2831
5600 ( 183
16000 ( 637
52300 ( 13600
207 ( 30
16300 ( 1300
12600 ( 1790
11500 ( 1720
18200 ( 2600
9600 ( 600
10a
10c
10d
10f
10g
10i
12a
12b
12c
H
H
Cl
Cl
F
H
H
H
H
F
CH3
Cl
H
H
H
9700 ( 900
F
F
9930 ( 1090
7970 ( 631
H
Cl
F
H
H
F
45 ( 3
24600 ( 2930
a
b
All compounds were tested as the HCl salt. All values are the mean ( SEM of three experiments performed in triplicate.
mologue 12b exhibited high affinity for SERT (Ki ) 61
and 45 nM, respectively). In addition, 12a and 12b each
exhibited a greater affinity for the SERT than DAT
(DAT/SERT ) 2.3 and 5.8, respectively). Moreover, the
unsubstituted derivative 12a exhibited a significantly
greater affinity for the NET (Ki ) 207 nM) than all of
the other compounds tested in this study. In addition,
12a and 12c exhibited the opposite trends in DAT
binding affinities compared to the homologues 9a and
F igu r e 1. Atoms/centroid selection of the template molecule
9g in that the 4,4-di-F-substituted 12c displayed higher
affinity for the DAT than the unsubstituted 12a . The
homologues 12a and 12b, however, exhibited low affin-
ity at muscarinic (M1) sites with binding affinities
similar to those of series 9 and 10.
14 used for alignments in model A.
The alignment of the compounds using four super-
imposing elements (Figure 1) gave model A, which
provided a PLS model having an r2cv value of 0.798 with
a standard error of prediction (SEP) of 0.517, using five
components. The non-cross-validated PLS analysis pro-
vided a conventional correlation coefficient of 0.970 with
a significant F value of 224.840. This CoMFA model
showed a strong correlation between the steric descrip-
tors because their global contribution (57.2) was more
than that for the electrostatic descriptors (42.8). This
suggests that hydrophobic groups on the molecules could
improve binding to DAT.
Figure 2 shows the CoMFA contour maps for model
A. The large green contours were found to surround the
2-position substituent, suggesting that large substitu-
ents in this region are well-tolerated, and many studies
have shown the existence of a large binding pocket in
this region. The existence of blue and red contours in
the vicinity of the 2-position indicates the role of
electrostatic interaction in this region. As such, ligands
having ester groups or the equivalent may form hydro-
gen bonds in this region.5 Therefore, the 2-position
substituent may bind in a cavity that is lined with
residues capable of forming hydrogen bonds but also has
a large hydrophobic binding pocket.
Molecu la r Mod elin g
To further investigate structural requirements for
optimal DAT binding and directly compare 3D struc-
tures of these analogues, a molecular modeling study
was undertaken. In the absence of protein structural
information of the DAT, the nature of binding inter-
actions must be inferred from indirect methods. The
three-dimensional quantitative structure-activity re-
lationship (3D QSAR) method, comparative molecular
field analysis (CoMFA), provides a tool in which the
contributions of the binding interactions can be inferred
via 3D contour graphs. The 3-substituted tropane
analogues provide a unique set of DAT inhibitors in
which several SAR and 3D-QSAR studies have already
been reported.2-4,10,14,37
In this study, the SAR of the 2-(diarylmethoxy)-
substituted tropanes was compared with other 2-, 3-,
and 6-substituted tropane-based DAT inhibitors. These
compounds contain structural features of several classes
of DAT inhibitors, namely, the benztropines, GBR
series, and 3-aryltropanes and, as such, provide a
unique opportunity to identify structural features re-
quired for high-affinity DAT binding. Hence, a data set
of compounds previously reported from our labora-
tory16,38,39 was used to derive a molecular model. This
model was used to further characterize structural
requirements of 2-substituted tropanes for binding with
DAT.
Con clu sion s
3â-Aryltropane analogues wherein the 2-position was
substituted with various (diarylmethoxy) substituents
were synthesized and evaluated for binding at the DAT,
SERT, NET, and muscarinic M1 receptors. The 2â-
analogues 9a -i generally demonstrated high-affinity

Aryltropane Derivatives
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7 1679
F igu r e 2. CoMFA steric and electrostatic STDEV*COEFF contour plots from the analysis of model A. The sterically favored
(contribution, 80%) and unfavored (contribution, 20%) plots are shown as green and yellow contours, respectively. The electrostatic
plots of positive (contribution, 80%) and negative (contribution, 20%) charge favoring areas are shown as blue and red contours,
respectively.
GA. Melting points were recorded on a Hoover Mel-Temp
apparatus and are uncorrected.
binding at DAT with good selectivity over the SERT,
NET, and M1 receptors. Alternatively, the 2R-isomers
10a -i were 10-fold less potent at DAT with poor
selectivity over SERT. The 2-(diarylmethoxyalkyl)-3â-
aryltropanes 9 and 10 exhibited SAR at DAT, SERT,
NET, and M1 that is consistent with the SAR of the
broad class of 2-substituted 3â-aryltropanes. A CoMFA-
based 3D-QSAR model was derived and provided fur-
ther insight into the structural requirements of 2-sub-
stituted tropanes for binding with DAT.
It is widely accepted that the DAT protein exists as
12 transmembrane-spanning helices, and presumably
the inhibitor binding regions are located within or across
these transmembrane regions. Structure-activity re-
lationships derived from different classes of DAT
ligands, as well as photoaffinity label studies, support
the existence of multiple binding regions or orientations
of the DAT.37 Subtle changes in the structures of these
molecules have resulted in distinct binding profiles,
which may ultimately influence in vivo behavioral
activity.40 This flexibility in binding interaction might
explain the consistently high-affinity binding profiles
for this structurally diverse family of compounds. Nev-
ertheless, it remains to be seen what compounds provide
in vitro and in vivo profiles that will aid in the design
of cocaine abuse medications. To that end, the dopamine
uptake inhibition, locomotor stimulant activities, and
discriminative stimulus effects of these compounds are
currently under investigation and will be reported in
due course.
Met h od A. R ed u ct ion of 2-Ca r b om et h oxy-3â-a r yl-
tr op a n es. To a stirred suspension of LiAlH4 (76 mg, 2.0 mmol)
in dry Et2O (25 mL) at 0 °C under a nitrogen atmosphere was
added dropwise a solution of 2-carbomethoxy-3â-aryltropane
(5 or 6) (2.0 mmol) in dry Et2O (5 mL). Stirring was continued
overnight at room temperature. The reaction mixture was
cooled to 0 °C, and an aqueous solution of NaOH (5%, 10 mL)
was added dropwise. The solids were filtered and washed with
ether. The combined filtrate and washings were then washed
with brine and the organic portion was separated, dried over
Na2SO4, and concentrated under reduced pressure to furnish
the alcohol (7 or 8). The alcohol was usually of sufficient purity
that chromatography was unnecessary for subsequent trans-
formations. An analytically pure sample of the alcohol could
be obtained by elution of the crude material through a short
silica gel column (petroleum ether: Et3N, 9:1).
2â-Hydr oxym eth yl-3â-tolyltr opan e (7a):23 general method
A; colorless oil (450 mg, 92%).
2â-Hydr oxym eth yl-3â-(4-flu or oph en yl)tr opan e (7b): gen-
eral method A; colorless oil (450 mg, 87%); mp 73-74 °C [lit.,18
75-78 °C].
2â-Hydr oxym eth yl-3â-(4-ch lor oph en yl)tr opan e (7c): gen-
eral method A; colorless oil (500 mg, 91%); mp 190-192 °C
[lit.,12 189 °C].
2r-Hydr oxym eth yl-3â-tolyltr opan e (8a):23 general method
A; colorless oil (460 mg, 95%).
2r-H yd r oxym et h yl-3â-(4-ch lor op h en yl)t r op a n e (8c):
general method A; white solid (470 mg, 85%); mp 202-206
1
°C; H NMR (CDCl3) δ 7.24 (d, J ) 8.0 Hz, 2H), 7.24 (d, J )
8.0 Hz, 2H), 3.48 (s, 1H), 3.43 (m, 1H), 3.33-3.22 (m, 3H), 2.36
(s, 3H), 2.35-2.27 (m, 1H), 2.24-2.19 (m, 1H), 2.15-2.07 (m,
1H), 1.94-1.91 (m, 1H), 1.89-1.86 (m, 1H), 1.80-1.75 (m, 1H),
1.61-1.55 (m 2H); [R]22 +24.2° (c 1, CHCl3). Anal. (C16H20
-
D
NOCl) C, H, N.
Exp er im en ta l Section
Gen er a l Meth od B. 2-(Dip h en ylm eth oxya lk yl)-3â-a r yl-
tr op a n e. Bromodiphenylmethane (300 mg, 1.2 mmol) was
added dropwise to a melt of the 2-substituted-3â-aryltropane
alcohol (1.0 mmol) at 160 °C (oil bath) over 3 min. Evolution
of HBr gas over 30 min resulted in a brown oil that solidified
into a glass upon cooling. The crude product was dissolved in
Et2O (30 mL) and was transferred to a separatory funnel. The
aqueous phase was made acidic (pH 2) with concentrated HCl,
and the Et2O layer was separated. The aqueous layer was
made basic with concentrated NH4OH and was extracted with
All chemicals and reagents not otherwise noted were
purchased from Aldrich Chemical Co. Ether was dried by
distillation from Na/benzophenone ketyl. The spectral data for
all compounds are reported for the free base. 1H and 13C NMR
spectra were recorded on a Varian Multiprobe 400 MHz
spectrometer. The free base was then converted into the
hydrochloride salt to give a hygroscopic solid or solid foam used
for microanalysis and biological testing. Microanalysis for C,
H, and N were performed by Atlantic Microlabs Inc, Norcross,

1680 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7
Xu et al.
Et2O (4 × 30 mL). The dried ethereal solution (Na2SO4) was
evaporated under reduced pressure to give a yellow oil. The
residue was purified by column chromatography (SiO2; petro-
leum ether/triethlamine, 9.5:0.5) to furnish the corresponding
2-diarylmethoxyalkyl-3â-aryltropane derivatives.
2â-(4-Ch lor op h en ylp h en ylm eth oxym eth yl)-3â-(4-flu o-
r op h en yl)tr op a n e (9e): general method C; colorless oil (270
mg, 60%); [R]21D -1.39° (c 1, CHCl3); 1H NMR (CDCl3) δ 7.44-
6.80 (m, 13H), 5.04, (s, 1H), 3.66 (t, J ) 8.6 Hz, 1H), 3.43, (m,
1H), 3.18 (m, 1H), 3.02 (m, 1H), 2.91 (m, 1H), 2.19 (s, 3H),
2.20-1.90 (m, 4H), 1.63 (m, 2H), 1.49 (m, 1H); 13C NMR
(CDCl3) δ 159.7, 142.1, 141.2, 138.4, 132.7, 128.2, 128.0, 127.2,
126.6, 114.9, 114.6, 82.8, 67.8, 64.0, 61.7, 47.0, 41.8, 34.2, 34.0,
26.0, 24.7. Anal. (C28H29NOFCl‚HCl‚2H2O) C, H, N.
Gen er al Meth od C. 2-[(4-Ch lor oph en yl)ph en ylm eth oxy-
a lk yl]-3â-a r ylt r op a n e Der iva t ives. The chloro(4-chloro-
phenyl)phenylmethane (280 mg, 1.2 mmol) was added drop-
wise to a melt of the 2-hydroxyalkyl-3â-aryltropane (1.0 mmol)
at 180 °C (oil bath) over 30 min. Evolution of HCl gas over 30
min resulted in a brown oil that solidified into a glass upon
cooling. The residue was dissolved in Et2O (30 mL) and
transferred to a separatory funnel. The aqueous phase was
made acidic (pH 2) with concentrated HCl, and the Et2O layer
was separated. The aqueous layer was then made basic with
concentrated NH4OH and was extracted with Et2O (4 × 30
mL). The dried ethereal solution (Na2SO4) was evaporated
under reduced pressure to give a yellow oil. The residue was
purified by column chromatography (SiO2; petroleum ether/
triethylamine, 9.5:0.5) to furnish the corresponding 2-[(4-
chlorophenyl)phenylmethoxyalkyl]-3â-aryltropane derivatives.
Gen er a l Meth od D. 2-[Bis(4-flu or op h en yl)m eth oxy-
a lk yl]-3â-a r ylt r op a n e Der iva t ives. Chlorobis(4-fluoro-
phenyl)methane (360 mg, 1.5 mmol) was added dropwise to a
melt of the 2-hydroxyalkyl-3â-aryltropane (1.0 mmol) at 180
°C (oil bath) over 1 h. Evolution of HCl gas over 30 min
resulted in a brown oil that solidified into a glass upon cooling.
The crude product was dissolved in Et2O (30 mL) and
transferred to a separatory funnel. The aqueous phase was
made acidic (pH 2) with concentrated HCl, and the Et2O layer
was separated. The aqueous layer was made basic with
concentrated NH4OH and was extracted with Et2O (4 × 30
mL). The dried ethereal solution (Na2SO4) was evaporated to
give a yellow oil. The residue was purified by column chro-
matography (SiO2; petroleum ether/triethylamine, 9.5:0.5) to
furnish the corresponding 2-[bis(4-fluorophenyl)methoxyalkyl]-
3â-aryltropane derivatives.
2â-[(4-Ch lor op h en yl)p h en ylm et h oxy]m et h yl]-3â-(4-
ch lor op h en yl)tr op a n e (9f): general method C; colorless oil
1
(300 mg, 64%); [R]21 -137° (c 1, CHCl3); H NMR (CDCl3) δ
D
7.30-6.93 (m, 13H), 5.05 (d, J ) 6.1 Hz, 1H), 3.66 (t, J ) 8.6
Hz, 1H), 3.44 (m, 1H), 3.23 (br s, 1H), 3.05 (m, Hz, 1H), 2.94
(m, 1H), 2.22 (s, 3H), 2.16-1.95 (m, 4H), 1.65 (m, 2H), 1.49
(m, 1H); 13C NMR (CDCl3) δ 141.8, 141.1, 140.9, 132.6, 131.4,
128.6, 128.1, 128.0, 127.8, 126.6, 126.4, 82.7, 67.8, 64.1, 63.9,
61.6, 46.8, 41.7, 34.0, 25.9, 24.6. Anal. (C28H29NOCl2‚HCl‚
0.5H2O) C, H, N.
2â-[Bis(4-flu or op h en yl)m et h oxym et h yl]-3â-t olylt r o-
p a n e (9g): general method D; colorless oil (190 mg,43%); mp
1
93-95 °C (HCl salt); H NMR (CDCl3) δ 7.33-6.96 (m, 12H),
5.01 (s, 1H), 3.66 (t, J ) 8.5 Hz, 1H), 3.40 (d, J ) 4.8 Hz, 1H),
3.21 (br s, 1H), 3.08-2.93 (m, 2H), 2.26 (s, 3H), 2.19 (s, 3H),
2.20-1.94 (m, 4H), 1.75-1.40 (m, 3H); 13C NMR (CDCl3) δ
163.3, 160.1, 139.6, 138.3, 134.9, 128.6, 128.3, 129.0, 127.1,
114.9, 114.6, 114.4, 81.8, 67.7, 63.9, 61.7, 47.0, 41.7, 34.1, 25.9,
24.7, 20.6. Anal. (C29H31NOF2‚HCl) C, H, N.
2â-[Bis(4-flu or op h e n yl)m e t h oxym e t h yl]-3â-(4-flu o-
r op h en yl)tr op a n e (9h ): general method D; colorless oil (230
mg, 50%); 1H NMR (CDCl3) δ 7.20-6.85 (m, 12H), 5.04 (s, 1H),
3.64 (t, J ) 8.6 Hz, 1H), 3.41 (d, J ) 4.8 Hz, 1H), 3.22 (m,
1H), 3.07 (m, 1H), 2.91 (m, 1H), 2.22 (s, 3H), 2.15-1.90 (m,
4H), 1.65 (t, J ) 11.6 Hz, 2H), 1.51 (m, 1H); 13C NMR (CDCl3)
δ 163.6, 162.7, 160.3, 138.2, 128.7, 128.4, 128.3, 128.1, 115.1,
114.9, 114.8, 114.7, 82.1, 67.8, 64.1, 61.8, 47.1, 41.9, 34.3, 34.1,
26.0, 24.8. Anal. (C28H28NOF3‚HCl) C, H, N.
2â-Dip h en ylm eth oxym eth yl-3â-tolyltr op a n e (9a ): gen-
eral method B; white solid (290 mg, 70%); mp 103-105 °C (free
base); [R]21D -121° (c 1, CHCl3); 1H NMR (CDCl3) δ 7.34-6.96
(m, 14H), 5.11 (s, 1H), 3.74 (t, J ) 9.0 Hz, 1H), 3.50 (d, J )
4.4 Hz, 1H), 3.22 (m, 1H), 3.45-2.92 (m, 2H), 2.25 (s, 3H), 2.22
(s, 3H), 2.22-1.94 (m, 4H), 2.75-1.40 (m, 3H); 13C NMR
(CDCl3) δ 142.6, 139.3, 135.1, 128.7, 128.0, 127.2, 126.7, 126.5,
83.3, 67.5, 63.8, 61.9, 46.8, 41.6, 34.1, 25.9, 24.6, 20.8. Anal.
(C29H33NO‚HCl‚H2O) C, H, N.
2â-[Bis(4-flu or op h e n yl)m e t h oxym e t h yl]-3â-(4-ch lo-
r op h en yl)tr op a n e (9i): general method D; colorless oil ( 270
mg, 58%); mp 125-127 °C (HCl salt); 1H NMR (CDCl3) δ 7.17-
6.81 (m, 12H), 5.00 (s, 1H), 3.62 (t, J ) 8.1 Hz, 1H), 3.36 (m,
1H), 3.15 (br s, 1H), 3.01 (m, 1H), 2.92 (q, J ) 4.3 Hz, 1H),
2.17 (s, 3H), 2.15-1.86 (m, 4H), 1.59 (m, 2H), 1.44 (m, 1H);
13C NMR (CDCl3) δ 163.5, 160.2, 141.4, 138.1, 131.4, 128.7,
128.2, 128.1, 115.1, 114.9, 114.8, 114.6, 82.1, 67.9, 64.2, 61.6,
47.0, 41.8, 34.2, 34.0, 26.0, 24.7. Anal. (C28H28NOClF2‚HCl)
C, H, N.
2r-(Dip h en ylm eth oxym eth yl)-3â-4-tolyltr op a n e (10a ):
general method B; colorless oil (270 mg, 65%); [R]21D +4.84° (c
1, CHCl3); 1H NMR (CDCl3) δ 7.26-6.99 (m, 14H), 5.06 (s, 1H),
3.49 (d, J ) 7.3 Hz, 1H), 3.20-3.04 (m, 2H), 2.35 (m, 2H), 2.34
(s, 3H), 2.26 (s, 3H), 2.10-1.94 (m, 2H), 1.84 (m, 2H), 1.68 (m,
1H), 1.52 (m, 2H); 13C NMR (CDCl3) δ 142.4, 142.2, 140.9,
135.4, 128.4, 128.0, 127.4, 126.4, 83.2, 69.0, 63.3, 61.7, 45.8,
40.9, 37.5, 25.8, 21.7, 20.8. Anal. (C29H33NO‚HCl‚H2O) C, H,
N.
2â-Dip h en ylm et h oxym et h yl-3â-(4-flu or op h en yl)t r o-
p a n e (9b): general method B; white solid (310 mg, 75%); mp
81-83 °C (free base); [R]21 -72.2° (c 1, CHCl3); 1H NMR
D
(CDCl3) δ 7.24-6.84 (m, 14H), 5.07 (s, 1H), 3.68 (t, J ) 9.0
Hz, 1H), 3.44 (d, J ) 5.0 Hz, 1H), 3.16 (m, 1H), 3.20 (m, 1H),
2.91 (m, 1H), 2.19 (s, 3H), 2.15-1.91 (m, 4H), 1.59 (m, 2H),
1.43 (m, 1H); 13C NMR (CDCl3) δ 159.4, 142.6, 138.4, 128.1,
128.0, 127.1, 127.0, 126.9, 126.8, 126.6, 114.9, 114.6, 83.5, 67.7,
63.9, 61.8, 47.1, 41.8, 34.3, 34.0, 26.0, 24.8. Anal. (C28H30NOF‚
HCl‚2H2O) C, H, N.
2â-(Dip h en ylm eth oxym eth yl)-3â-(4-ch lor op h en yl)tr o-
p a n e (9c): general method B; white solid (350 mg, 80%); mp
2r-(Dip h en ylm eth oxy)m eth yl-3â-(4-ch lor op h en yl)tr o-
p a n e (10c): general method C; colorless oil (290 mg, 66%);
99-101 °C (free base); [R]21 -7.45° (c 1, CHCl3); 1HNMR
[R]21 -27.95° (c 1, CHCl3); 1H NMR (CDCl3) δ 7.60-6.90 (m,
D
D
(CDCl3) δ 7.29-6.96 (m, 14H), 5.06 (s, 1H), 3.67 (t, J ) 8.7
Hz, 1H), 3.42 (d, J ) 4.6 Hz, 1H), 3.13 (br s, 1H), 3.05-2.90
(m, 2H), 2.17 (s, 3H), 2.20-1.85 (m, 4H), 1.57 (m, 2H), 1.42
(m, 1H); 13C NMR (CDCl3) δ 142.6, 141.4, 131.4, 128.8, 128.2,
128.1, 126.8, 126.6, 83.5, 67.7, 64.0, 61.7, 47.0, 41.9, 34.2, 34.0,
26.1, 24.8. Anal. (C28H30NOCl‚HCl‚H2O) C, H, N.
14H), 5.09 (s, 1H), 3.68 (t, J ) 8.6 Hz, 1H), 3.46 (br s, 1H),
3.20 (br s, 1H), 3.10-2.90 (m, 2H), 2.22 (s, 3H), 2.15-1.90 (m,
4H), 1.64 (t, J ) 11.2 Hz, 2H), 1.48 (m, 1H); 13C NMR (CDCl3)
δ 142.6, 135.2, 131.4, 130.7, 128.8, 128.4, 128.0, 127.4, 127.3,
127.0, 126.9, 83.5, 67.8, 64.1, 61.8, 47.0, 41.9, 34.3, 26.1 24.9,
21.0. Anal. (C28H30NOCl‚HCl‚H2O) C, H, N.
2â-[(4-Ch lor op h en yl)p h en ylm eth oxym eth yl]-3â-tolyl-
2r-[(4-Ch lor op h en yl)p h en ylm eth oxym eth yl]-3â-tolyl-
tr op a n e (9d ): general method C; colorless oil (220 mg, 50%);
tr op a n e (10d ): general method C; colorless oil (200 mg, 45%);
1
1
[R]21 -81.5° (c 1, CHCl3); H NMR (CDCl3) δ 7.24-6.92 (m,
[R]21 +29.1° (c 1, CHCl3); H NMR (CDCl3) δ 7.45-6.95 (m,
D
D
13H), 5.05 (s, 1H), 3.69 (t, J ) 6.3 Hz, 1H), 3.45 (br s, 1H),
3.21 (br s, 1H), 3.10-2.90 (m, 2H), 2.26, (s, 3H), 2.21 (s, 3H),
2.20-1.95 (m, 4H), 1.76-1.42 (m, 3H); 13C NMR (CDCl3) δ
142.2, 141.3, 135.2, 132.7, 132.6, 128.8, 128.2, 128.0, 127.3,
127.0, 126.9, 126.5, 82.7, 67.9, 63.9, 61.9, 46.9, 41.8, 34.2, 26.0,
24.8, 20.8. Anal. (C29H32NOCl‚HCl‚H2O) C, H, N.
13H), 5.53 (s, 1H), 3.46 (m, 1H), 3.20 (m, 1H), 3.07 (d, J ) 6.6
Hz, 2H), 2.37 (s, 3H), 2.30 (s, 3H), 2.15-1.98 (m, 2H), 1.97-
1.76 (m, 2H), 1.75-1.46 (m, 4H); 13C NMR (CDCl3) δ 141.8,
140.8, 135.6, 133.0, 132.7, 129.0, 128.3, 128.2, 127.5, 127.2,
126.8, 126.4, 82.6, 69.0, 63.4, 61.8, 45.8, 40.8, 37.5, 25.8, 21.8,
20.9. Anal. (C29H32NOCl‚HCl‚2H2O) C, H, N.

Aryltropane Derivatives
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7 1681
2r-[(4-Ch lor oph en yl)ph en ylm eth oxym eth yl]-3â-(4-ch lo-
r op h en yl)tr op a n e (10f): general method C; colorless oil (220
mg, 48%); [R]21D +46.9° (c 1, CHCl3); 1H NMR (CDCl3) δ 7.27-
7.08 (m, 13H), 5.06 (s, 1H), 3.45 (d, J ) 6.5 Hz, 1H), 3.22 (m,
1H), 3.07 (d, J ) 5.0 Hz, 2H), 3.83 (br s, 1H), 2.38 (s, 3H), 2.05
(m, 2H), 2.00-1.63 (m, 3H), 1.58 (m, 2H); 13C NMR (CDCl3) δ
142.6, 141.8, 140.9, 132.9, 131.7, 129.1, 128.5, 128.4, 128.3,
127.6, 126.8, 126.5, 82.7, 69.2, 63.5, 61.7, 46.1, 41.0, 40.9, 37.7,
25.8, 21.9. Anal. (C28H29NOCl2‚HCl‚H2O) C, H, N.
of criterioa where at least a 5% increase in r2 value was
cv
observed with addition of each component and the point where
use of additional components did not show a 5% increase in
r2 the previous components were considered optimum. The
cv
CoMFA contour graphs were derived automatically. The
training set consisted of 41 compounds in which 18 compounds
were 2-substituted 3-phenyltropanes (Table 2) and 23 com-
pounds were 6-substituted 3-benzyltropanes (Table 3).
Ack n ow led gm en t. We are grateful to the National
Institute on Drug Abuse (Grant DA11528) and NIDA-
IRP for the financial support of this research. The
authors thank Bettye Campbell and Dawn French for
technical support, Patty Ballerstadt for administrative
and clerical support, and Dawn French for expert data
analysis.
2r-[Bis(4-flu or op h en yl)m et h oxy]m et h yl]-3â-t olylt r o-
p a n e (10g): general method D; colorless oil (140 mg, 32%);
1
mp 170-172 °C (HCl salt); H NMR (CDCl3) δ 7.22-6.87 (m,
12H), 5.03 (s, 1H), 3.43 (d, J ) 5.1 Hz, 1H), 3.18 (br s, 1H),
3.05 (d, J ) 6.0 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 2.15-1.96
(m, 2H), 1.94-1.78 (m, 2H), 1.72-1.47 (m, 4H); 13C NMR
(CDCl3) δ 163.3, 159.9, 140.7, 137.9, 137.5, 135.2, 128.7, 128.2,
127.8, 127.2, 114.8, 114.5, 81.5, 68.7, 63.1, 61.4, 45.9, 40.5, 37.4,
25.5, 21.5, 20.5. Anal. (C29H31NOF2‚HCl) C, H, N.
Su p p or tin g In for m a tion Ava ila ble: Tables 2 and 3
listing the activities and structures of aryl- and benzyltro-
panes. This material is available free of charge via the Internet
at http://pubs.acs.org.
2r-[Bis(4-flu or op h en yl)m et h oxym eh yl]-3â-(4-ch lor o-
p h en yl)tr op a n e (10i): general method D; colorless oil (160
mg, 35%); 1H NMR (CDCl3) δ 7.30-6.92 (m, 12H), 5.29 (s, 1H),
3.78-3.62 (m, 2H), 3.16 (br s, 1H), 2.70 (m, 1H), 2.30 (s, 3H),
2.06, (br s, 4H), 1.94 (t, J ) 13.1, Hz, 1H), 1.55 (m, 1H), 1.36
(m, 2H); 13C NMR (CDCl3) δ 163.7, 160.5, 140.8, 137.7, 130.6,
128.5, 128.4, 128.3, 128.2, 128.1, 115.4, 115.1, 83.4, 73.2, 70.0,
64.7, 62.1, 48.7, 46.1, 42.1, 25.2, 20.6. Anal. (C28H28NOClF2‚
HCl) C, H, N.
Refer en ces
(1) Mathias, R. Cocaine, Marijuana and Heroin Abuse Up, Meth-
amphetamine Abuse Down. NIDA Notes 2000, 15 (3), 4-5.
(2) Carroll, F. I.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . Cocaine
Receptors: Biochemical Characterization and Structure-Activ-
ity Relationships of Cocaine Analogues at the Dopamine Trans-
porter. J . Med. Chem. 1992, 35, 969-981.
(3) Carroll, F. I.; Howell, L. L.; Kuhar, M. J . Pharmacotherapies
for the Treatment of Cocaine Abuse: Preclinical Aspects. J . Med.
Chem. 1999, 42, 2721-2736.
(4) Carroll, F. I.; Lewin, A. H.; Kuhar, M. J . Dopamine Transporter
Uptake Blockers: Structure-Activity Relationships. In Neuro-
transmitter Transporters: Structure, Function, and Regulation;
Reith, M. E. A., Ed.; Humana Press: Totowa, NJ , 1997; pp 263-
295.
(5) Lewin, A. H.; Gao, Y.; Abraham, P.; Boja, J . W.; Kuhar, M. J .;
Carroll, F. I. 2â-Substituted Analogues of Cocaine: Synthesis
and Inhibition of Binding to the Cocaine Receptor. J . Med. Chem.
1992, 35, 135-140.
(6) Carroll, F. I.; Abraham, P.; Lewin, A. H.; Parham, K. A.; Boja,
J . W.; Kuhar, M. J . Isopropyl and phenyl esters of 3â-(4-
substituted-phenyl)tropan-2â-carboxylic acids. Potent and selec-
tive compounds for the dopamine transporter. J . Med. Chem.
1992, 35, 2497-2500.
(7) Carroll, F. I.; Kotian, P.; Gray, J . L.; Abraham, P.; Kuzemko,
M. A.;Lewin, A. H.;Boja, J . W.;Kuhar, M. J . 3â-(4′-Chlorophenyl)-
tropan-2â-carboxamides and Cocaine Amide Analogues: New
High Affinity and Selective Compounds for the Dopamine
Transporter. Med. Chem. Res. 1993, 3, 468-472.
(8) Kozikowski, A. P.; Roberti, M.; Xiang, L.; Bergmann, J . S.;
Callahan, P. M.; Cunningham, K. A.; J ohnson, K. M. Structure-
Activity Relationship Studies of Cocaine: Replacement of the
C-2 Ester Group by Vinyl Argues against H-Bonding and
Provides Esterase-Resistant, High Affinity Cocaine Analogues.
J . Med. Chem. 1992, 35, 4764-4766.
(9) Kozikowski, A. P.; Roberti, M.; J ohnson, K. M.; Bergmann, J .
S.; Ball, R. C. SAR of Cocaine: Further Exploration of the
Structural Variations at the C-2 Center Provides Compounds
of Subnanomolar Binding Potency. Bioorg. Med. Chem. Lett.
1993, 1327-1332.
(10) 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)- and 3â-(3′,4′-
Disubstituted phenyl)tropane 2â-Carboxylic Acid Methyl Esters.
J . Med. Chem. 1994, 37, 2865-2873.
(11) Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray, J . L.; Kuzemko,
M. A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J . W.;
Kuhar, M. J . Cocaine and 3â-(4′-Substituted phenyl)tropane 2â-
Carboxylic Acid Ester and Amide Analogues. New High Affinity
and Selective Compounds for the Dopamine Transporter. J . Med.
Chem. 1995, 38, 379-388.
(12) Kozikowski, A. P.; Saiah, M. K. E.; J ohnson, K. M.; Bergmann,
J . S. Chemistry and Biology of the 2â-Alkyl-3â-phenyl Analogues
of Cocaine: Subnanomolar Affinity Ligands That Suggest a New
Pharmacophore Model at the C-2 Position. J . Med. Chem. 1995,
38, 3086-3093.
(13) 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.
2â-[3-(Diphenylmethoxy)propyl]-3â-phenyltropane (12a):
general method B; colorless oil (370 mg, 86%); [R]21 -117° (c
D
1, CHCl3); 1H NMR (CDCl3) δ 7.32-7.10 (m, 15H), 5.16 (s, 1H),
3.35-3.10 (m, 4H), 3.04 (m, 1H), 2.18 (s, 3H), 2.14-2.06 (m,
2H), 2.10-1.90 (m, 1H), 1.62-1.53 (m, 4H), 1.53-1.40 (m, 2H),
1.34-1.18 (m, 1H), 0.97-0.80 (m, 1H); 13C NMR (CDCl3) δ
143.4, 142.3, 128.0, 127.9, 127.6, 127.0, 126.7, 125.5, 83.2, 69.1,
64.3, 61.8, 45.9, 41.9, 36.2, 33.3, 27.7, 26.2, 24.6, 23.2. Anal.
(C20H35NO‚HCl‚H2O) C, H, N.
2â-[3-(4-C h lo r o p h e n y lp h e n y lm e t h o x y )p r o p y l]-3â-
p h en yltr op a n e (12b): general method B; colorless oil (300
mg, 66%); [R]21 -64.0° (c 1 CHCl3); 1H NMR (CDCl3) δ 7.35-
D
7.04 (m, 14H), 5.11 (s, 1H), 3.35-3.00 (m, 6H), 2.18 (s, 3H),
2.12 (m, 1H), 1.99 (m, 1H), 1.70-1.40 (m, 6H), 1.30-1.15 (m,
1H), 0.86 (m, 1H); 13C NMR (CDCl3) δ 143.5, 142.0, 141.2,
132.8, 128.3, 128.2, 128.1, 128.0, 127.8, 127.4, 126.8, 125.7,
82.6, 69.3, 64.5, 66.0, 46.0, 42.1, 36.3, 33.4, 27.8, 26.4, 24.8,
23.4. Anal. (C30H34NOCl‚HCl‚2H2O) C, H, N.
2â-[3-{Bis(4-flu or op h en yl)m eth oxy}p r op yl]-3â-p h en yl-
tr op a n e (12c): general method D; colorless oil (330 mg, 71%);
mp 54-56 °C (HCl salt); 1H NMR (CDCl3) δ 7.28-6.90 (m,
13H), 5.13 (s, 1H), 3.30-3.06 (m, 5H), 2.21 (s, 3H), 2.20-2.10
(m, 2H), 2.10-1.95 (m, 1H), 1.70-1.55 (m, 4H), 1.55-1.40 (m,
2H), 1.25 (m, 1H), 0.89 (m, 1H); 13C NMR (CDCl3) δ 163.5,
160.2, 143.5, 138.0, 128.4, 128.3, 127.9, 127.6, 125.6, 115.1,
114.8, 81.8, 69.1, 64.4, 61.9, 46.0, 42.0, 36.2, 33.3, 27.7, 26.3,
24.7, 23.3. Anal. (C30H33NOF2‚HCl) C, H, N.
Molecu la r Mod elin g Meth od s. The 3D-QSAR studies
were performed using CoMFA method with SYBYL 6.7 run-
ning on Silicon Graphics Octane workstation. The X-ray crystal
structural data of compounds 16, 30, and 37 (see Supporting
Information) were used to build the closest structure. The
nitrogen of the tropane ring was considered as a neutral atom.
The structures were assigned semiempirical AM1 charges and
energy-minimized to the local minima. The conformations of
the compounds were explored by systematic conformational
searching of all nonterminal rotatable bonds for 360° with an
increment of 15°. The low-energy conformers were extracted
and minimized by conjugate gradient minimization. The
compounds were superimposed by selecting the atoms/centroid
shown in Figure 1. The compounds containing a diarylmethoxy
substituent at the 2-position were used as a validation set.
The standard steric and electrostatic CoMFA interaction fields
were calculated by default parameters. The statistical analyses
of the descriptors were performed by a partial least-squares
(PLS) algorithm leave one out (LOO) cross-validation method.
The optimum number of components was chosen on the basis

1682 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7
Xu et al.
(14) 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-(3′-
Substituted phenyl)-2â-heterocyclic Tropanes: Evidence for an
Electrostatic Interaction at the 2â-Position. J . Med. Chem. 1996,
39, 2753-2763.
(15) Blough, B. E.; Abraham, P.; Lewin, A. H.; Kuhar, M. J .; Boja, J .
W.; Carroll, F. I. Synthesis and Transporter Binding Properties
of 3â-(4′-Alkyl-, 4′-alkenyl and 4′-alkynylphenyl)nortropane 2â-
Carboxylic Acid Methyl Esters: Serotonin Transporter Selective
Analogues. J . Med. Chem. 1996, 39, 4027-4035.
(16) Xu, L.; Kelkar, S. V.; Lomenzo, S. A.; Izenwasser, S.; Katz, J .
L.; Kline, R. H.; Trudell, M. L. Synthesis, Dopamine Transporter
Affinity, Dopamine Uptake Inhibition and Locomotor Stimulant
Activity of 2-Substituted 3â-Phenyltropane Derivatives. J . Med.
Chem. 1997, 40, 858-863.
(17) Emond, P.; Garreau, L.; Chalon, S.; Boazi, M.; Caillet, M.;
Bricard, J .; Frangin, Y.; Mauclaire, L.; Besnard, J . C.; Guilloteau,
D. Synthesis, and Ligand Binding of Nortropane Derivatives.
N-Substituted 2â-Carboxymethyl-3â-(4′-iodophenyl)nortropane
and N-(3-Iodoprop-(2E)-enyl)-2â-carboxymethyl-3â-(3′,4′-disub-
stituted phenyl)nortropane. New High-Affinity and Selective
Compounds for the Dopamine Transporter. J . Med. Chem. 1997,
40, 1366-1372.
(18) Keverline-Frantz, K. I.; Boja, J . W.; Kuhar, M. J .; Abraham, P.;
Burgess, J . P.; Lewin, A. H.; Carroll, F. I. Synthesis and Ligand
Binding of Tropanes Ring Analogues of Paroxetine. J . Med.
Chem. 1998, 41, 247-257.
(19) J iang, C.; Chang, A.-C.; Abraham, P.; Kuhar, M. J .; Carroll, F.
I. Synthesis and Transporter Binding of (R)-2â,3â- and (R)-
2R,3R-Diaryltropanes. Bioorg. Med. Chem. Lett. 1998, 8, 3689-
3692.
(20) Kozikowski, A. P.; Araldi, G. L.; Prakash, K. R. C.; Zhang, M.;
J ohnson, K. M. Synthesis and Biological Properties of New 2â-
Alkyl and 2â-Aryl-3-(substituted phenyl)tropane derivative.
Stereochemical Effect of C-3 on Affinity and Selectivity for
Neuronal Dopamine and Serotonin Transporters. J . Med. Chem.
1998, 41, 4973-4982.
(21) Tamagnan, G.; Baldwin, R. M.; Kula, N. S.; Baldessarini, R. J .;
Innis, R. B. Synthesis and Monoamine Transporter Affinity of
2â-Carbomethoxy-3â-(2′,3′, or 4′-Substituted) Biphenyl-tropanes.
Bioorg. Med. Chem. Lett. 2000, 10, 1783-1785.
(27) Newman, A. H.; Robarge, M. J .; Howard, J . M.; Wittkopp, S. L.;
George, C.; Kopajtic, T.; Izenwasser, S.; Katz, J . L. Structure-
Activity Relationships at Monoamine Transporters and Musca-
rinic receptors for N-Substituted-2R-(3′-chloro, 4′-chloro and
4′,4′′-Dichloro-substituted diphenyl)methoxytropanes. J . Med.
Chem. 2001, 44, 633-640.
(28) van der Zee, P.; Koger, H. S.; Gootjes, J .; Hespe, W. Aryl 1,4-
Dialk(en)ylpiperazines as Selective and Very Potent Inhibitors
of Dopamine Uptake. Eur. J . Med. Chem. 1980, 15, 363-370.
(29) Andersen, P. H. Biochemical and Pharmacological Characteriza-
tion of [3H]GBR 12935 Binding in Vitro to Rat Striatial Mem-
branes: Labeling of the Dopamine Uptake Complex. J . Neuro-
chem. 1987, 48, 1887-1896.
(30) Andersen, P. H. The Dopamine Uptake Inhibitor GBR 12909:
Selectivity and Molecular Mechanism of Action. Eur. J . Phar-
macol. 1989, 166, 493-504.
(31) Zhang, Y.; J oseph, D. B.; Bowen, W. D.; Flippen-Anderson, J .
L.; Dersch, C. M.; Rothman, R. B.; J acobson, A. E.; Rice, K. C.
Synthesis and Biological Evaluation of Tropane-like 1-{2-[Bis-
(4-fluorophenyl)methoxy]ethyl}-4-3-(phenylpropyl)piperazine (GBR
12909) Analogues. J . Med. Chem. 2001, 44, 3937.
(32) Bradley, A. L.; Izenwasser, S.; Wade, D.; Klein-Stevens, C.; Zhu,
N.; Trudell, M. L. Synthesis and Dopamine Transporter Binding
Affinities of3R-Benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]-
octanes. Bioorg. Med. Chem. Lett. 2002, 12, 2387-2390.
(33) Bradley, A. L.; Izenwasser, S.; Wade, D.; Cararas, S.; Trudell,
M. L. Synthesis of Dopamine Transporter Selective 3-{2-(Di-
arylmethoxy)ethylidene}-8-alkylaryl-8-azabicyclo[3.2.1]octanes.
Bioorg. Med. Chem. Lett. 2003, 13, 629-632.
(34) Xu, L.; Trudell, M. L. Stereoselective Synthesis of 2â-Carbo-
methoxy-3â-phenyltropane Derivatives. Enhanced Stereoselec-
tivity Observed for the Conjugate Addition Reaction of Phenyl-
magnesium Bromide Derivatives with Anhydroecgonine Methyl
Ester in Dichloromethane. J . Heterocycl. Chem. 1996, 33, 2037-
2039.
(35) Zhu, N.; Manning, K.; Xu, L.; Trudell, M. L.; Klein-Stevens, C.
A Structural Study of Cocaine Analogs: X-ray Crystal Structure
of 2â-Hydroxymethyl-3â-tolyltropane Hydrochloride, 2â-[Bis(4-
fluorophenyl)methoxymethyl]-3â-tolyltropane Tetrahydrate and
2â-[Bis(4-fluorophenyl)methoxymethyl]-3â-(4-chlorophenyl)tro-
pane Tetrahydrate. J . Undergrad. Chem. Res. 2002, 3, 101-
106.
(36) Izenwasser, S.; Rosenberger, J . G.; Cox, B. M. The Cocaine
Analog WIN 35,428 Binds to Two Sites in Fresh Rat Caudate-
putamen: Significance of Assay Procedures. Life Sci. 1993, 52,
PL 141.
(22) Davies, H. M. L.; Gilliat, V.; Kuhn, L. A.; Saikali, E.; Ren, P.;
Hammand, P. S.; Sexton, T.; Childers, S. R. Synthesis of 2â-
Acyl-3â-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes and
Their Binding Affinities at Dopamine and Serotonin Transport
Sites. J . Med. Chem. 2001, 44, 1509-1515.
(23) Xu, L.; Izenwasser, S.; Katz, J . L.; Kopajtic, T.; Klein-Stevens,
C.; Zhu, N.; Lomenzo, S. A.; Winfield, L.; Trudell, M. L. Synthesis
and Biological Evaluation of 2-Substituted 3â-Tolyltropane
Derivatives at Dopamine, Serotonin and Norepinephrine Trans-
porters. J . Med. Chem. 2002, 45, 1203-1210.
(24) Newman, A. H.; Kline, R. H.; Allen, A. C.; Izenwasser, S.; George,
C.; Katz, J . L. Novel 4′-Substituted and 4′,4′′-Disubstituted 3R-
(diphenylmethoxy)tropane Analogs as Potent and Selective
Dopamine Uptake Inhibitors. J . Med. Chem. 1995, 38, 3933-
3940.
(37) Newman, A. H.; Kulkarni, S. S. Probes for the Dopamine
Transporter: New Leads toward a Cocaine-Abuse Therapeutics
A Focus on Analogues of Benztropine and Rimcazole. Med. Res.
Rev. 2002, 22, 429-464.
(38) Lomenzo, S. A.; Izenwasser, S.; Katz, J . L.; Terry, P. D.; Zhu,
N.; Klein, C.; 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.
(39) Kelkar, S. V.; Izenwasser, S.; Katz, J . L.; Klein, C. L.; Zhu, N.;
Trudell, M. L. Synthesis, Cocaine Receptor Affinity, and Dopam-
ine Uptake Inhibition of Several New 2â-Substituted 3â-Phenyl-
tropanes. J . Med. Chem. 1994, 37, 3875-3877.
(40) Reith, M. E. A.; Berfield, J . L.; Wang, L. C.; Ferrer, J . V.; J avitch,
J . A. The Uptake Inhibitors Cocaine and Benztropine Differen-
tially Alter the Conformation of the Human Dopamine Trans-
porter. J . Biol. Chem. 2001, 276, 29012-29018.
(25) Kline, R. H.; Izenwasser, S.; Katz, J . L.; J oseph, D. B.; Bowen,
W. D.; Newman, A. H. 3′-Chloro-3R-(diphenylmethoxy)tropane
but Not 3′-Chloro-3R-(diphenylmethoxy)tropane Produces
a
Cocaine-like Behavorial Profile. J . Med. Chem. 1997, 40, 851-
857.
(26) 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.
J M030430A