Further studies on conformationally constrained tricyclic tropane analogues and their uptake inhibition at monoamine transporter sites: Synthesis of (z)-9-(substituted arylmethylene)-7-azatricyclo[4.3.1.03,7]decanes as a Novel class of serotoni

Article abstract of DOI:10.1021/jm0105373

A novel series of conformationally constrained tricyclic tropane analogues, (Z)-9-(substituted arylmethylene)-7-azatricyclo[4.3.1.0^3,7]decanes, were prepared, and their abilities to inhibit high-affinity uptake of dopamine (DA), serotonin (5-HT

Full text of DOI:10.1021/jm0105373

1930
J . Med. Chem. 2002, 45, 1930-1941
F u r th er Stu d ies on Con for m a tion a lly Con str a in ed Tr icyclic Tr op a n e An a logu es
a n d Th eir Up ta k e In h ibition a t Mon oa m in e Tr a n sp or ter Sites: Syn th esis of
(Z)-9-(Su bstitu ted a r ylm eth ylen e)-7-a za tr icyclo[4.3.1.03,7]d eca n es a s a Novel
Cla ss of Ser oton in Tr a n sp or ter In h ibitor s
Ao Zhang,† Guochun Zhou,† Alexander Hoepping,† J ayanta Mukhopadhyaya,† Kenneth M. J ohnson,‡
Mei Zhang,‡ and Alan P. Kozikowski*,†
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3900 Reservoir Road Northwest,
Washington, DC 20007-2197, and Department of Pharmacology and Toxicology, University of Texas Medical Branch,
Galveston, Texas 77555-1031
Received November 26, 2001
A novel series of conformationally constrained tricyclic tropane analogues, (Z)-9-(substituted
arylmethylene)-7-azatricyclo[4.3.1.03,7]decanes, were prepared, and their abilities to inhibit high-
affinity uptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain
nerve endings (synaptosomes) were evaluated. First, a systematic screening of a variety of
different substituents on the phenyl ring indicated that the substitution pattern plays an
important role in the monoamine transporter activity. Most compounds in this series possessed
a very low activity at the DA transporter (DAT) but a good to excellent affinity for the 5-HT
transporter (SERT). In the case of para-substituted phenyl analogues, the electronic character
of the substituent did not affect uptake inhibition as dramatically as observed in some
benztropine analogues. Among these compounds, the 4-bromophenyl and 4-isopropylphenyl
analogues 8d and 8j exhibited the highest potency at the SERT with a Ki value of 10 nM. In
the 3,4-disubstituted phenyl series, even more potent and highly selective compounds were
discovered. Compound 8o has a Ki value of 2.3 nM for uptake inhibition at the SERT, a DAT/
SERT uptake ratio of 2360, and a NET/SERT uptake ratio of 200. Compound 8p exhibited a
Ki value of 1.8 nM for uptake inhibition at the SERT, a DAT/SERT uptake ratio of 1740, and
a NET/SERT uptake ratio of 151. These compounds are 3-4-fold more potent than the
antidepressant medication fluoxetine, and the selectivities for SERT over DAT and NET are
also better than those of fluoxetine. Second, a variety of functional modifications on the ester
moiety were investigated. Substitution by other esters or amides as well as alkenes did not
increase potency, while most of the acetates or benzoates (16-21, 23, and 24) and the ketone
28 exhibited significantly improved activity. A good hydrogen-bonding ability of the substituent
is believed to be required for high activity. The most potent and selective ligand is compound
23, which displayed a Ki value of 0.06 nM and has essentially no activity at the DAT or NET.
The present results have important implications for drug addiction as well as a number of
psychiatric diseases.
In tr od u ction
binds with moderate and comparable affinity to all three
of the monoamine transporters and thereby inhibits the
reuptake of the neurotransmitters dopamine (DA),
serotonin (5-HT), and norepinephrine (NE) into pre-
synaptic neurons. A study employing knockout mice has
also demonstrated that cocaine provides its rewarding
cues to humans through its effects on several different
systems and not just the dopaminergic system.6,7 There-
fore, a complete understanding of cocaine’s action
depends on the synthesis of cocaine analogues with
defined selectivities at each of these three transporter
sites.
Cocaine abuse and addiction has devastated families
and communities and seems unlikely to dissipate any-
time soon.1 As a consequence, immediate strategies are
needed for the treatment of individuals who have
become addicted to this powerfully reinforcing drug.
Because the biological actions of cocaine were initially
thought to occur primarily through inhibition of dopam-
ine uptake, most of the compounds synthesized and
developed as potential therapeutics have been designed
to exhibit high potency at and selectivity for the dop-
amine transporter.2-5 Unfortunately, despite many
notable efforts, ligands targeted solely at this protein
have not led to a clinically useful medication. Studies
have shown that cocaine actually has multiple effects
on endogenous central neurotransmitter systems. It
Some evidence has suggested that the 5-HT trans-
porter (SERT) also plays a crucial role in mediating the
neurochemical and behavioral actions of cocaine.8-10
Serotonin selective reuptake inhibitors such as flu-
oxetine and paroxetine have been developed for the
treatment ofdepression and related psychiatricdisorders.10c
Interestingly, indirect 5-HT agonists lacking dopamin-
ergic activity have been found not to produce reward or
* To whom correspondence should be addressed. Tel.: 202-687-0686.
Fax: 202-687-5065. E-mail: Kozikowa@georgetown.edu.
† Georgetown University Medical Center.
‡ University of Texas Medical Branch.
10.1021/jm0105373 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/27/2002

Tricyclic Tropane Analogues and Uptake Inhibition
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9 1931
Sch em e 1
Sch em e 2a
euphoria in primates.11 A detailed interpretation of this
result still remains elusive.12-16
a
Reagents and conditions: (i) Saturated NaHCO3; (ii) CH3-
In the course of our efforts to discover ligands selec-
tive for the SERT for possible use as medications, we
recently identified a novel series of rigidified cocaine
analogues that contain a ring constraint between the
C3-position of the tropane moiety and the nitrogen
atom. This series of compounds was assembled by
employment of a radical cyclization combined with the
Stille coupling reaction.17 The preliminary results re-
ported in our previous paper indicated that the substit-
uents on the phenyl ring play a critical role in mono-
amine transporter selectivity. Some compounds of this
series exhibited high potency in the SERT, norepineph-
rine transporter (NET), or combined NET/SERT re-
uptake inhibition. For example, the 3,4-dichlorophenyl-
substituted analogue, (1S,3S,6R,10S)-(Z)-9-(3,4-dichloro-
benzylidene)-7-azatricyclo[4.3.1.03,7]decane-10-carboxylic
acid methyl ester (8k ) (Scheme 1), gave remarkable
potency and selectivity at the SERT with 96-fold higher
activity than at the dopamine transporter (DAT) and
about 50-fold higher activity than at the NET. The
biphenylyl derivative 11 was 50-fold selective at both
the NET and the SERT over the DAT. These results
encouraged a further study of this novel selectivity
profile.
CH(Cl)OCOCl, 1,2-dichloroethane, K2CO3, reflux, 9 h; (iii) MeOH,
reflux, 7 h; (iv) propargyl bromide, K2CO3, MeCN, reflux, 18 h;
(v) 2 N HCl, reflux, 15 h; (vi) POCl3, reflux, 2 h; (vii) MeOH, -78
°C to room temperature; (viii) AIBN, n-Bu3SnH, benzene.
Sch em e 3
Sch em e 4
Structurally, compound 8k is intriguing because it
maintains cocaine’s methyl ester moiety and the aro-
matic ring (although shifted to a position above the
basal plane of the tropane ring), both of which represent
important pharmacophoric groups.18-20 The distance
between the nitrogen atom and the centroid of the
aromatic ring is 5.6 Å, a value which seems optimal for
high activity.21 In the present paper, the effects of a
systematic variation of the aromatic ring substitution
pattern as well as the replacement of the methyl ester
moiety by a variety of other functional groups on the
activities at all three monoamine transporters are
reported. The aim of this study was to identify ligands
with superior potency and selectivity for the SERT.
In the case of 1,4-diiodobenzene 7e, the desired
coupling product 8e was obtained as the major product,
while the 2:1 product 10 formed by a second coupling
reaction was also isolated. The formation of compound
10 can be limited by employing iodide 7e in excess
(Scheme 4). Coupling of compound 5 with 2-chloro-1,4-
diiodobenzene (7p ) resulted in two regioisomers 8p and
8q, which were separable only by high-performance
liquid chromatography (HPLC).
To investigate the effect of modifications of the ester
group, methyl ester 8k was refluxed with hydrochloric
acid to give the acid 12, which was subsequently
converted into acid chloride 13 by treatment with either
thionyl chloride or oxalyl chloride. The acid chloride 13
was then condensed with an appropriate alcohol, phenol,
or amine to give the esters and amides 14a -d (Scheme
5).26
Ch em istr y
Our drug design strategy was first based on modifica-
tion of the aryl group while leaving the ester moiety
intact. The flexible approach to the tricyclic skeleton
starting from cocaine (1) that we have developed earlier
was utilized as described in Scheme 2.17,22,23 The key
step, the radical cyclization of enyne 4, afforded pre-
dominantly the Z-isomer of vinyl stannane 5, which was
then subjected to Stille coupling with aryl iodides 724
to give the target products 8 in moderate yields.
Compound 925 resulting from competing protodestan-
nylation was formed as the major byproduct (Scheme
3).
To prepare the reverse esters 16-21 and 24 (Scheme
6), the appropriate methyl esters 8 were reduced with

1932 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9
Zhang et al.
Sch em e 5a
Sch em e 8a
a
Reagents and conditions: (i) 6 N HCl, reflux; (ii) SOCl2,
CH2Cl2, reflux; (iii) alcohol, phenol, or amine, Et3N, THF, 0 °C to
room temperature.
Sch em e 6a
a
Reagents and conditions: (i) LiAlH4 or DIBAL-H, THF, room
temperature; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C; (iii)
Ph3P+CH2PhBr-, n-BuLi, THF, room temperature; (iv) HN(CH3)-
OCH3, Et3N, CH2Cl2; (v) EtMgBr, THF.
a
Reagents and conditions: (i) LiAlH4 or DIBAL-H, THF, room
Sch em e 9a
temperature; (ii) Ac2O or acid chloride, Et3N, THF, 0 °C to room
temperature.
Sch em e 7
a
Reagents and conditions: (i) Ph3P, EtOOCNdNCOOEt, 4-io-
LiAlH4 or DIBAL-H to give the alcohols 15, which were
further treated with acetic anhydride or acid chlorides.
This procedure was not applicable for the preparation
of the iodide 23 since ester reduction was in this case
accompanied by deiodination. To avoid this undesired
side reaction, iodine was introduced after ester reduc-
tion starting from the corresponding bromide 21 by way
of the arylstannane 22 (Scheme 7).27,28
The alkene 26 was synthesized by a three-step reac-
tion sequence involving reduction with LiAlH4, Swern
oxidation, and Wittig reaction (Scheme 8). The newly
formed double bond was exclusively trans-configured as
evidenced by the vicinal coupling constant between the
olefinic protons (J ) 15 Hz).
For the synthesis of the ethyl ketone analogue 28, acid
chloride 13 was reacted with N,O-dimethylhydroxyl-
amine to provide the Weinreb amide 27, which on
treatment with ethylmagnesium bromide then provided
the desired ketone almost quantitatively29 (Scheme 8).
Ether 29 was prepared from alcohol 15 by means of
a Mitsunobu reaction.30 The “dimeric” reverse ester 30
was obtained from alcohol 15 by esterification with
sebacoyl chloride (Scheme 9).
dophenol, THF; (ii) ClCO(CH2)8COCl, Et3N, CH2Cl2, 0 °C.
nerve endings (synaptosomes) prepared from brain
regions enriched in transporters for these biogenic
amine neurotransmitters.31,32 The protocols used are
described in the Experimental Section. Table 1 sum-
marizes the activities of those compounds that contain
a methyl ester moiety. For comparison purposes, some
data from our preliminary paper (compounds 8a , 8g,
8i, 8k , and 8t) and data for (-)-cocaine and fluoxetine
are also included.17 Nearly all of the 4-substituted
phenyl derivatives 8a -f and 8h -j exhibit good to
excellent inhibitory activity at the SERT but much lower
activities at the DAT and NET. In contrast, compound
8g with an unsubstituted phenyl group displayed a very
low affinity for the SERT but a high affinity for the NET
and a moderate affinity for the DAT. The substituent
in the phenyl ring thus plays an important role in
driving the affinity and selectivity from the NET or the
DAT to the SERT. Both electron-withdrawing and
electron-donating substituents contribute to this change
in selectivity. Among the compounds with an electron-
withdrawing substituent, potency in inhibition of 5-HT
reuptake decreases in the sequence 4-Br ≈ 4-CF3 > 4-I
> 4-Cl > 3-Cl > 4-F. The p-bromophenyl and p-
(trifluoromethylphenyl) analogues 8d and 8f display
almost the same potency (Ki ) 11 nM) at the SERT, but
P h a r m a cologica l Resu lts
All final compounds were tested for their ability to
inhibit high-affinity reuptake of DA, 5-HT, and NE into

Tricyclic Tropane Analogues and Uptake Inhibition
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9 1933
Ta ble 1. Inhibition of Reuptake at Monoamine Transporters (Ki ( SEM (nM))a
[3H]DA uptake
[3H]5-HT uptake
[3H]NE uptake
uptake ratio (based on Ki)
compd
R
Ki (nM)
Ki (nM)
Ki (nM)
DA/5-HT
NE/DA
NE/5-HT
cocaine
fluoxetine
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
8t
8u
8v
8w
10
423 ( 147
4580 ( 550
6620 ( 460
853 ( 58
155 ( 0.4
7.3 ( 0.7
335 ( 45
34.3 ( 2.9
53.6 ( 17.2
11 ( 3.0
21.9 ( 0.3
12.6 ( 0.5
1140 ( 70
15 ( 0.4
108 ( 3.5
167 ( 15
584 ( 163
208 ( 111
231 ( 44
178 ( 9
213 ( 31
1830 ( 211
53 ( 16
146 ( 28
187 ( 5.0
1110 ( 200
1000 ( 280
1210 ( 358
4100 ( 500
394 ( 98
459 ( 80
272 ( 55
508 ( 21
198 ( 10
659 ( 128
5370 ( 580
157 ( 13
N/T
2.7
0.26
0.04
0.09
0.24
0.03
0.36
0.28
N/T
0.11
0.22
0.06
N/T
0.52
1.42
0.73
0.05
0.08
0.09
0.08
<0.02
N/T
0.7
23
1.7
6.0
4.3
16
9.7
145
0.05
9.7
3.3
109
50
3.4
9.4
3.9
200
151
6.9
31
627
19.7
24.8
145
45
34.9
N/T
0.42
43.3
55.9
N/T
96
4-fluorophenyl
4-chlorophenyl
3-chlorophenyl
4-bromophenyl
4-iodophenyl
4-trifluoromethylphenyl
Ph
4-methylphenyl
4-methoxyphenyl
4-isopropylphenyl
3,4-dichlorophenyl-
2,3-dichlorophenyl
3,5-dichlorophenyl
3,4-difluorophenyl
4-bromo-3-chlorophenyl
3-chloro-4-iodophenyl
2-chloro-4-iodophenyl
3-chloro-4-methylphenyl
3,4-dimethylphenyl
1-naphthyl
7780 ( 1580
495 ( 13
764 ( 11
N/T
481 ( 11
649 ( 2.0
3130 ( 160
N/T
56 ( 4.0
10.2 ( 0.4
20 ( 1
1920 ( 260
850 ( 107
5600 ( 400
7440 ( 19
5420 ( 940
3140 ( 450
6640 ( 2080
>10 000
354 ( 188
437 ( 0.3
101 ( 8.7
2.3 ( 0.1
1.8 ( 0.3
74 ( 12.2
6.4 ( 1.3
10.1 ( 1.1
121 ( 3
2.4
12.8
73.7
2360
1740
89.7
>1560
N/T
80.3
35
N/T
65
44
7.5
N/T
56
9720 ( 700
735 ( 235
9920 ( 906
1640 ( 30
38 900 ( 1050
0.55
0.21
N/T
7.93
0.86
2-naphthyl
1-pyrenyl
9-phenanthryl
21 ( 9.9
860 ( 20.6
233 ( 44
993 ( 110
11.5
7.0
39.2
13 000 ( 1300
33 400 ( 3340
34
a
Ki values are mean ( SEM from two to four independent experiments, each consisting of six drug concentrations (in triplicate) that
were selected on the basis of preliminary screening experiments to bracket the approximate IC50 value.
the former compound also exhibits a moderate NET
activity (Ki ) 178 nM). Among the compounds with an
electron-donating substituent, the 4-methylphenyl ana-
logue 8h displays a high affinity for the SERT (Ki ) 15
nM) coupled with moderate NET potency (Ki ) 146 nM).
The most potent compound in this series is compound
8j containing the bulky isopropyl substituent, which
exhibits a high potency for the SERT (Ki ) 10 nM) and
a 109-fold selectivity over the NET.
NET/SERT uptake ratio of 200. Compound 8p displays
a Ki value of 1.8 nM at the SERT and only slightly lower
selectivities. The regioisomer 8q is less potent and
selective for the SERT in comparison to 8p .
An additional set of compounds were designed to
extend the sp2 carbon framework of the aryl moiety.
First, we replaced the phenyl group with a â-naphthyl
group as the same structural modification has led to
very potent WIN type tropanes.33-35 As expected, com-
pound 8u exhibits a good activity at the SERT (Ki ) 21
nM), which is a 6-fold better result than for the
R-naphthyl analogue 8t, but unexpectedly, compound
8u also showed a fairly good activity at the NET (Ki )
157 nM) and a lower activity at the DAT (Ki ) 735 nM).
Replacement of phenyl with 1-pyrenyl (8v) and 9-phen-
anthryl (8w ) resulted in a decrease in the potency and
selectivity but still with a favorable SERT selectivity
vs DAT and NET. The “dimeric” compound 10 exhibits
only weak activity at the SERT but still remains 34-
fold more potent than at the DAT and NET.
In summary, nearly all of the above compounds, with
the notable exception of the unsubstituted phenyl
congener 8g, possess a low activity at the DAT but good
to excellent potency at the SERT. This finding indicates
that a large lipophilic pocket is present at the SERT
but not at the DAT uptake site in the binding position
of the aryl ring of these ligands. The electronic character
of the substituent in the 4-monosubstituted phenyl
series does not affect activity as dramatically as ob-
served in some benztropine analogues,34 since the
4-bromophenyl and 4-isopropylphenyl analogues 8d and
8j have the same SERT potency. Among the disubsti-
tuted compounds, the position and electronic character
of the two substituents significantly affects the activity,
with 3,4-disubstitution giving the best results in line
with literature reports.36 Thus, from the first part of
our studies, several highly active compounds emerged
The disubstituted phenyl analogues 8k -s are poorly
active at the DAT and, at best, only moderately active
at the NET. The 3,4-dichloro derivative 8k exhibits a
good potency (Ki ) 20 nM) for the SERT and a high
selectivity over the DAT (96-fold) and the NET (50-fold).
Its regioisomers 8l and 8m display at least 17-fold lower
potency for the SERT than 8k , and the selectivities for
the SERT over the DAT and the NET are also reduced.
Similarly, the 3,4-difluoro compound 8n has a 5-fold
lower potency at the SERT (Ki ) 101 nM) and a 13-fold
lower selectivity for the SERT vs the NET. On the
contrary, a 2-fold higher potency at the SERT (Ki ) 10
nM) was found for the 3,4-dimethyl derivative 8s as
compared to 8k . Compound 8r , in which only the
4-chloro substituent of 8k is replaced with methyl,
exhibits high potency at the SERT (Ki ) 6.4 nM) and a
dramatically increased SERT selectivity of more than
1500-fold over the DAT and 30-fold over the NET. This
result is comparable to or even better than that of the
antidepressant medication fluoxetine, which has a
potency of 7.3 nM at the SERT, a 627-fold SERT
selectivity over the DAT, and a 23-fold SERT selectivity
over the NET. Even more exciting results were obtained
for the 3-chloro-4-bromophenyl and 3-chloro-4-iodo-
phenyl analogues 8o and 8p , which are significantly
more potent and SERT selective than fluoxetine. Com-
pound 8o has a Ki value of 2.3 nM for uptake inhibition
at the SERT, a DAT/SERT uptake ratio of 2360, and a

1934 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9
Zhang et al.
Ta ble 2. Inhibition of Reuptake at Monoamine Transporters (Ki ( SEM (nM))
no.
Ar/X
[3H]DA uptake [3H]5-HT uptake [3H]NE uptake
DA/5-HT
15.0
NE/DA
0.25
NE/5-HT
3.8
14a
Ar ) 3,4-dichlorophenyl,
X ) COOPri
1290 ( 405
4440 ( 605
3780 ( 50
6680 ( 1440
1870 ( 90
14100 ( 103
17700 ( 850
>10 000
85.7 ( 4.7
48.3 ( 14.9
29.8 ( 4.8
28.9 ( 2.7
1.6 ( 0.4
3.1 ( 0.1
48.7 ( 0.6
9.3 ( 0.3
4.4 ( 0.9
0.1 ( 0.0
92.9 ( 8.4
11 ( 0.3
325 ( 2.2
2410 ( 510
417 ( 7.5
14b Ar ) 3,4-dichlorophenyl,
X ) COOPh
14c
91.9
127
0.54
0.11
0.30
0.34
0.22
0.48
<0.60
1.03
0.58
0.20
1.63
<0.82
1.35
<0.38
a
49.9
14.0
Ar ) 3,4-dichlorophenyl,
X ) CONHMe
14d Ar ) 3,4-dichlorophenyl,
X ) CONMe2
16a
2020 ( 115
638 ( 86
231
1170
4550
363
69.9
Ar ) 3,4-dichlorophenyl,
X ) CH2OCOCH3
399
16b Ar ) 3,4-dichlorophenyl,
X ) CH2OCOPh
16c
3070 ( 49
8590 ( 140
5950 ( 80
672 ( 59
990
Ar ) 3,4-dichlorophenyl,
X ) CH2OCOC6H4I-p
176
16d Ar ) 3,4-dichlorophenyl,
X ) CH2OCO-2-naphthyl
17a
>1070
148
640
Ar ) 2-naphthyl,
X ) CH2OCOCH3
652 ( 113
5530 ( 305
5980 ( 626
4040 ( 333
>10 000
153
17b Ar ) 2-naphthyl,
X ) CH2OCOPh
18a
3220 ( 117
1180 ( 192
6580 ( 950
8190 ( 1450
4470 ( 471
3840 ( 290
55 300
32 200
12.7
Ar ) 3-chlorophenyl,
X ) CH2OCOCH3
64.4
18b Ar ) 3-chlorophenyl,
X ) CH2OCOPh
367
>100 000
835
598
19
20
21
23
24
26
27
28
29
30
Ar ) 4-iodophenyl,
X ) CH2OCOPh
Ar ) 4-bromophenyl,
X ) CH2OCOPh
Ar ) 4-bromo-3-chlorophenyl,
X ) CH2OCOPh
Ar ) 3-chloro-4-iodophenyl,
X ) CH2OCOPh
Ar ) 3-chloro-4-methylphenyl, >10 000
X ) CH2OCOPh
Ar ) 3,4-dichlorophenyl,
X ) (E)-CHdCHPh
Ar ) 3,4-dichlorophenyl,
X ) CON(CH3)OCH3
Ar ) 3,4-dichlorophenyl,
X ) COCH2CH3
Ar ) 3,4-dichlorophenyl,
X ) CH2OPh-4-I
0.1 ( 0.04
3.95 ( 0.65
3.2 ( 0.3
0.06 ( 0.02
2.0 ( 0.6
245 ( 31
30.7 ( 1.5
2.2 ( 0.3
1170 ( 181
8.5 ( 0.3
81 900
1130
3300 ( 67
>10 000
>3120
1200
>10 000
>10 000
>10 000
2790 ( 306
>6 000 000
>20 000
>6 000 000
>20 000
11.4
a
2110 ( 457
8.6
1.32
0.05
0.10
0.18
a
8620 ( 87
6840 ( 135
13 700 ( 1580
>10 000
396 ( 68
651 ( 13
281
12.9
3110
296
2510 ( 269
11.7
>1170
2.1
>10 000
>1170
a
Ratio cannot be determined.
that we hoped to further modify to obtain even more
potent and selective 5-HT reuptake inhibitors.
studies. The esters 14a and 14b with increased bulk of
the alcohol (phenol) moiety are inferior to methyl ester
8k , but among those two compounds, the phenyl ester
14b is more potent and selective at the SERT than the
isopropyl ester 14a . Compound 14a also exhibits mod-
erate activity at the NET. The amides 14c and 14d are
almost as potent as the parent 8k , but the bulkier
dimethylamide 14d is more selective than the mono-
methylamide 14c. Apparently esters and amides of
increased steric bulk participate less efficiently in
hydrogen bonding, on which the role of the methyl ester
pharmacophoric group in cocaine is believed to be based.
We consequently prepared the inverted esters 16a -
d , which may be assumed to retain a strong ability to
engage in hydrogen bonding by means of their carbonyl
oxygens. This type of modification, which has previously
found little use in cocaine-related work,18 greatly in-
creased the inhibitory activity at and selectivity for the
SERT. Besides the acetate 16a described in our previous
paper,17 the benzoate 16b also exhibits high activity at
Although several previous investigations indicated
that the C2 substituent does not impact significantly
on the activity of cocaine-related ligands, our prelimi-
nary study of the present tricyclic ring system17 sug-
gested to the contrary that the activity of this ligand
type could be further improved upon by appropriate
modification of the ester group. For example, the
inverted ester 16a exhibits a Ki of 1.6 nM at the SERT
with a 400-fold selectivity over the NET and a more
than 1000-fold selectivity over the DAT. These data
constitute an improvement over the precursor, methyl
ester 8k , by 1 order of magnitude and encouraged us to
further explore the chemical modification of the ester
moiety. Activity data for the prepared compounds are
summarized in Table 2.
Emphasis was placed on analogues of compound 8k
because 3,4-dichloro substitution has been the most
widely employed substitution pattern in cocaine-related

Tricyclic Tropane Analogues and Uptake Inhibition
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9 1935
relative to internal tetramethylsilane (TMS). Coupling con-
stants are given in hertz (Hz). Thin-layer chromatography
(TLC) was performed using Merck silica gel 60F-254 plates.
Column chromatography was performed using Merck silica gel
(60-200 mesh). Mass spectra were measured in the EI mode
at an ionization potential of 70 eV. Starting materials were
obtained from Aldrich, Alfa Aesar, or Acros. Solvents were
obtained from Fisher Scientific (or VWR) and were used
without further purification unless otherwise noted. Dimethyl
formamide (DMF; DriSolv) was obtained from EM Science.
Iodides 7a ,b were prepared from the corresponding anilines,
and iodides 7b-d were obtained from the corresponding
bromides.24 To ensure proper elemental analyses and for easy
handling, parts of the final compounds were converted into
salts by common methods.
Rep r esen ta tive P r oced u r e for Ra d ica l Cycliza tion . A
solution of compound 4 (340 mg, 1.67 mmol) in deoxygenated
anhydrous benzene (30 mL) was heated to 80 °C, and a
solution of tri-n-butylstannane (920 µL, 3.33 mmol) and AIBN
(275 mg, 1.67 mmol) in deoxygenated anhydrous benzene (18
mL) was then added via a syringe pump over 6 h. After it was
stirred at 80 °C for a further 6 h, the mixture was concen-
trated, and the residue was subjected to column chromatog-
raphy with hexanes/ethyl acetate (6/1 to 1/1) as the eluent to
give the two isomers 5 and 6.
Gen er a l P r oced u r e for Stille Cou p lin g. The appropriate
aryl iodides 7 (0.16 mmol), tri-o-tolylphosphine (4.0 mg, 13
µmol), Pd2(dba)3 (3.0 mg, 3.2 µmol), and CuI (2.5 mg, 13 µmol)
were dissolved in DMF (2 mL) and stirred at room temperature
for 15 min under nitrogen. Then the stannane 5 (100 mg, 0.16
mmol) in DMF (2 mL) was added, and the mixture was stirred
at 45-50 °C for 12 h. The solution was poured into ice-cold 2
N HCl, and the aqueous phase was extracted with ether (3 ×
20 mL). The organic phase was reextracted with 2 N hydro-
chloric acid (2 × 15 mL), and the combined acidic solutions
were basified with NH4OH and extracted with ethyl acetate
(4 × 20 mL). The solution was dried over anhydrous Na2SO4,
the solvent was evaporated, and the residue was chromato-
graphed on silica gel using ethyl acetate/hexanes 1/1 to give
the desired product 8.
HP LC Con d ition s for Isola tion of Com p ou n d s 8p ,q. A
Chirex (S)-Pro and (R)-NEA (250 × 10 mm) column was used
with a flow rate of 5 mL/min. A mixture of hexanes, dichlo-
romethane, ethanol, and CF3COOH (75/22/3/0.1) was employed
as the solvent. The crude product mixture was injected as a
solution in dichloromethane/hexanes. The retention times for
compounds 8q and 8p are 14.5 and 18.2 min, respectively.
Peaks were detected by UV absorption at 265 nm. The isolated
products were suspended in ether, potassium carbonate was
added to remove the trifluoroacetic acid, and the pure free
bases 8p and 8q were obtained after filtration and removal of
the solvent.
the SERT and even higher DAT/SERT and NET/SERT
uptake ratios. SERT potencies and selectivities fall as
the acyl moiety is further changed to 2-naphthoyl and
finally to 4-iodobenzoyl. Particularly interesting are the
2-naphthyl analogues 17a and 17b of which the latter
exhibits outstanding potency and selectivity at the
SERT while the parent methyl ester 8u is rather
unexceptional. Contrary to the situation involving the
3,4-dichlorophenyl-substituted acetate and benzoate 16a
and 16b, the benzoate 17b is 44-fold more potent at the
SERT than the acetate 17a , and its selectivity at the
SERT over the DAT and NET is increased 200-400
times as compared to the acetate. A less-pronounced but
qualitatively similar trend is also observed for the
acetate/benzoate pair 18a and 18b. The “dimeric” ester
30 also exhibits a high potency for 5-HT uptake inhibi-
tion with a Ki value of 8.5 nM, while losing activity at
the DAT and NET.
Replacement of the ester with a vinyl or ether group
decreased activity; compounds 26 and 29 are 12- and
58-fold less potent at the SERT than the parent com-
pound 8k . This result may again be attributed to a loss
of or decrease in hydrogen bonding. As others have
demonstrated13,15 in the tropane and piperidine series
of ligands that a ketone function in place of the ester
moiety can lead to increased potency at the SERT, we
also implemented this modification in our compounds.
Ligand 28 exhibits a potency of 2.2 nM at the SERT,
which is a 9-fold improvement over ester 8k , with
excellent selectivity for the SERT vs the DAT and NET.
The carbonyl oxygen alone therefore appears to be
sufficient for effective hydrogen bonding.
Among the reverse esters prepared, the benzoate
analogues have proven optimal with regard to potency
and selectivity at the SERT. Thus, several benzoates
19-21, 23, and 24 obtained from the corresponding
methyl esters (8e, 8d , 8o, 8p , and 8r ) were additionally
evaluated. In line with our expectation, the potencies
of four out of these five compounds increased to varying
degrees, with Ki values between 0.06 and 4.0 nM. The
most potent and selective ligand is compound 23, which
displays a Ki value of 0.06 nM at the SERT and
essentially no inhibition at the DAT and NET. This
compound is the most potent 5-HT reuptake inhibitor
presently known, and the benzoate 19 comes close.
In summary, after identifying the optimum substit-
uents on the aryl ring, a variety of modifications to the
ester moiety have been investigated. Most of the reverse
esters (acetates and benzoates, 16-21, 23, and 24) and
the ketone 28 exhibit improved activity whereas other
esters, amides, and an alkene do not. Benzoates 17b
and 19 display the same exceptional potency at the
SERT (Ki ) 0.1 nM). The most potent and selective
ligand, however, is compound 23 with a Ki of 0.06 nM
and essentially no activity at the DAT and NET.
Because some evidence suggests that inhibition of 5-HT
reuptake modulates the reinforcing properties of co-
caine,37 these compounds are interesting candidates for
cocaine abuse studies.
(1S ,3S ,6R ,10S )-(Z)-9-(4-C h lor o b e n zy lid e n e )-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
ter (8b). [R]25 +53.2° (c 0.8, CHCl3). 1H NMR: δ 1.49 (m,
D
3H), 2.06 (m, 1H), 2.18 (m, 2H), 2.41 (t, J ) 3.0 Hz, 1H), 2.70
(m, 1H), 3.28 (m, 1H), 3.65 (s, 3H), 3.76 (m, 1H), 3.86 and 4.00
(ABq, J ) 18.3 Hz, both d with J ) 2.4 Hz, 2H), 6.08 (m, 1H),
7.11 (d, J ) 8.4 Hz, 2H), 7.27 (d, J ) 8.4 Hz, 2H). 13C NMR:
δ 32.2, 32.8, 36.6, 37.5, 48.4, 52.1, 52.5, 53.9, 56.5, 121.1, 128.7,
129.8, 132.0, 136.0, 141.7, 174.5. MS m/z (%): 318 (M+ + 1,
27), 317 (M+, 77), 316 (M+ - 1, 36), 286 (12), 258 (100), 244
(15), 141 (27), 110 (62), 83 (79), 49 (83). The free base was
converted to the hydrochloride salt. Anal. (C18H21Cl2NO2‚
0.5H2O) C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-(3-C h lor o b e n zy lid e n e )-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
ter (8c). [R]25 +37.2° (c 0.33, CHCl3). 1H NMR: δ 1.51 (m,
D
3H), 2.08 (m, 1H), 2.14 (m, 2H), 2.41 (t, J ) 3.0 Hz, 1H), 2.70
(q, J ) 3.0 Hz, 1H), 3.27 (m, 1H), 3.67 (s, 3H), 3.75 (m, 1H),
3.90 and 4.02 (ABq, J ) 18.4 Hz, both d with J ) 2.4 and 2.7
Hz, respectively, 2H), 6.07 (m, 1H), 7.68 (d, J ) 7.8 Hz, 1H),
7.16 (m, 2H), 7.25 (d, J ) 7.5 Hz, 1H). 13C NMR: δ 32.2, 32.8,
36.6, 37.5, 48.4, 52.1, 52.4, 53.9, 56.5, 121.0, 126.4, 126.5, 128.6,
Exp er im en ta l Section
Nuclear magnetic resonance (NMR) spectra were recorded
on a Varian Unity Inova spectrometer at 300 MHz for proton
and 75.46 MHz for carbon-13 spectra. CDCl3 was used as
solvent. Chemical shifts are reported in parts per million

1936 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9
Zhang et al.
129.7, 134.4, 139.3, 142.9, 174.4. MS m/z (%): 318 (M+ + 1,
11), 317 (M+, 32), 316 (M+ - 1, 18), 286 (10), 258 (82), 244
(11), 141 (22), 110 (26), 83 (100), 68 (53). Anal. (C18H20ClNO2‚
0.5H2O) C, H, N.
133.2, 137.1, 143.6, 174.2. MS m/z (%): 353 (M+ + 1, 3), 352
(M+, 3), 351 (M+ - 1, 6), 292 (34), 141 (18), 111 (10), 83 (100),
68 (60), 43 (83). The free base was converted to the tartrate
salt. Anal. (C22H25Cl2NO8‚1.0H2O) C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-(4-B r o m o b e n zy lid e n e )-7-a za -
(1S,3S,6R,10S)-(Z)-9-(3,5-Dich lor oben zylid en e)-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
ter (8d ). [R]25 +57.2° (c 0.6, CHCl3). 1H NMR: δ 1.49 (m,
ter (8m ). [R]25 +51.0° (c 0.50, CHCl3). H NMR: δ 1.51 (m,
1
D
D
3H), 2.06 (m, 1H), 2.15 (m, 2H), 2.41 (t, J ) 3.0 Hz, 1H), 2.69
(m, 1H), 3.28 (m, 1H), 3.66 (s, 3H), 3.77 (m, 1H), 3.80 and 3.98
(ABq, J ) 18.4 Hz, both d with J ) 2.1 and 2.5 Hz, respectively,
2H), 6.07 (t, J ) 2.4 Hz, 1H), 7.04 (d, J ) 8.7 Hz, 2H), 7.44 (d,
J ) 8.4 Hz, 2H). 13C NMR δ 31.9, 32.6, 36.4, 37.3, 48.2, 51.9,
52.2, 53.7, 56.3, 119.9, 120.9, 129.9, 131.4, 136.2, 141.8, 174.2.
The free base was converted to the hydrochloride salt. Anal.
(C18H21ClBrNO2) C, H, N.
3H), 2.06 (m, 1H), 2.18 (m, 2H), 2.44 (t, J ) 3.0 Hz, 1H), 2.71
(m, 1H), 3.32 (m, 1H), 3.65 (s, 3H), 3.78 (m, 1H), 3.90 and 3.98
(ABq, J ) 18.2 Hz, both d with J ) 2.4 Hz, 2H), 6.02 (t, J )
2.3 Hz, 1H), 7.05 (m, 2H), 7.17 (m, 1H). 13C NMR: δ 31.8, 32.4,
36.1, 37.2, 48.1, 52.0, 52.1, 53.8, 56.4, 120.0, 126.1, 126.6, 134.8,
139.9, 174.0. MS m/z (%): 353 (M+ + 1, 5), 352 (M+, 5), 351
(M+ - 1, 8), 292 (31), 141 (13), 111 (15), 83 (100), 68 (70), 43
(86). The free base was converted to the tartrate salt. Anal.
(C22H25Cl2NO8‚1.0H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-(4-Iod oben zylid en e)-7-a za tr icyclo-
[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Ester (8e).
(1S,3S,6R,10S)-(Z)-9-(3,4-Diflu or ob en zylid en e)-7-a za -
1
[R]25 +52.7° (c 0.46, CHCl3). H NMR: δ 1.47 (m, 3H), 2.07
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
D
1
(m, 1H), 2.16 (m, 2H), 2.41 (t, J ) 3.0 Hz, 1H), 2.69 (q, J ) 3.0
Hz, 1H), 3.27 (m, 1H), 3.65 (s, 3H), 3.76 (m, 1H), 3.85 and 3.98
(ABq, J ) 18.0 Hz, both d with J ) 2.4 and 2.7 Hz, respectively,
2H), 6.05 (t, J ) 2.4 Hz, 1H), 6.92 (d, J ) 8.4 Hz, 2H), 7.63 (d,
J ) 8.4 Hz, 2H). 13C NMR: δ 32.3, 32.9, 36.7, 37.6, 48.5, 52.2,
52.6, 54.0, 56.5, 121.3, 130.4, 134.4, 137.7, 142.4, 174.5. MS
m/z (%): 410 (M+ + 1, 13), 409 (M+, 78), 408 (M+ - 1, 31), 394
(7), 378 (10), 350 (91), 336 (13), 141 (29), 111 (33), 83 (100), 68
(44). Anal. (C18H20INO2) C, H, N.
ter (8n ). [R]25 +36.5° (c 0.25, CH2Cl2). H NMR: δ 1.49 (m,
D
3H), 2.05 (m, 1H), 2.16 (m, 2H), 2.41 (t, J ) 3.3 Hz, 1H), 2.68
(dd, J ) 3.3, 6.0 Hz, 1H), 3.29 (m, 1H), 3.66 (s, 3H), 3.75 (m,
1H), 3.85 and 3.98 (ABq, J ) 18.3 Hz, both d with J ) 2.4 and
2.7 Hz, respectively, 2H), 6.04 (t, J ) 2.4 Hz, 1H), 6.88 (m,
1H), 6.95 (m, 1H), 7.01 (m, 1H). MS m/z (%): 319 (M+, 4), 318
(M+ - 1, 2), 260 (7), 151 (3), 84 (50), 68 (6), 49 (100). Anal.
(C19H19F2NO2) C, H, N.
(1S,3S,6R,10S)-(Z)-9-(4-Br om o-3-ch lor oben zylid en e)-7-
a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (8o). [R]25D +57.6° (c 0.50, CHCl3). 1H NMR: δ 1.50 (m,
3H), 2.04 (m, 1H), 2.18 (m, 2H), 2.41 (m, 1H), 2.69 (m, 1H),
3.28 (m, 1H), 3.65 (s, 3H), 3.75 (m, 1H), 3.92 (m, 2H), 6.02 (br
s, 1H), 6.93 (d, J ) 8.1 Hz, 1H), 7.26 (s, 1H), 7.53 (d, J ) 7.8
Hz, 1H). 13C NMR: δ 32.2, 32.8, 36.5, 37.5, 48.4, 52.2, 52.4,
53.9, 56.5, 119.8, 120.1, 127.9, 130.2, 133.7, 134.5, 138.2, 143.9,
174.4. MS m/z (%): 398 (M+ + 1, 1), 397 (M+, 3), 396 (M+ - 1,
2), 382 (1), 366 (1), 338 (6), 141 (3), 110 (5), 83 (11), 58 (30), 43
(100). Anal. (C19H19BrClNO2) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[4-(Tr iflu or om eth yl)ben zylid en e]-
7-a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (8f). [R]25 +40.3° (c 0.35, CH2Cl2). 1H NMR: δ 1.50
D
(m, 3H), 2.06 (m, 1H), 2.12 (m, 2H), 2.43 (t, J ) 2.7 Hz, 1H),
2.73 (dd, J ) 3.3, 6.3 Hz, 1H), 3.29 (m, 1H), 3.66 (s, 3H), 3.76
(m, 1H), 4.04 and 3.91 (ABq, J ) 18.3 Hz, both d with J ) 2.4
and 2.7 Hz, respectively, 2H), 6.17 (br s, 1H), 7.27 (d, J ) 8.4
Hz, 2H), 7.57 (d, J ) 8.4 Hz, 2H). 13C NMR: δ 32.2, 32.8, 36.6,
37.6, 48.5, 52.1, 52.5, 53.9, 56.5, 121.1, 125.5 (q, J ) 4 Hz),
125.5, 128.6, 144.3, 174.4 (CF3 and the adjacent aromatic C
not observed). MS m/z (%): 352 (M+ + 1, 10), 351 (M+, 49),
350 (M+ - 1, 28), 292 (63), 223 (4), 183 (10), 159 (10), 141 (13),
111 (28), 83 (51), 68 (59), 49 (100). Anal. (C19H20F3NO2‚1/3H2O)
C, H, N.
(1S,3S,6R,10S)-(Z)-9-(3-Ch lor o-4-iod ob en zylid en e)-7-
a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (8p ). [R]25 +28.0° (c 0.15, CH2Cl2). 1H NMR: δ 1.65
D
(m, 3H), 2.28 (m, 1H), 2.43 (m, 2H), 2.61 (m, 1H), 2.88 (m,
1H), 3.31 (m, 1H), 3.70 (s, 3H), 3.73 (m, 1H), 3.85 and 3.98
(ABq, J ) 18.3 Hz, both d with J ) 2.4 and 2.7 Hz, respectively,
2H), 6.14 (m, 1H), 6.74 (dd, J ) 1.8, 8.1 Hz, 1H), 7.22 (d, J )
1.8 Hz, 1H), 7.82 (d, J ) 8.1 Hz, 1H). 13C NMR: δ 30.0, 30.8,
34.2, 35.6, 46.5, 51.3, 53.5, 56.2, 58.2, 124.7, 127.6, 128.0,
129.4, 130.8, 138.1, 141.1, 141.3, 171.5. MS m/z (%): 444 (M+
+ 1, 5), 443 (M+, 16), 442 (M+ - 1, 6), 386 (10), 384 (31), 316
(2), 141 (15), 83 (100), 68 (47). Anal. (C18H19ClINO2) C, H,
N.
(1S ,3S ,6R ,10S )-(Z)-9-(4-Me t h ylb e n zylid e n e )-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
ter (8h ). [R]25 +57.0° (c 0.99, CHCl3). 1H NMR: δ 1.50 (m,
D
3H), 2.08 (m, 1H), 2.17 (m, 2H), 2.43 (t, J ) 3.0 Hz, 1H), 2.72
(q, J ) 3.0 Hz, 1H), 2.86 (s, 3 H), 3.28 (m, 1H), 3.65 (s, 3H),
3.80 (m, 1H), 3.93 and 4.02 (ABq, J ) 18.3 Hz, both d with J
) 2.1 and 2.4 Hz, respectively, 2H), 6.13 (t, J ) 2.4 Hz, 1H),
7.18 (d, J ) 8.4 Hz, 2H), 7.23 (d, J ) 8.1 Hz, 2H). 13C NMR:
δ 32.3, 32.9, 34.1, 36.9, 37.6, 48.6, 52.2, 52.8, 54.7, 56.5, 122.2,
126.7, 128.6, 135.3, 139.7, 147.2, 174.1. The free base was
converted to the corresponding hydrochloride salt. Anal.
(C19H24ClNO2‚1.1H2O) C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-(2-C h lo r o -4-io d o p h e n y lb e n z-
yliden e)-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
1
Meth yl Ester (8q). H NMR: δ 1.55 (m, 3H), 2.14 (m, 3H),
(1S,3S,6R,10S)-(Z)-9-(4-Isop r op ylb en zylid en e)-7-a za -
2.43 (t, J ) 3.0 Hz, 1H), 2.79 (m, 1H), 3.29 (m, 1H), 3.69 (s,
3H), 3.78 (m, 3H), 6.27 (m, 1H), 6.88 (d, J ) 8.1 Hz, 1H), 7.53
(dd, J ) 1.8, 8.4 Hz, 1H), 7.72 (d, J ) 1.8 Hz, 1H). 13C NMR:
δ 29.8, 30.6, 33.9, 35.0, 45.7, 51.0, 53.3, 55.9, 57.7, 122.7, 130.4,
131.4, 131.8, 132.4, 134.2, 136.6, 138.5, 171.3. MS m/z (%): 444
(M+ + 1, 12), 443 (M+, 32), 442 (M+ - 1, 12), 408 (36), 384
(48), 316 (4), 149 (100), 83 (81), 68 (42). Anal. (C18H19ClINO2)
C, H, N.
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
1
ter (8j). [R]25 +29.6° (c 0.52, CHCl3). H NMR: δ 1.23 (d, J
D
) 7.2 Hz, 6H), 1.48 (m, 3H), 2.05 (m, 1H), 2.15 (m, 2H), 2.39
(t, J ) 3.0 Hz, 1H), 2.69 (q, J ) 3.0 Hz, 1H), 2.88 (m, 1 H),
3.27 (m, 1H), 3.65 (s, 3H), 3.78 (m, 1H), 3.92 and 4.02 (ABq, J
) 18.3 Hz, both d with J ) 2.4 Hz, 2H), 6.10 (t, J ) 2.4 Hz,
1H), 7.13 (d, J ) 8.4 Hz, 2H), 7.19 (d, J ) 8.1 Hz, 2H). 13C
NMR: δ 24.2, 32.2, 32.9, 34.0, 36.9, 37.5, 48.5, 52.1, 52.6, 54.0,
56.4, 122.1, 126.7, 128.6, 135.2, 139.6, 147.1, 174.5. MS m/z
(%): 326 (M+ + 1, 18), 325 (M+, 38), 324 (M+ - 1, 14), 266
(1S,3S,6R,10S)-(Z)-9-(3-Ch lor o-4-m eth ylben zylid en e)-
7-a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (8r ). [R]25D +48.4° (c 0.39, CHCl3). 1H NMR: δ 1.49 (m,
3H), 2.04 (m, 1H), 2.17 (m, 2H), 2.34 (s, 3H), 2.40 (t, J ) 3.0
Hz, 1H), 2.68 (q, J ) 3.3 Hz, 1H), 3.28 (m, 1H), 3.66 (s, 3H),
3.76 (m, 1H), 3.89 and 4.00 (ABq, J ) 18.0 Hz, both d with J
) 2.1 and 2.4 Hz, respectively, 2H), 6.04 (m, 1H), 6.98 (d, J )
7.8 Hz, 1H), 7.16 (d, J ) 7.8 Hz, 2H). 13C NMR: δ 29.9, 32.2,
32.8, 36.7, 37.5, 48.4, 52.1, 52.5, 53.9, 56.5, 120.9, 126.7, 129.0,
131.0, 134.0, 134.5, 136.8, 141.6, 174.5. MS m/z (%): 332 (M+
+ 1, 20), 331 (M+, 39), 330 (M+ - 1, 18), 274 (28), 272 (88),
156 (10), 141 (24), 83 (100), 68 (52). Anal. (C19H22ClNO2) C,
H, N.
(67), 155 (15), 141 (21), 128 (18), 83 (100), 68 (43). Anal. (C21H27
-
NO2‚0.5H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-(2,3-Dich lor oben zylid en e)-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
ter (8l). [R]25 +22.6° (c 0.50, CHCl3). 1H NMR: δ 1.49 (m,
D
3H), 2.13 (m, 3H), 2.43 (t, J ) 3.0 Hz, 1H), 2.78 (m, 1H), 3.29
(m, 1H), 3.70 (s, 3H), 3.74 (m, 1H), 3.81 and 3.92 (ABq, J )
18.4 Hz, both d with J ) 2.4 Hz, 2H), 6.34 (t, J ) 2.6 Hz, 1H),
7.14 (m, 2H), 7.31 (m, 1H). 13C NMR: δ 31.9, 32.5, 36.0, 36.8,
47.2, 52.0, 52.2, 53.8, 56.2, 118.8, 126.8, 127.6, 128.4, 131.3,

Tricyclic Tropane Analogues and Uptake Inhibition
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9 1937
(1S,3S,6R,10S)-(Z)-9-(3,4-Dim eth ylben zylid en e)-7-a za -
evaporated. The residue was purified by column chromatog-
raphy using ethyl acetate/hexanes (1/1) as the eluent to give
ester 14a . H NMR (CDCl3): δ 1.19 (d, J ) 7.2 Hz, 6H), 1.52
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
ter (8s). [R]25 +47.6° (c 0.50, CHCl3). 1H NMR: δ 1.48 (m,
1
D
3H), 2.07 (m, 3H), 2.21 (s, 6H), 2.39 (t, J ) 3.0 Hz, 1H), 2.68
(q, J ) 3.0 Hz, 1H), 3.27 (m, 1H), 3.67 (s, 3H), 3.79 (m, 1H),
3.91 and 4.04 (ABq, J ) 18.3 Hz, both d with J ) 2.4 and 2.7
Hz, respectively, 2H), 6.07 (t, J ) 2.4 Hz, 1H), 6.93 (d, J ) 7.8
Hz, 1H), 6.98 (s, 1H), 7.08 (d, J ) 7.8 Hz, 1H). 13C NMR: δ
19.6, 20.1, 32.2, 32.9, 36.9, 37.5, 48.5, 52.1, 52.7, 54.0, 56.4,
122.1, 126.0, 129.8, 130.0, 134.8, 135.3, 136.6, 139.4, 174.6.
MS m/z (%): 312 (M+ + 1, 14), 313 (M+, 23), 310 (M+ - 1, 9),
252 (63), 183 (10), 156 (10), 141 (16), 118 (28), 83 (100), 68
(35). Anal. (C20H25NO2‚0.1H2O) C, H, N.
(m, 3H), 2.06 (m, 1H), 2.20 (m, 2H), 2.38 (t, J ) 3.3 Hz, 1H),
2.71 (m, 1H), 3.30 (m, 1H), 3.80 (m, 1H), 3.96 and 4.03 (ABq,
J ) 18.3 Hz, both d with J ) 2.4 and 2.7 Hz, respectively,
2H), 4.98 (m, 1H), 6.03 (t, J ) 2.4 Hz, 1H), 7.02 (d, J ) 8.4
Hz, 1H), 7.28 (s, 1H), δ 7.37 (d, J ) 8.4 Hz, 1H). MS m/z (%):
380 (M+ + 1, 8), 379 (M+, 17), 336 (M+ - 1, 15), 292 (51), 110
(29), 83 (100), 68 (61), 49 (46). The free base was converted to
the hydrochloride salt. Anal. (C20H24Cl3NO2‚0.75H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-(3,4-Dich lor oben zylid en e)-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid P h en yl Es-
ter (14b). To a solution of NaOH (500 mg, 12.5 mmol) and
phenol (500 mg, 5.3 mmol) in dioxane (2 mL) at 0 °C was added
slowly a solution of the acid chloride prepared as above from
ester 8k (37 mg, 0.1 mmol) followed by tetrabutylammonium
hydroxide (5 mg, 40% solution in water) in dioxane (5 mL).
The mixture was stirred at room temperature overnight,
diluted with water, and extracted with ethyl acetate (4 × 20
mL). The combined extracts were washed with water and then
brine and dried over Na2SO4. After the solvent was removed,
the residue was subjected to column chromatography using
ethyl acetate/hexanes (3/2) as the eluent to give ester 14b. 1H
NMR (CDCl3): δ 1.62 (m, 3H), 2.20 (m, 3H), 2.71 (t, J ) 3.0
Hz, 1H), 2.96 (dd, J ) 3.2, 6.3 Hz, 1H), 3.37 (m, 1H), 3.90 (m,
1H), 4.01 and 4.08 (ABq, J ) 18.3 Hz, both d with J ) 2.4 Hz,
2H), 6.23 (t, J ) 2.7 Hz, 1H), 6.98 (m, 1H), 7.01 (m, 1H), 7.24
(m, 1H), 7.36 (m, 5H). MS m/z (%): 414 (M+ + 1, 2), 413 (M+,
5), 412 (M+ - 1, 1), 320 (13), 292 (10), 84 (57), 68 (19), 49 (100).
The free base was converted to the hydrochloride salt. Anal.
(C23H22Cl3NO2‚1.1H2O) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of Ca r boxa m id es
(14c,d ). The acid chloride hydrochloride prepared as above was
suspended in 5 mL of CH2Cl2 under nitrogen at 0 °C and
treated with 2.0 equiv of methylamine hydrochloride or
dimethylamine hydrochloride and 4.0 equiv of triethylamine.
The mixture was stirred at room temperature overnight and
then basified with 3 N NaOH or concentrated NH4OH. The
phases were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 10 mL). The combined organic phases were
dried (Na2SO4), filtered, and evaporated in vacuo. The crude
product was purified by column chromatography (ethyl acetate
as the eluent).
(1S ,3S ,6R ,10S )-(Z)-9-(2-Na p h t h ylm e t h yle n e )-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
1
ter (8u ). [R]25 +44.0° (c 0.65, CH2Cl2). H NMR: δ 1.52 (m,
D
3H), 2.18 (m, 3H), 2.45 (t, J ) 3 Hz, 1H), 2.77 (m, 1H), 3.33
(m, 1H), 3.66 (s, 3H), 3.83 (m, 1H), 4.12 (m, 2H), 6.28 (t, J )
2.7 Hz, 1H), 7.35 (dd, J ) 1.8, 8.4 Hz, 1H), 7.44 (m, 2H), 7.63
(br s, 1H), 7.78 (m, 3H). 13C NMR: δ 32.2, 32.9, 36.8, 37.7,
48.6, 52.2, 52.7, 54.0, 56.5, 122.3, 125.9, 126.4, 127.1, 127.3,
127.7, 128.0, 128.1, 132.1, 133.7, 135.1, 174.6. MS m/z (%): 334
(M+ + 1, 2), 333 (M+, 10), 274 (16), 231 (2), 205 (5), 191 (7),
178 (9), 165 (14), 136 (25), 83 (100), 68 (41). Anal. (C22H23NO2‚
1/3H2O) C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-(1-P y r e n y lm e t h y le n e )-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
ter (8v). [R]25D +16.0° (c 0.1, CHCl3). 1H NMR: δ 1.54 (m, 3H),
1.69 (m, 1H), 2.20 (m, 3H), 2.49 (t, J ) 2.7 Hz, 1H), 2.95 (m,
1H), 3.31 (m, 1H), 3.79 (s, 3H), 3.86 (m, 2H), 6.67 (m, 1H),
7.60 (m, 5H), 7.83 (d, J ) 7.5 Hz, 1H), 8.02 (d, J ) 8.1 Hz,
1H), 8.66 (d, J ) 7.5 Hz, 2H). 13C NMR: δ 32.1, 32.7, 36.7,
37.1, 47.4, 52.3, 52.6, 54.2, 56.7, 120.5, 124.2, 124.8, 125.0,
125.1, 125.3, 126.1, 126.5, 127.3, 127.5, 127.6, 128.6, 130.4,
131.1, 131.6, 174.6. MS m/z (%): 408 (M+ + 1, 9), 407 (M+,
35), 348 (39), 279 (9), 265 (17), 252 (17), 239 (37), 174 (73), 83
(100), 68 (39). Anal. (C28H25NO2‚0.7H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-(9-P h en a n th r ylm eth ylen e)-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl Es-
1
ter (8w ). [R]25 +30.8° (c 0.18, CHCl3). H NMR: δ 1.57 (m,
D
4H), 2.21 (m, 3H), 2.53 (t, J ) 2.7 Hz, 1H), 2.99 (m, 1H), 3.33
(m, 1H), 3.80 (s, 3H), 3.86 (m, 2H), 6.98 (m, 1H), 7.86 (d, J )
7.8 Hz, 1H), 8.08 (m, 8H). 13C NMR: δ 32.3, 32.8, 36.8, 36.9,
47.2, 52.2, 52.6, 54.1, 56.7, 119.8, 122.6, 123.2, 125.4, 126.5,
126.6, 126.7, 126.8, 126.9, 128.6, 129.9, 130.6, 131.2, 131.8,
132.5, 142.4, 174.7. MS m/z (%): 384 (M+ + 1, 3), 383 (M+, 4),
324 (25), 255 (7), 241 (11), 215 (21), 161 (37), 83 (100), 68 (38).
Anal. (C26H25NO2‚0.8HCl) C, H, N.
(1S,3S,6R,10S)-(Z)-9-(3,4-Dich lor oben zylid en e)-7-a za -
tr icyclo[4.3.1.03,7]decan e-10-(N-m eth ylcar boxam ide) (14c).
1H NMR (CDCl3): δ 1.51 (m, 3H), 2.00 (m, 1H), 2.20 (m, 2H),
2.51 (m, 1H), 2.81 (m, 3H), 3.32 (m, 1H), 3.87 (m, 1H), 3.90
and 4.06 (ABq, J ) 18.3 Hz, both d with J ) 2.4 and 2.7 Hz,
respectively, 2H), 5.55 (br s, 1H), 6.05 (t, J ) 2.4 Hz, 1H), 7.05
(dd, J ) 2.1, 8.4 Hz, 1H), 7.30 (d, J ) 2.1 Hz, 1H), 7.40 (d, J
) 8.4 Hz, 1H). MS m/z (%): 351 (M+ + 1, 11), 350 (M+, 27),
349 (M+ - 1, 8), 292 (100), 278 (10), 191 (10), 110 (33), 83 (79),
68 (57), 57 (43). The free base was converted to the hydro-
chloride salt. Anal. (C18H21Cl3N2O‚0.75H2O) C, H; N: calcd,
6.97; found, 6.46.
Com p ou n d 10. 1H NMR: δ 1.50 (m, 6H), 2.07 (m, 2H), 2.17
(m, 4H), 2.42 (t, J ) 3.0 Hz, 2H), 2.71 (m, 2H), 3.29 (m, 2H),
3.64 (s, 6H), 3.81 (m, 2H), 3.93 and 4.03 (ABq, J ) 18.3 Hz,
both d with J ) 2.1 and 2.4 Hz, respectively, 4H), 6.11 (t, J )
2.4 Hz, 2H), 7.15 (s, 4 H). 13C NMR: δ 31.9, 32.5, 36.4, 37.3,
48.3, 51.9, 52.4, 53.8, 56.3, 121.8, 128.4, 135.3, 140.2, 174.2.
MS m/z (%): 489 (M+ + 1, 0.58), 488 (M+, 1), 429 (2), 406 (4),
72 (20), 58 (74), 44 (100). Anal. (C30H36N2O4‚2/3HCl) C, H, N.
(1S,3S,6R,10S)-(Z)-9-(3,4-Dich lor oben zylid en e)-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-(N,N-d im eth ylca r boxa m id e)
(14d ). 1H NMR (CDCl3): δ 1.50 (m, 3H), 2.05 (m, 1H), 2.20
(m, 2H), 2.52 (m, 1H), 2.78 (m, 1H), 2.90 (s, 3H), 3.08 (s, 3H),
3.22 (m, 1H), 3.90 (m, 1H), 3.80 and 4.18 (ABq, J ) 18.3 Hz,
both parts of d with J ) 2.4 Hz, 2H), 5.92 (br s, 1H), 7.01 (dd,
J ) 2.1, 8.4 Hz, 1H), 7.23 (d, J ) 2.1 Hz, 1H), 7.38 (d, J ) 8.4
Hz, 1H). MS m/z (%): 365 (M+ + 1, 6), 364 (M+, 17), 364 (M+
- 1, 2), 292 (76), 278 (11), 205 (27), 149 (11), 118 (42), 83 (48),
72 (87), 68 (79), 41 (100). The free base was converted to the
hydrochloride salt. Anal. (C19H23Cl3N2O‚0.75H2O) C, H; N:
calcd, 6.74; found, 6.29.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
16-21 a n d 24. DIBAL-H (1 N in pentane, 1.5 mmol) or LiAlH4
(1.5 mmol) was added to a solution of the appropriate ester 8
(0.5 mmol) in tetrahydrofuran (THF; 10 mL) at 0 °C under N2
at room temperature. The reaction mixture was stirred
overnight, quenched with concentrated Rochelle salt solution
(1S,3S,6R,10S)-(Z)-9-(3,4-Dich lor oben zylid en e)-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Isop r op yl
Ester (14a ). Ester 8k (99 mg, 0.27 mmol) was dissolved in 6
N HCl (10 mL), the mixture was heated to reflux for 8 h, the
solvent was removed, and the residue was dried in vacuo to
give the acid 12 as the hydrochloride salt in quantitative yield.
1H NMR (D2O): δ 1.99 (m, 3H), 2.26 (m, 3H), 2.95 (m, 2H),
3.92 (m, 1H), 4.35 (m, 3H), 6.25 (m, 1H), 6.89 (m, 1H), 7.05
(m, 1H), 7.25 (m, 1H).
The crude acid hydrochloride was suspended in CH2Cl2 (20
mL) and cooled to 0 °C. Thionyl chloride (1.5 mL) was added
dropwise. The reaction mixture was stirred at room temper-
ature for 10 min and then at 60 °C for 2 h. After the solvent
was removed and cooled to 0 °C, 2-propanol (2 mL) was added
slowly, and the resulting mixture was stirred for 1 h. The
reaction was quenched by adding saturated NaHCO3. The
product was extracted into ethyl acetate (4 × 15 mL), and the
combined organic phases were dried (Na2SO4), filtered, and

1938 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9
Zhang et al.
(15 mL), and extracted with EtOAc (3 × 10 mL). The combined
organic phases were washed with brine (20 mL), dried over
MgSO4, and concentrated under reduced pressure to afford the
alcohol 15.
To a solution of the crude alcohol 15, pyridine (1 mL) and a
catalytic amount of DMAP (1 mg) in THF (5 mL) was added
dropwise the appropriate acid chloride (1.5 equiv) at 0 °C under
N2. The solution was stirred overnight and extracted with
EtOAc (3 × 20 mL). The combined organic phases were washed
with a saturated solution of NaHCO3 (2 × 10 mL), dried, and
concentrated under reduced pressure. The crude product was
purified by column chromatography using ethyl acetate/
hexanes (2/1) as the eluent.
(1S ,3S ,6R ,10S )-(Z)-10-(Ace t oxym e t h yl)-9-(3-ch lor o-
ben zylid en e)-7-a za tr icyclo[4.3.1.03,7]d eca n e (18a ). [R]25
D
+71.1° (c 0.22, CHCl3). 1H NMR: δ 1.52 (m, 3H), 1.77 (m, 1H),
2.09 (m, 6H), 2.35 (m, 1H), 2.83 (dd, J ) 5.4, 2.7 Hz, 1H), 3.30
(t, J ) 6.4 Hz, 1H), 3.94 (m, 4H), 6.07 (br s, 1H), 7.09 (d, J )
7.5 Hz, 1H), 7.25 (m, 3H). 13C NMR: δ 21.1, 32.4, 33.0, 36.2,
37.3, 45.4, 48.7, 54.1, 58.4, 67.3, 121.4, 126.4, 126.6, 128.5,
129.8, 134.5, 139.3, 142.9, 171.3. MS m/z (%): 331 (M+, 2), 274
(3), 272 (8), 258 (2), 84 (62), 51 (30), 49 (100). Anal. (C19H22
-
ClNO2‚0.5H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-10-(Ben zoyloxym et h yl)-9-(3-ch lo-
r oben zylid en e)-7-a za tr icyclo[4.3.1.03,7]d eca n e (18b). [R]25
D
+111° (c 0.22, CHCl3). 1H NMR: δ 1.54 (m, 3H), 1.94 (m, 1H),
2.08 (m, 3H), 2.45 (m, 1H), 2.94 (dd, J ) 3.0, 5.4 Hz, 1H), 3.33
(t, J ) 6.6 Hz, 1H), 3.96 (dd, J ) 2.7, 4.5 Hz, 2H), 4.22 (m,
2H), 6.11 (t, J ) 2.1 Hz, 1H), 7.07 (d, J ) 7.8 Hz, 1H), 7.16
(m, 1H), 7.24 (m, 2H), 7.43 (m, 2H), 7.54 (m, 1H), 8.02 (m,
2H). 13C NMR: δ 32.4, 33.1, 36.4, 37.4, 45.6, 48.8, 54.1, 58.4,
67.6, 121.5, 126.3, 126.6, 128.5, 128.6, 129.7, 129.8, 130.3,
133.2, 134.5, 139.3, 142.9, 166.7. MS m/z (%): 394 (M+ + 1,
6), 393 (M+, 17), 392 (M+ + 1, 5), 274 (31), 272 (100), 258 (25),
105 (28), 84 (52), 77 (25), 49 (86). Anal. (C24H24ClNO2‚1.1H2O)
C, H, N.
(1S,3S,6R,10S)-(Z)-10-(Ben zoyloxym eth yl)-9-(3,4-dich lo-
r oben zylid en e)-7-a za tr icyclo[4.3.1.03,7]d eca n e (16b). [R]25
D
+82.4° (c 0.35, CH2Cl2). 1H NMR: δ 1.61 (m, 3H), 2.04 (m,
1H), 2.15 (m, 1H), 2.31 (m, 2H), 2.52 (m, 1H), 3.15 (m, 1H),
3.48 (m, 1H), 4.07 (m, 2H), 4.26 (m, 2H), 6.12 (br s, 1H), 7.00
(dd, J ) 2.1, 8.4 Hz, 1H), 7.24 (d, J ) 1.8 Hz, 1H), 7.43 (m,
3H), 7.58 (m, 1H), 8.01 (m, 2H). 13C NMR: δ 31.9, 32.5, 36.0,
36.9, 45.3, 48.3, 54.5, 58.6, 67.0, 121.4, 127.6, 128.6, 129.7,
130.0, 130.3, 130.5, 132.7, 133.3, 136.9, 140.9, 166.5. MS m/z
(%): 429 (M+ + 2, 12), 428 (M+ + 1, 9), 427 (M+, 18), 426 (M+
- 1, 6), 308 (65), 306 (100), 294 (18), 292 (24), 117 (26), 105
(65), 83 (39), 68 (63). Anal. (C24H23Cl2NO2‚0.7H2O) C, H,
N.
(1S,3S,6R,10S)-(Z)-10-(Ben zoyloxym et h yl)-9-(4-iod o-
ben zylid en e)-7-a za tr icyclo[4.3.1.03,7]d eca n e (19). [R]25
D
+169° (c 0.25, CHCl3). 1H NMR: δ 1.51 (m, 3H), 1.95 (m, 1H),
2.10 (m, 3H), 2.46 (m, 1H), 2.94 (dd, J ) 3.0, 5.7 Hz, 1H), 3.33
(t, J ) 6.9 Hz, 1H), 3.93 (m, 2H), 4.22 (m, 2H), 6.09 (t, J ) 2.7
Hz, 1H), 6.92 (d, J ) 8.4 Hz, 2H), 7.43 (d, J ) 8.4 Hz, 2H),
7.56 (m, 1H), 7.63 (dd, J ) 1.8, 6.6 Hz, 2H), 8.03 (m, 2H). 13C
NMR: δ 32.4, 33.0, 36.4, 37.3, 45.6, 48.7, 54.2, 58.4, 67.6, 121.8,
128.5, 128.6, 129.7, 129.8, 130.4, 133.2, 136.9, 137.7, 142.1,
166.7. MS m/z (%): 486 (M+ + 1, 4), 485 (M+, 25), 364 (73),
350 (18), 141 (11), 128 (14), 105 (29), 83 (26), 77 (22), 44 (100).
Anal. (C24H24INO2) H, N; C: calcd, 59.39; found, 59.97.
(1S,3S,6R,10S)-(Z)-9-(3,4-Dich lor ob en zylid en e)-10-(4-
iod ob en zoyloxym et h yl)-7-a za t r icyclo[4.3.1.03,7]d eca n e
(16c). [R]25D +87.4° (c 0.25, CH2Cl2). 1H NMR: δ 1.51 (m, 3H),
1.94 (m, 1H), 2.15 (m, 3H), 2.45 (m, 1H), 2.85 (m, 1H), 3.32
(m, 1H), 3.93 (m, 2H), 4.12 (m, 2H), 6.04 (br s, 1H), 7.00 (dd,
J ) 1.8, 8.4 Hz, 1H), 7.26 (d, J ) 2.1 Hz, 1H), 7.37 (d, J ) 8.4
Hz, 1H), 7.74 (m, 4H). 13C NMR: δ 32.4, 33.0, 36.5, 37.3, 45.5,
48.7, 54.1, 58.3, 67.7, 127.6, 129.7, 130.1, 130.2, 130.4, 131.1,
132.6, 137.4, 138.0, 143.6, 166.1. MS m/z (%): 556 (M+ + 2,
4), 555 (M+ + 1, 12), 554 (M+, 7), 553 (M+ - 1, 23), 308 (61),
306 (100), 292 (26), 231 (24), 202 (16), 83 (44), 68 (55). Anal.
(C24H22Cl2INO2‚1/6H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-10-(Ben zoyloxym eth yl)-9-(4-br om o-
ben zylid en e)-7-a za tr icyclo[4.3.1.03,7]d eca n e (20). 1H
NMR: δ 1.46 (m, 3H), 1.94 (m, 1H), 2.15 (m, 3H), 2.45 (m,
1H), 2.94 (m, 1H), 3.32 (t, J ) 6.9 Hz, 1H), 3.94 (m, 2H), 4.21
(m, 2H), 6.10 (s, 1H), 7.06 (d, J ) 8.1 Hz, 2H), 7.25 (s, 1H),
7.43 (m, 3H), 7.55 (m, 1H), 8.01 (d, J ) 6.9 Hz, 2H). 13C NMR:
δ 32.5, 33.1, 36.4, 37.4, 45.7, 48.8, 54.2, 58.4, 67.7, 121.7, 128.7,
129.0, 129.7, 130.1, 130.4, 131.1, 131.7, 133.2, 137.1, 166.7.
MS m/z (%): 439 (M+ + 2, 27), 437 (M+, 34), 318 (95), 316
(100), 302 (19), 141 (24), 118 (23), 105 (55), 83 (37), 77 (50), 68
(54).
(1S,3S,6R,10S)-(Z)-9-(3,4-Dich lor ob en zylid en e)-10-(2-
n aph th oyloxym eth yl)-7-azatr icyclo[4.3.1.03,7]decan e (16d).
[R]25 +340° (c 0.26, CHCl3). 1H NMR: δ 1.57 (m, 3H), 2.10
D
(m, 1H), 2.49 (m, 1H), 3.03 (m, 1H), 3.34 (t, J ) 6.9 Hz, 1H),
3.95 (s, 3H), 4.30 (m, 2H), 6.07 (t, J ) 2.4 Hz, 1H), 6.98 (dd, J
) 2.1, 8.4 Hz, 1H), 7.24 (d, J ) 2.1 Hz, 1H), 7.31 (d, J ) 8.4
Hz, 1H), 7.57 (m, 2H), 7.90 (m, 3H), 8.01 (dd, J ) 1.8, 8.7 Hz,
3H), 8.55 (s, 1H). 13C NMR: δ 32.4, 33.0, 36.5, 37.4, 45.7, 48.8,
54.1, 58.4, 67.5, 120.5, 125.2, 126.9, 127.5, 127.6, 128.0, 128.4,
128.5, 129.5, 130.0, 130.2, 130.4, 131.2, 132.6, 135.7, 135.8,
(1S,3S,6R,10S)-(Z)-10-(Ben zoyloxym eth yl)-9-(4-br om o-
3-ch lor oben zylid en e)-7-a za tr icyclo[4.3.1.03,7]d eca n e (21).
137.5, 143.7, 166.8. MS m/z (%): 479 (M+ + 2, 17), 478 (M+
+
[R]25 +100° (c 0.33, CHCl3). 1H NMR: δ 1.52 (m, 3H), 1.94
D
1, 11), 477 (M+, 30), 308 (62), 306 (100), 292 (23), 155 (27),
(m, 1H), 2.12 (m, 3H), 2.45 (m, 1H), 2.95 (dd, J ) 3.0, 5.4 Hz,
1H), 3.33 (t, J ) 6.9 Hz, 1H), 3.92 (m, 2H), 4.22 (m, 2H), 6.05
(t, J ) 2.4 Hz, 1H), 6.92 (dd, J ) 2.1, 8.4 Hz, 1H), 7.26 (s, 1H),
7.43 (m, 2H), 7.54 (m, 2H), 8.01 (m, 2H). 13C NMR: δ 32.5,
33.0, 36.5, 37.3, 45.6, 48.8, 54.1, 58.4, 67.5, 120.6, 126.7, 127.9,
128.6, 129.7, 130.2, 130.3, 133.2, 133.7, 134.6, 138.2, 144.0,
166.6. MS m/z (%): 474 (M+ + 1, 6), 473 (M+, 21), 472 (8), 354
(23), 352 (100), 350 (77), 338 (29), 141 (19), 117 (41), 105 (71),
83 (49), 77 (55), 44 (74). Anal. (C24H23BrClNO2‚2/3H2O) C, H,
N.
127 (53), 83 (15), 68 (34). Anal. (C28H25Cl2NO2‚1.9H2O) C, H,
N.
(1S,3S,6R,10S)-(Z)-10-(Acetoxym eth yl)-9-(2-n a p h th yl-
m et h ylen e)-7-a za t r icyclo[4.3.1.03,7]d eca n e (17a ). [R]25
D
+78.7° (c 0.23, CHCl3). 1H NMR: δ 1.54 (m, 3H), 1.81 (m, 1H),
2.05 (s, 3H), 2.15 (m, 3H), 2.41 (m, 1H), 2.91 (m, 1H), 3.36 (m,
1H), 4.02 (d, J ) 7.5 Hz, 2H), 4.10 (m, 2H), 6.30 (br s, 1H),
7.40 (m, 3H), 7.65 (s, 1H), 7.80 (m, 3H). 13C NMR: δ 21.0, 32.2,
32.8, 36.0, 37.2, 45.3, 48.7, 54.0, 58.3, 67.2, 122.7, 125.7, 126.2,
126.9, 127.0, 127.5, 127.9, 171.1. MS m/z (%): 348 (M+ + 1,
2), 347 (M+, 10), 288 (27), 274 (11), 178 (10), 165 (11), 136 (11),
84 (63), 49 (100), 44 (75). Anal. (C23H25NO2‚0.8H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-10-(Ben zoyloxym eth yl)-9-[3-ch lor o-
4-(tr i-n -bu tylstan n yl)ben zyliden e]-7-azatr icyclo[4.3.1.03,7]-
d eca n e (22). A solution of compound 21 (0.10 mmol) in toluene
(1 mL) was degassed by bubbling nitrogen into the mixture
for 15 min, and bis(tributyltin) (123 µL, 0.23 mmol) followed
by tetrakis(triphenylphosphine)palladium (2.0 mg) were added.
The mixture was stirred under N2 at 90 °C for 6 h. The solvent
was removed, and the residue was purified by preparative TLC
(hexane/EtOAc 1:1) to give the product in 47% yield. 1H
NMR: δ 0.90 (m, 12H), 1.13 (t, J ) 6.6 Hz, 6H), 1.36 (m, 9H),
1.53 (m, 3H), 1.94 (m, 1H), 2.13 (m, 3H), 2.45 (m, 1H), 2.96
(dd, J ) 2.7, 5.1 Hz, 1H), 3.34 (t, J ) 6.0 Hz, 1H), 3.99 (m,
2H), 4.22 (m, 2H), 6.09 (br s, 1H), 7.03 (dd, J ) 1.5, 7.5 Hz, 1
H), 7.17 (d, J ) 1.2 Hz, 1H), 7.32 (d, J ) 7.5 Hz, 1H), 7.43 (m,
2H), 7.52 (m, 1H), 8.00 (dd, J ) 1.5, 8.4 Hz, 2H). 13C NMR: δ
(1S,3S,6R,10S)-(Z)-10-(Ben zoyloxym eth yl)-9-(2-n a p h th -
ylm eth ylen e)-7-a za tr icyclo[4.3.1.03,8]d eca n e (17b). [R]25
D
+93.5° (c 0.185, CHCl3). 1H NMR: δ 1.56 (m, 3H), 1.97 (m,
1H), 2.18 (m, 3H), 2.53 (m, 1H), 2.98 (m, 1H), 3.37 (t, J ) 6.9
Hz, 1H), 4.12 (m, 2H), 4.28 (d, J ) 7.8 Hz, 2H), 6.33 (br s,
1H), 7.46 (m, 6H), 7.64 (s, 1H), 7.78 (m, 3H), 8.05 (m, 2H). 13
C
NMR: δ 32.5, 33.1, 36.4, 37.5, 45.7, 49.0, 54.2, 58.5, 67.7, 122.8,
125.9, 126.3, 127.1, 127.2, 127.7, 128.0, 128.1, 128.6, 129.7,
130.4, 132.0, 133.1, 133.6, 135.0, 141.3, 166.7. MS m/z (%): 410
(M+ + 1, 6), 409 (M+, 22), 304 (48), 288 (56), 274 (34), 218
(15), 178 (21), 165 (21), 136 (30), 105 (36), 84 (56), 49 (100).
Anal. (C28H27NO2‚0.3H2O) C, H, N.

Tricyclic Tropane Analogues and Uptake Inhibition
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9 1939
10.7, 13.9, 27.5, 29.2, 32.4, 33.0, 36.4, 37.4, 45.6, 48.8, 54.2,
58.4, 67.5, 121.7, 125.9, 128.1, 128.6, 129.7, 130.3, 133.2, 137.7,
139.2, 140.7, 142.2, 143.1, 166.6. MS m/z (%): 626 (M+ - C4H9,
55), 570 (29), 392 (14), 272 (35), 236 (34), 195 (87), 178 (51),
153 (43), 105 (54), 57 (48), 41 (100).
with a saturated solution of NaHCO3, and extracted with CH2-
Cl2 (2 × 30 mL). The combined organic phases were dried and
concentrated under reduced pressure, and the residue was
purified by column chromatography (ethyl acetate/hexane, 1/1).
1H NMR: δ 1.61 (m, 3H), 2.18 (m, 5H), 3.02 (m, 1H), 3.33 (m,
1H), 3.98 (br s, 2H), 6.08 (m, 2H), 6.38 (d, J ) 15.9 Hz, 1H),
7.06 (dd, J ) 2.1, 8.4 Hz, 1H), 7.25 (m, 6H), 7.40 (d, J ) 8.4
Hz, 1H). 13C NMR: δ 28.9, 32.2, 33.0, 37.3, 40.2, 48.8, 51.1,
53.8, 61.8, 120.5, 126.3, 127.4, 127.7, 128.7, 130.0, 130.2, 130.5,
133.6. MS m/z (%): 397 (M+ + 2, 22), 396 (M+ + 1, 19), 395
(M+, 38), 306 (10), 304 (15), 236 (100), 128 (26), 91 (65), 83
(59), 68 (63). Anal. (C24H23Cl2N‚1.4H2O) C, H; N: calcd, 3.32;
found, 2.60.
(1S,3S,6R,10S)-(Z)-9-(3,4-Dich lor oben zylid en e)-7-a za -
tr icyclo[4.3.1.03,7]decan e-10-(N-m eth oxy-N-m eth ylcar box-
a m id e) (27). Compound 27 was prepared by the same
procedure as compounds 14c and 14d . 1H NMR: δ 1.50 (m,
3H), 2.04 (m, 1H), 2.19 (m, 2H), 2.61 (m, 1H), 2.72 (m, 1H),
3.16 (s, 3H), 3.28 (m, 1H), 3.71 (s, 3H), 3.76 (m, 1H), 3.80 (dd,
J ) 2.4, 18.0 Hz, 1H), 4.10 (dd, J ) 2.1, 18.0 Hz, 1H), 5.97 (t,
J ) 2.4 Hz, 1H), 7.03 (dd, J ) 1.8, 8.4 Hz, 1 H), 7.27 (d, J )
1.8 Hz, 1H), 7.35 (d, J ) 8.4 Hz, 1H). MS m/z (%): 382 (M++1,
24), 381 (M+, 17), 380 (39), 322 (62), 320 (100), 290 (47), 141
(12), 128 (11), 80 (27), 41 (53).
(1S,3S,6R,10S)-(Z)-9-(3,4-Dich lor oben zylid en e)-10-p r o-
p a n oyl-7-a za tr icyclo[4.3.1.03,7]d eca n e (28). To a solution
of Weinreb amide 27 (0.11 mmol) in anhydrous THF (5 mL)
was added ethylmagnesium bromide (3 M in diethyl ether, 110
µL) dropwise at 0 °C under N2. The reaction mixture was
slowly warmed to room temperature and stirred overnight. The
reaction was then quenched with saturated aqueous NH4Cl
solution, and the mixture was extracted with ethyl acetate (4
× 20 mL). The combined extracts were dried over anhydrous
Na2SO4. After the solvent was removed, the product was
(1S,3S,6R,10S)-(Z)-10-(Ben zoyloxym eth yl)-9-(3-ch lor o-
4-iod oben zylid en e)-7-a za tr icyclo[4.3.1.03,7]d eca n e (23). A
solution of compound 22 (0.046 mmol) in CH2Cl2 (2.0 mL) was
deoxygenated by bubbling with nitrogen for 10 min. Then, a
solution of iodine (72 mg, 0.28 mmol) in CH2Cl2 (0.5 mL) was
added. The mixture was stirred at room temperature overnight
under N2. Solutions of NaHSO3 (1 mL, 5% in water) and KF
(0.5 mL, 1 M in MeOH) were added successively. The mixture
was stirred for 5 min, and the phases were separated. The
aqueous phase was extracted with CH2Cl2, and the combined
organic phases were dried over Na2SO4, filtered, and concen-
trated to give the crude product. Preparative TLC (hexane/
1
EtOAc 1:1) gave compound 23 in 64% yield. H NMR: δ 1.54
(m, 3H), 1.93 (m, 1H), 2.13 (m, 3H), 2.45 (m, 1H), 2.94 (m,
1H), 3.32 (t, J ) 6.9 Hz, 1H), 3.92 (m, 2H), 4.21 (m, 2H), 6.03
(br s, 1H), 6.76 (dd, J ) 1.8, 8.4 Hz, 1 H), 7.26 (d, J ) 1.8 Hz,
1H), 7.42 (m, 2H), 7.53 (m, 1H), 7.75 (d, J ) 8.4 Hz, 1H), 7.99
(d, J ) 8.4 Hz, 2H). 13C NMR: δ 32.4, 33.0, 36.5, 37.3, 45.6,
48.8, 54.1, 58.3, 67.4, 120.6, 127.9, 128.6, 129.2, 129.7, 130.3,
133.2, 138.6, 139.2, 140.1, 144.3, 166.6. MS m/z (%): 520 (M+
+ 1, 12), 519 (M+, 42), 400 (33), 398 (100), 384 (33), 141 (15),
105 (45), 83 (25), 77 (43), 68 (31). Anal. (C24H23IClNO2‚1.5H2O)
C, H, N.
(1S,3S,6R,10S)-(Z)-10-(Ben zoyloxym eth yl)-9-(3-ch lor o-
4-m eth ylben zylid en e)-7-a za tr icyclo[4.3.1.03,7]d eca n e (24).
1
[R]25 +84.0° (c 0.20, CHCl3). H NMR: δ 1.55 (m, 3H), 1.93
D
(m, 1H), 2.15 (m, 3H), 2.34 (s, 3H), 2.44 (m, 1H), 2.94 (m, 1H),
3.32 (t, J ) 7.2 Hz, 1H), 3.95 (m, 2H), 4.21 (m, 2H), 6.08 (br s,
1H), 6.99 (dd, J ) 1.8, 8.1 Hz, 1 H), 7.18 (m, 2H), 7.43 (m,
2H), 7.54 (m, 1H), 8.00 (d, J ) 8.4 Hz, 2H). 13C NMR: δ 19.9,
32.5, 33.1, 36.3, 37.4, 45.7, 48.8, 54.1, 58.4, 67.7, 121.3, 126.7,
128.6, 129.0, 129.7, 130.4, 131.0, 133.2, 133.9, 134.5, 136.8,
141.6, 166.7. MS m/z (%): 409 (M+ + 1, 6), 408 (M+, 6), 407
(M+ - 1, 16), 288 (32), 286 (100), 272 (36), 141 (13), 105 (42),
83 (48), 77 (45), 68 (49). Anal. (C25H26ClNO2‚2/3H2O) C, H,
N.
obtained in 90% yield by column chromatography (ethyl
1
acetate/ Et3N 100:1). [R]25 +43.1° (c 1.3, CHCl3). H NMR: δ
D
1.04 (t, J ) 7.5 Hz, 3H), 1.44 (m, 2H), 1.56 (m, 1H), 2.14 (m,
3H), 2.40 (m, 2H), 2.49 (m, 1H), 2.68 (m, 1H), 3.25 (m, 1H),
3.78 (dd, J ) 2.1, 18.3 Hz, 1H), 3.82 (m, 1H), 3.95 (dd, J )
2.1, 18.3 Hz, 1H), 5.96 (t, J ) 2.4 Hz, 1H), 6.98 (dd, J ) 2.1,
8.4 Hz, 1 H), 7.24 (d, J ) 1.8 Hz, 1H), 7.35 (d, J ) 8.4 Hz, 1H).
13C NMR: δ 7.7, 31.7, 32.6, 34.2, 37.1, 37.5, 47.9, 53.6, 54.6,
59.2, 119.5, 127.4, 129.7, 129.9, 130.0, 132.2, 137.0, 143.5,
210.9. MS m/z (%): 351 (M+ + 1, 16), 350 (M+, 7), 349 (26),
292 (100), 190 (11), 149 (15), 110 (20), 83 (26), 68 (31), 41 (59).
Anal. (C19H21Cl2NO‚0.07H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-(3,4-Dich lor oben zylid en e)-7-a za -
tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxa ld eh yd e (25). Oxalyl
chloride (0.10 mL, 1.08 mmol) was dissolved in anhydrous CH2-
Cl2 (10 mL), and the solution was cooled to -78 °C. Dimethyl
sulfoxide (DMSO; 0.15 mL, 2.16 mmol) was added, and after
5 min, the alcohol 15 (0.25 g, 1.08 mmol) was added as a
solution in CH2Cl2 (5 mL). Stirring was continued for 30 min.
The reaction was quenched by adding Et3N (1.4 mL), and the
resulting solution was warmed to room temperature, diluted
with CH2Cl2 (30 mL), washed with saturated NH4Cl (2 × 30
mL), dried, and concentrated under reduced pressure to give
25 as a colorless oil. This material was used in the next step
without further purification. 1H NMR: δ 1.56 (m, 3H), 2.16
(m, 3H), 2.33 (t, J ) 2.4 Hz, 1H), 2.83 (dd, J ) 3.3, 6.0 Hz,
1H), 3.32 (m, 1H), 3.74 (m, 1H), 3.88 (m, 2H), 6.10 (t, J ) 2.7
Hz, 1H), 6.99 (dd, J ) 2.1, 8.4 Hz, 1H), 7.25 (s, 1H), 7.37 (d, J
) 8.1 Hz, 1H), 9.67 (s, 1H). 13C NMR: δ 32.1, 32.8, 35.6, 37.0,
48.6, 53.9, 54.3, 58.7, 120.8, 127.7, 130.3, 130.5, 132.1, 137.1,
202.7. MS m/z (%): 322 (M+ + 1, 1), 321 (M+, 2), 292 (6), 223
(4), 164 (6), 136 (9), 110 (4), 83 (57), 68 (9), 49 (100).
(1S,3S,6R,10S)-(Z)-9-(3,4-Dich lor ob en zylid en e)-10-(E-
styr yl)-7-a za tr icyclo[4.3.1.03,7]d eca n e (26). n-BuLi (2.20
mL, 2.62 mmol, 1.2 M in hexane) was added to freshly distilled
THF (10 mL), and the solution was cooled to 0 °C. A solution
of benzyltriphenylphosphonium chloride (2.62 mmol) in THF
(4 mL) was added slowly under nitrogen. The resulting yellow-
orange solution was stirred at 0 °C for 30 min, then the cooling
bath was removed, and the crude aldehyde 25 (0.87 mmol) was
added in THF (2 mL). The reaction mixture was stirred for 15
h at room temperature, diluted with EtOAc (20 mL), and
washed with NH4Cl (2 × 30 mL). The combined organic phases
were extracted with 10% HCl (3 × 10 mL). The combined
aqueous phases were washed with EtOAc (30 mL), neutralized
(1S,3S,6R,10S)-(Z)-9-(3-Ch lor o-4-m eth ylben zylid en e)-
10-(4-io d o p h e n o x y m e t h y l)-7-a za t r ic y c lo [4.3.1.03 ,7 ]-
d eca n e (29). To a stirred solution of the alcohol 15 (0.067
mmol), 4-iodophenol (16 mg, 0.07 mmol), and triphenylphos-
phine (19.4 mg, 0.074 mmol) in anhydrous THF (2 mL) was
added at 0 °C and under nitrogen diethyl azodicarboxylate (14
mg, 0.08 mmol). The mixture was stirred at 0 °C for 1 h and
at room temperature for 24 h. The solvent was evaporated
under reduced pressure, and the residue was subjected to
column chromatography (1:1 ethyl acetate/hexanes) to give the
1
pure product as an oil (54%). H NMR: δ 1.51 (m, 3H), 1.93
(m, 1H), 2.16 (m, 3H), 2.49 (m, 1H), 2.86 (m, 1H), 3.33 (t, J )
6.9 Hz, 1H), 3.75 (m, 2H), 3.89 (ABq, J ) 18.3, both parts d
with J ) 2.4 Hz, 2H), 5.99 (br s, 1H), 6.50 (d, J ) 8.4 Hz, 2 H),
6.95 (dd, J ) 2.1, 8.4 Hz, 1H), 7.21 (d, J ) 2.1, 1H), 7.36 (d, J
) 8.1 Hz, 1H), 7.53 (dd, J ) 2.1, 7.2 Hz, 2H). 13C NMR: δ
32.5, 33.0, 36.0, 37.0, 46.0, 48.8, 54.2, 58.3, 70.9, 117.2, 120.5,
127.6, 130.0, 130.2, 130.4, 132.6, 135.7, 137.5, 138.4, 143.9,
159.1. Anal. (C23H22Cl2NIO) C, H, N.
Dim er 30. Dimer 30 was prepared as described for com-
1
pounds 16b-d . H NMR: δ 1.51 (m, 12H), 1.77 (m, 6H), 2.08
(m, 8H), 2.28 (t, J ) 7.5 Hz, 4H), 2.34 (m, 2H), 2.85 (m, 2H),
3.25 (m, 2H), 3.92 (m, 8H), 6.01 (br s, 2H), 6.94 (dd, J ) 1.8,
8.4 Hz, 2 H), 7.28 (d, J ) 1.8 Hz, 2H), 7.54 (d, J ) 8.4 Hz, 2H).
13C NMR: δ 25.2, 29.4, 32.4, 33.0, 34.5, 36.3, 37.2, 45.4, 48.7,
54.1, 58.4, 67.0, 119.8, 120.5, 127.8, 129.0, 130.2, 131.1, 133.7,
138.2, 174.0. The free base was converted to the hydrochloride
salt. Anal. (C44H52Cl4N2O4‚1.3 HCl) C, H, N.

1940 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9
Zhang et al.
Syn a p t osom a l Up t a k e of [3H ]DA, [3H ]5-H yd r oxy-
tr yp ta m in e, a n d [3H]NE. Compounds were tested as the free
base or their respective salts. The effect of candidate com-
pounds in antagonizing biogenic amine high-affinity uptake
was determined using a method similar to that previously
employed for [3H]DA uptake.28 Striatum, midbrain, and pari-
etal/occipital cortex were dissected and used as a source of rat
DAT, SERT, and NET, respectively. These brain regions were
homogenized with a Teflon-glass pestle in ice-cold 0.32 M
sucrose and centrifuged for 10 min at 1000g. The supernatant
was centrifuged at 17500g for 20 min. This P2 synaptosomal
pellet was resuspended in 30 volumes of ice-cold modified KRH
buffer consisting of (in mM) NaCl (125), KCl (4.8), MgSO4 (1.2),
CaCl2 (1.3), KH2PO4 (1.2), glucose (5.6), nialamide (0.01), and
HEPES (25) (pH 7.4).25 An aliquot of the synaptosomal
suspension was preincubated with the buffer and drug for 30
min at 4 °C and then for 15 min at 37 °C before uptake was
initiated by the addition of [3H]biogenic amine (∼5 nM for [3H]-
DA and [3H]5-HT, 9 nM for [3H]NE, final concentration). After
5 min, uptake was terminated by adding 5 mL of cold buffer
containing glucosamine as a substitute for NaCl and then
finally by rapid vacuum filtration over GF/C glass-fiber filters,
followed by washing with two 5 mL volumes of ice-cold,
sodium-free buffer. The bound and free [3H]biogenic amines
were separated by rapid vacuum filtration over Whatman
GF/C filters, using a Brandel M24R cell harvester, followed
by two washes with 5 mL of cold buffer. Radioactivity on the
filters was then extracted by allowing the filters to sit
overnight with 5 mL of scintillation fluid. The vials were
vortexed and counted. Specific uptake of [3H]DA was defined
as that which is sensitive to inhibition by 30 µM cocaine.
Amounts of 10 µM fluoxetine and 3 µM desipramine, respec-
tively, were used to define the specific uptake of [3H]5-HT and
[3H]NE. In each instance, it was virtually identical to that
calculated by subtracting the mean of identical tubes incubated
at 0 °C. IC50 values were determined using the computer
program LIGAND. The Cheng-Prusoff equation for classic,
competitive inhibition was used for calculating Ki from IC50
values in uptake experiments. The Km values used were 67
nM for [3H]DA, 53 nM for [3H]5-HT, and 54 nM for [3H]NE.
(8) Rothman, R. B.; Elmer, G. I.; Shippenberg, T. S.; Rea, W.;
Baumann, M. H. Phentramine and Fenfluramine. Preclinical
Studies in Animal Models of Cocaine Addiction. Ann. N. Y. Acad.
Sci. 1998, 844, 59-74.
(9) Howell, L. L.; Byrd, L. D. Serotonergic Modulation of the
Behavioral Effects of Cocaine in the Squirrel Monkey. J .
Pharmacol. Exp. Ther. 1996, 276, 1551-1559.
(10) (a) Brody, A. L.; Saxena, S.; Schwartz, J . M.; Stoessel, P. W.;
Maidment, K.; Pheleps, M. E.; Baxter, L. R., J r. FDG-PET
Predictors of Response to Behavioral Therapy and Pharmaco-
therapy in Obsessive Compulsive Disorder. Psychiatry Res. 1998,
84, 1-6. (b) Walsh, S. L.; Sullivan, J . T.; Fromme, R.; Bigelow,
G. E. Fluoxetine Response on Cocaine Response: a Double-blind
Laboratory Assessment in Humans. In Problems on Drug
Dependence 1994; Harris, L. S., Ed.; U.S. Government Printing
Office: Washington, DC, 1995; p 310.
(11) Batki, S. L.; Washburn, A. M.; Delucchi, K.; J ones, R. T. A
Controlled Use of Fluoxetine in Crack Cocaine Dependence. Drug
Alcohol Depend. 1996, 41, 137-142.
(12) Blough, B. E.; Abraham, P.; Lewin, A. H.; Kuhar, M. J .; Boja, J .
W.; Caroll, F. I. Synthesis and Transporter Binding of 3-(4′-
Alkyl-, 4′-alkenyl-, and 4′-alkynylphenyl)nortropane-2-carboxylic
Acid Methyl Ester: Serotonin Transporter Selective Analogues.
J . Med. Chem. 1996, 39, 4027-4035.
(13) Davis, H. M. L.; Kuhn, L. A.; Thornly, C.; Matasi, J . J .; Sexton,
T.; Childers, S. Synthesis of 3-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.
(14) Tamiz, A. P.; Zhang, J .; Flippen-Anderson, J . L.; Zhang, M.;
J ohnson, K. M.; Deschaux, O.; Tella, S.; Kozikowski, A. P.
Further SAR Studies of Piperidine-Based Analogues of Cocaine.
2. Potent Dopamine and Serotonin Reuptake Inhibitors. J . Med.
Chem. 2000, 43, 1215-1222.
(15) Davies, H. M. L.; Gilliatt, V.; Kuhn, L. A.; Saikali, E.; Ren, P.;
Hammond, 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.
(16) Smith, M. P.; J ohnson, K. M.; Zhang, M.; Flippen-Anderson, J .
L.; Kozikowski, A. P. Tuning the selectivity of monoamine
transporter inhibitors by the stereochemistry of the nitrogen lone
pair. J . Am. Chem. Soc. 1998, 120, 9072-9073.
(17) Hoepping, A.; J ohnson, K. M.; George, C.; Flippen-Anderson, J .;
Kozikowski, A. P. Novel Conformationally Constrained Tropane
Analogues by 6-endo-trig Radical Cyclization and Stille Coupling
- Switch of Activity toward the Serotonin and/or Norepinephrine
Transporter. J . Med. Chem. 2000, 43, 2064-2071.
(18) Singh, S. Chemistry, design, and structure-activity relationship
of cocaine antagonists. Chem. Rev. 2000, 100, 925-1024.
(19) Smith, M. P.; Hoepping, A.; J ohnson, K. M.; Trzcinska, M.;
Kozikowski, A. P. Dopaminergic agents for the treatment of
cocaine abuse. Drug Discovery Today 1999, 4, 322-332.
(20) Carroll, F. I.; Howell, L. L.; Kuhar, M. J . Pharmacotherapies
for treatment of drug abuse: Preclinical aspects. J . Med. Chem.
1999, 42, 2721-2736.
(21) Interatomic distances obtained by energy minimization using
the MMFF 94 force field in Cerius 2. Cerius 2, a molecular
modeling system, was supplied by Molecular Simulations Inc.,
200 Fifth Avenue, Waltham, MA 01803-5279.
(22) Olofson, R. A.; Martz, J . T.; Senet, J . P.; Piteau, M.; Malfroof,
T. A new reagent for the selective, high-yield N-dealkylation of
tertiary amines: Improved syntheses of naltrexone and nalbu-
phine. J . Org. Chem. 1984, 49, 2081-2082.
(23) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.;
Kulicke, K. J .; Trach, F. Radical Cyclization Reactions. Org.
React. 1996, 48, 301-856.
(24) (a) Singh, S.; Basmadjian, G. P.; Avor, K. S.; Pouw, P.; Seale, T.
W. Synthesis and Ligand Binding Studies of 4′-Iodobenzoyl
Esters of Tropanes and Piperidines at the Dopamine Trans-
porter. J . Med. Chem. 1997, 40, 2474-2481. (b) Suzuki, H.;
Kondo, A.; Inouye, M.; Ogawa, T. An Alternative Synthetic
Method for Polycyclic Aromatic Iodides. Synth. Commun. 1985,
121-122.
(25) Hoepping, A.; George, C.; Flippen-Anderson, J .; Kozikowski, A.
P. Radical cyclization strategies for the formation of ring
constrained tricyclic tropane analogues. Tetrahedron Lett. 2000,
41, 7427-7432.
(26) Lewin, A. H.; Gao, Y.; Abraham, P.; Boja, J . W.; Kuhar, M. J .;
Carroll, F. I. 2-Substituted Analogues of cocaine. Synthesis and
Inhibition of Binding to the Cocaine Receptor. J . Med. Chem.
1992, 35, 135.
(27) Swahn, C. G.; Halldin, C.; Gu¨nther, I.; Patt, J .; Ametamey, S.
Synthesis of unlabeled, 3H- and 125I-labeled â-CIT and its
ω-fluoroalkyl analogues â-CIT-FE and â-CIT-FP, including
synthesis of precursors. J . Labelled Compd. Radiopharm. 1996,
38, 675-685.
Ack n ow led gm en t. We are indebted to the NIH,
National Institute on Drug Abuse (DA10458, DA11548)
for their support of these studies.
Refer en ces
(1) (a) Substance Abuse and Mental Health Services Administration
National Household Survey on Drug Abuse: Main Findings
1997; Department of Health and Human Services: Washington,
DC, 1998. (b) Swan, N. Drug Abuse Cost to Society Set at $97.9
Billion, Continuing Steady Increase Since 1975. NIDA Notes
1998, 13. (c) The Economic Cost of Alcohol and Drug Abuse in
the United States; National Clearinghouse for Alcohol and Drug
Use, 1992; BKD265.
(2) (a) Ritz, M. C.; Lamb, R. J .; Goldberg, S. R.; Kuhar, M. Cocaine
receptors on dopamine transporters are related to self-admin-
istration of cocaine. Science 1987, 237, 1219-1223. (b) Calligaro,
D. O.; Elderfrawi, M. E. High affinity stereospecific binding of
[3H]cocaine in striatum and its relationship to the dopamine
transporter. Membr. Biochem. 1988, 7, 87-106.
(3) Kuhar, M. J .; Ritz, M. C.; Boja, J . W. The dopamine hypothesis
of the reinforcing properties of cocaine. Trends Neurosci. 1991,
14, 299-302.
(4) Robinson, I.; Barridge, K. C. The neural basis of drug craving:
An incentive-sensitization theory of addiction. Brain Res. Rev.
1993, 18, 247-291.
(5) (a) Carroll, F. I.; Lewin, A. H.; Kuhar, M. A. In Neurotransmitter
Transporters: Structure, Function and Regulation; Reith, M. E.
A., Ed.; Humana Press Inc.: Totowa, NJ , 1997; pp 263-295. (b)
Rothman, R. B.; Glowa, J . R. Mol. Neurobiol. 1995, 11, 1-19.
(c) Carroll, F. I.; Howell, L. L.; Kuhar, M. J . Pharmacotherapies
for the Treatment of Cocaine Abuse: Preclinical Aspects. J . Med.
Chem. 1999, 42, 1-16.
(6) Taylor, D.; Ho, B. T. Comparison of inhibition of monoamine
uptake by cocaine, methylphenidate and amphetamine. Res.
Commun. Chem. Pathol. Pharmacol. 1978, 21, 67-75.
(7) Walsh, S. L.; Cunningham, K. A. Serotonergic mechanisms
involved in the discriminative stimulus, reinforcing and subjec-
tive effects of cocaine. Psychopharmacology 1997, 130, 41-58.

Tricyclic Tropane Analogues and Uptake Inhibition
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9 1941
(28) Zhuang, Z. P.; Kung, M. P.; Hou, C.; Skovronsky, D. M.; Gur, T.
L.; Plo¨ssl, K.; Trojanowski, J . Q.; Lee, V. M.-Y.; Kung, H. F.
Radioiodinated Styrylbenzenes and Thioflavins as Probes for
Amyloid Aggregates. J . Med. Chem. 2001, 44, 1905-1914.
(29) Meltzer, P. C.; Wang, B.; Chen, Z.; Blundell, P.; J ayaraman, M.;
Gonzalez, M. D.; George, C.; Madras, B. K. Synthesis of 6- and
7-Hydroxy-8-azabicyclo[3.2.1]octanes and Their Binding Affinity
for the Dopamine and Serotonin Transporters. J . Med. Chem.
2001, 44, 2619-2635.
(30) Guarna, A.; Menchi, G.; Berti, G.; Cini, N.; Bottoncetti, A.;
Raspanti, S.; Politi, A.; Pupi, A. Synthesis and preliminary
biological characterization of a new potential 125I-Radioligand
for dopamine and serotonin receptors. Bioorg. Med. Chem. 2001,
9, 3197-3206.
(31) Wang, S.; Sakamuri, S.; Enyedy, I. J .; Kozikowski, A. P.;
Deschaux, O.; Bandyopadhyay, B. C.; Tella, S. R.; Zaman, W.
A.; J ohnson, K. M. Discovery of a novel dopamine transporter
inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-
methylphenyl ketone, as a potential cocaine antagonist through
3D-database pharmacophore searching. Molecular modeling,
structure-activity relationships, and behavioral pharmacological
studies. J . Med. Chem. 2000, 43, 351-360.
(32) Slusher, B. S.; Tiffany, C. W.; Olkowski, J . L.; J ackson, P. F.
Use of identical assay conditions for cocaine analogue binding
and dopamine uptake to identify potential cocaine antagonists.
Drug Alcohol Depend. 1997, 48, 43-50.
(33) Newman, A. H.; Agoston, G. E. Novel benztropine [3R-(diphe-
nylmethoxy)tropane] analogues as probes for dopamine trans-
porter. Curr. Med. Chem. 1998, 5, 305-319.
(34) Davies, H. M. L.; Saikali, E.; Huby, N. J . S.; Gilliatt, V. J .;
Matasi, J . J .; Sexton, T.; Childers, S. R. Synthesis of novel 2â-
acyl-3â-aryl-8-azabicyclo[3.2.1]octanes and their binding affini-
ties at dopamine and serotonin transport sites in rat striatum
and frontal cortex. J . Med. Chem. 1994, 37, 1262-1268.
(35) Bennett, B. A.; Wichems, C. H.; Hollingsworth, C. K.; Davies,
H. M. L.; Thornley, C.; Sexton, T.; Childers, S. R. Novel
2-substituted cocaine analogues: uptake and ligand binding
studies at dopamine, serotonin and norepinephrine transport
sites in the rat brain. J . Pharmacol. Exp. Ther. 1995, 272, 1176-
1186.
(36) 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.
(37) Spealman, R. D. Modification of behavioral effects of cocaine by
selective serotonin and dopamine uptake inhibitors in squirrel
monkeys. Psychopharmacology 1993, 112, 93-99.
J M0105373