Biaryl analogues of conformationally constrained tricyclic tropanes as potent and selective norepinephrine reuptake inhibitors: Synthesis and evaluation of their uptake inhibition at monoamine transporter sites

Article abstract of DOI:10.1021/jm020596w

A series of novel conformationally constrained tricyclic tropane derivatives containing a biaryl moiety, (Z)-9-(biarylylmethylene)-7-azatricyclo[4.3.1.0^3,7]decanes, were synthesized and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) by the DA, 5-HT, and NE transporters. Most of the compounds containing a methoxycarbonyl substituent at C-10 exhibit moderate to high inhibitory activity at the NET but lower activity at the DAT and SERT. Among these new compounds, some potent, NET-selective ligands were identified. The p-methoxy derivative 11a has a K_i value of 39 nM for uptake inhibition at the NET and moderate to high selectivity over the SERT (100-fold) and the DAT (20-fold). Compound 11f exhibits a remarkable potency (K_i = 9.7 nM) at the NET and a 25-fold selectivity over both the SERT and the DAT. Analogue 23 containing a thiophene ring as a bioisosteric replacement of the phenyl ring Ar¹ displays a high activity (K_i = 10.3 nM) for the NET and similar selectivity over the SERT (50-fold) and the DAT (37-fold). The selectivity profile of biaryl analogues differs from that of the monoaryl series, as most members of that series display excellent potency at and selectivity for the SERT (J. Med. Chem. 2002, 45, 1930). This finding suggests that the different shape and size of the lipophilic recognition pocket that encompasses the aryl ring(s) of these tropanes are major determinants of a ligand's transporter activity at either the NET or the SERT. Some of the compounds in this series may also be valuable in sorting out the contribution of the individual transporters to cocaine's reinforcing properties.

Full text of DOI:10.1021/jm020596w

J . Med. Chem. 2003, 46, 1997-2007
1997
Bia r yl An a logu es of Con for m a tion a lly Con str a in ed Tr icyclic Tr op a n es a s P oten t
a n d Selective Nor ep in ep h r in e Reu p ta k e In h ibitor s: Syn th esis a n d Eva lu a tion
of Th eir Up ta k e In h ibition a t Mon oa m in e Tr a n sp or ter Sites
J ia Zhou,† Ao Zhang,† Thomas Kla¨ss,† Kenneth M. J ohnson,‡ Cheng Z. Wang,‡ Yan Ping Ye,‡ and
Alan P. Kozikowski*,†
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3970 Reservoir Road, NW,
Washington, D.C. 20057-2197, and Department of Pharmacology and Toxicology, University of Texas Medical Branch,
Galveston, Texas 77555-1031
Received December 31, 2002
A series of novel conformationally constrained tricyclic tropane derivatives containing a biaryl
moiety, (Z)-9-(biarylylmethylene)-7-azatricyclo[4.3.1.03,7]decanes, were synthesized and evalu-
ated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine
(NE) by the DA, 5-HT, and NE transporters. Most of the compounds containing a methoxy-
carbonyl substituent at C-10 exhibit moderate to high inhibitory activity at the NET but lower
activity at the DAT and SERT. Among these new compounds, some potent, NET-selective
ligands were identified. The p-methoxy derivative 11a has a Ki value of 39 nM for uptake
inhibition at the NET and moderate to high selectivity over the SERT (100-fold) and the DAT
(20-fold). Compound 11f exhibits a remarkable potency (Ki ) 9.7 nM) at the NET and a 25-
fold selectivity over both the SERT and the DAT. Analogue 23 containing a thiophene ring as
a bioisosteric replacement of the phenyl ring Ar1 displays a high activity (Ki ) 10.3 nM) for
the NET and similar selectivity over the SERT (50-fold) and the DAT (37-fold). The selectivity
profile of biaryl analogues differs from that of the monoaryl series, as most members of that
series display excellent potency at and selectivity for the SERT (J . Med. Chem. 2002, 45, 1930).
This finding suggests that the different shape and size of the lipophilic recognition pocket that
encompasses the aryl ring(s) of these tropanes are major determinants of a ligand’s transporter
activity at either the NET or the SERT. Some of the compounds in this series may also be
valuable in sorting out the contribution of the individual transporters to cocaine’s reinforcing
properties.
Ch a r t 1
In tr od u ction
The abuse of cocaine (1) (Chart 1) represents a major
and increasing threat to our economy, communities, and
public health.1-3 Consequently, considerable effort has
been directed toward understanding cocaine’s mecha-
nism of action and its behavioral effects as well as
toward the discovery of possible medications. Cocaine
is known to have multiple effects on endogenous central
neurotransmitter systems. It binds with moderate and
roughly equal affinity to all three of the monoamine
transporters and thereby inhibits the presynaptic re-
uptake of dopamine (DA), serotonin (5-HT), and nore-
pinephrine (NE) into neurons. Because the importance
of the interaction of cocaine with the dopaminergic
system (“DA hypothesis”) is strongly supported by
experimental data, most of the drugs generated to date
have targeted either DA receptors or the DA transporter
(DAT).4-6 However, a study employing knockout mice
has demonstrated that cocaine provides its rewarding
cues through its effects on additional systems besides
the dopaminergic system.7,8 Recent work suggests that
both the serotonin (SERT) and the norepinephrine
transporters (NET) may also play prominent roles in
cocaine addiction.9-15 Research with compounds that
vary both in their transporter selectivity and in rein-
forcing strength may help unravel the pharmacological
mechanisms relevant to drug addiction. To further
elucidate the role of the different transporter systems
in cocaine reward and craving, novel ligands with
defined potency at each of these three transporter sites
may be of value. In view of our own recent work, it is
even reasonable to suggest that drugs with a differential
selectivity for the monoamine transporters may exhibit
only partial cocaine-like properties and thus serve as
medications in the treatment of cocaine craving.16
To date, a large variety of tropane-based or non-
tropane analogues of cocaine have been synthesized
with two general aims in mind: (1) to further elucidate
* 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/jm020596w CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/08/2003

1998 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Zhou et al.
Ch a r t 2
Sch em e 1a
structure-activity relationships (SAR) at the DAT and
(2) to identify ligands of improved potency and DAT
selectivity that could be used in cocaine addiction.17-28
In contrast to the substantial body of research on DAT-
selective ligands, fewer studies have focused on the SAR
relevant to creating ligands imbued with varying levels
of transporter selectivity.3,4,29 As part of our research
program aimed at the discovery of possible medications
for cocaine abuse, we have been exploring a new series
of conformationally constrained analogues in an effort
to learn how to “dial in” certain levels of transporter
a
Reagents and conditions: (a) Saturated NaHCO3, 96%; (b)
CH3CH(Cl)OCOCl, 1,2-dichloroethane, reflux, 7 h, 91%; (c) MeOH,
reflux, 8 h, 90%; (d) propargyl bromide, K2CO3, MeCN, reflux, 24
h, 88%; (e) 2 N HCl, reflux, 16 h; (f) POCl3, reflux, 2 h; (g) MeOH,
-78 °C to room temperature, 84% (3 steps); (h) AIBN, n-Bu3SnH,
benzene, reflux, 16 h, 75%.
Sch em e 2a
selectivity. For example, in our recent studies,30-32
a
series of tropane analogues (2) were synthesized and
several highly potent and selective serotonin reuptake
inhibitors identified. Compound 2a exhibited a Ki value
of 0.1 nM at the SERT and Ki values of more than
10 000 and 8190 nM at the DAT and NET, respectively,
whereas compound 2b displayed an even higher inhibi-
tory potency and selectivity with a Ki value of 0.06 nM
at the SERT and Ki values of more than 10 000 nM both
at the DAT and NET.31 Furthermore, these SAR studies
revealed that the selectivity of such compounds for the
individual transporters could be tuned through struc-
tural modifications to its pharmacophoric group. For
example, the biphenylyl analogue 3 is a potent NET-
selective inhibitor with a Ki value of 12 nM and about
50-fold selectivity over both the SERT and the DAT.30
More recently, compound 3 has been investigated by
others as a new positron emission tomography (PET)
imaging agent displaying good brain uptake in both rats
and baboons and a certain degree of selectivity for the
NET in vivo.33
A growing body of evidence has shown that norepi-
nephrine plays an important role in the central nervous
system and, although the exact mechanism still remains
unknown, could be involved in a variety of psychiatric
disorders.34-38 For example, reboxetine is a relatively
selective NET inhibitor that has demonstrated efficacy
in depression and panic disorders.34,38 Even the broad
therapeutic efficacy of paroxetine, which is generally
considered to be a selective SERT inhibitor, may result
in part from its action on the NET in the treatment of
depression, panic disorder, social anxiety disorder, and
posttraumatic stress disorder.39 Biaryls and their ho-
mologues represent an important class of organic com-
pounds and comprise important partial structures of
natural products, polymers, advanced materials, liquid
crystals, supermolecules, and pharmaceuticals.40 To
gain a better understanding of the structural features
required for high activity and selectivity at norepineph-
rine transporters, we have synthesized and evaluated
the transporter activities of a series of (Z)-9-(biarylyl-
methylene)-7-azatricyclo[4.3.1.03,7]decanes (4) (Chart 2)
in a continuation of our previous work.
a
Reagents and conditions: (a) Pd2(dba)3, Ph3As, CuI, DMF, 45
°C.
starting from cocaine hydrochloride (5).30 Thus, norco-
caine (6) was prepared by N-demethylation of cocaine
with R-chloroethyl chloroformate.41 The subsequent
alkylation with propargyl bromide afforded N-propar-
gylnorcocaine (7), which was then subjected to saponi-
fication, dehydration, and reesterification to provide
N-propargylnoranhydroecgonine methyl ester (8) in
good yield. The key step, the radical cyclization of enyne
8 using syringe pump methodology, produced predomi-
nantly the Z-isomer of vinyl stannane 9.42,43
We first modified the substituents on the biphenylyl
group while leaving the ester moiety intact. As il-
lustrated in Scheme 2, biaryl analogues 11a ,b were
prepared by Stille coupling of tin precursor 9 with the
corresponding biarylyl iodides in moderate yields. Be-
cause of the limited availability of biarylyl iodides, the
remaining compounds 11 were prepared in a stepwise
manner with the use of a Suzuki coupling in the second
step as described in Scheme 3. The key intermediate
13 was obtained by coupling of the vinyl stannane 9
with 1,4-diiodobenzene (12) in the presence of Pd2(dba)3
and Ph3As in a yield of 57%. The subsequent Suzuki
coupling of the iodide 13 with substituted phenylboronic
acids in the presence of Pd(PPh3)4 as the catalyst
provided the desired compounds 11c-k in moderate
yields. In the course of our synthetic studies, we
optimized the Stille coupling conditions for the confor-
mationally constrained tropane substrates and found
that the yields were significantly improved by utilizing
the catalyst system with the ligand Ph3As instead of
(o-CH3C6H4)3P that was previously used.30-32
Ch em istr y. Scheme 1 outlines our synthetic ap-
proach to the construction of the tricyclic skeleton

Biaryl Analogues of Constrained Tricyclic Tropanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1999
Sch em e 3a
Sch em e 6a
a
Reagents and conditions: (a) Pd2(dba)3, Ph3As, CuI, DMF,
45 °C.
Sch em e 7a
a
Reagents and conditions: (a) Pd2(dba)3, Ph3As, CuI, DMF,
45 °C, 16 h; (b) ArB(OH)2, Pd(PPh3)4, Na2CO3, toluene/H2O, reflux,
31 h.
Sch em e 4a
a
Reagents and conditions: (a) Pd2(dba)3, Ph3As, CuI, DMF,
45 °C; (b) 4-methoxyphenylboronic acid, Pd(PPh3)4, Na2CO3,
toluene/H2O, reflux.
a
Reagents and conditions: (a) Pd2(dba)3, Ph3As, CuI, DMF,
45 °C.
Sch em e 8a
Sch em e 5a
a
Reagents and conditions: (a) ArB(OH)2, Pd(PPh3)4, Na2CO3,
toluene/H2O, reflux.
a
Reagents and conditions: (a) 1-bromo-2-chloro-4-iodobenzene,
To investigate the effect of changing Ar2 to a het-
eroaromatic ring, compound 15 was prepared by cou-
pling of the vinyl stannane 9 with 1-(4-iodophenyl)-
pyrrole (14) (Scheme 4). Compounds 16a ,b, 17, and 18
were obtained by Suzuki coupling of the iodide 13 with
2- or 3-thienylboronic acids or 2-furylboronic acid (Scheme
5).
Pd2(dba)3, Ph3As, CuI, DMF, 45 °C, 24 h; (b) Bu6Sn2, Pd(PPh3)4,
toluene, reflux, 9 h; (c) I2, CH2Cl2, room temperature, 15 h; (d)
ArB(OH)2, Pd(PPh3)4, Na2CO3, toluene/H2O, reflux, 31 h.
The modification of Ar1 with different substituents
was somewhat limited by the availability of the ap-
propriate precursors. As illustrated in Scheme 8, com-
pounds 27a ,b with a 3-chloro substituent on Ar1 were
obtained by coupling with the iodide 26, which in turn
was derived from the corresponding bromide 24 by a
two-step conversion.
The biaryl analogues 20 and 23 with a thiophene
moiety as Ar1 were synthesized in similar fashion from
the iodides 19 or 22 (Schemes 6 and 7).

2000 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Zhou et al.
Sch em e 9a
selectivity, we synthesized and examined compounds
11a -k . Among the compounds with an electron-donat-
ing substituent, potency in inhibition of NET reuptake
decreases in the sequence 4-Me > 4-MeO > 4-NMe2, and
all of these compounds display a fairly good activity at
and selectivity for the NET. The 4-methoxy analogue
11a exhibits a good potency (Ki ) 39 nM) at the NET
and selectivity vs the SERT (100-fold) and the DAT (20-
fold). The 4-methyl analogue 11c has a better potency
(Ki ) 23 nM) at the NET and a 50-fold selectivity vs
the SERT and 10-fold vs the DAT. Compound 11i,
containing a bulky 4-(dimethylamino) substituent, dis-
plays reduced activity at the NET (Ki ) 58 nM) with a
20-fold selectivity vs both the SERT and DAT. Among
the compounds with an electron-withdrawing substitu-
ent, activity to the NET decreases in the sequence 3-Cl
> 4-CN > 4-I > 4-Cl > 4-CF3. The 3-chloro analogue
11e exhibits a good potency (Ki ) 17 nM) at the NET
and a 13-fold selectivity vs the SERT. The 4-cyano
analogue 11k displays a Ki of 32 nM at the NET and a
25-fold selectivity vs the SERT. Both of these two
compounds also have a moderate to good activity to the
DAT. The disubstituted analogues 11f-h exhibit a
moderate to high activity at the NET. The 3,4-dichloro
derivative 11f has a remarkable potency (Ki ) 9.7 nM)
at the NET and a 25-fold selectivity vs both the SERT
and the DAT. It is interesting that the 3,4-dichlorophe-
nyl substitution pattern also led to one of the most DAT-
active compounds (IC50 ) 0.79 nM) in the WIN series45
and one of the most SERT-active analogues (Ki ) 1.6
nM) in the conformationally constrained tricyclic tro-
pane series.30
a
Reagents and conditions: (a) LiAlH4, THF, 0 °C to room
temperature, 3 h; (b) Ac2O, pyridine, DMAP, room temperature,
2 h.
Sch em e 10a
To investigate the effect of using heteroaromatic
rings, such as pyrrolyl, thienyl, and furyl, as the group
Ar2, we synthesized and examined compounds 15-18.
Analogue 15, containing a pyrrolyl ring, displays a good
activity (Ki ) 46 nM) at the NET and moderate
selectivity vs the SERT (3-fold) and the DAT (12.5-fold).
Analogues 16a ,b and 17, containing a 2-thienyl, 5-meth-
yl-2-thienyl, or 3-thienyl group, display a better potency
(Ki ≈ 20 nM) at the NET and somewhat better selectiv-
ity vs the SERT (4-9-fold) and the DAT (8-33-fold).
Compound 18 with a 2-furyl ring exhibits a high activity
(Ki ) 13.9 nM) at the NET and moderate selectivity vs
the SERT (17-fold) and the DAT (7-fold). Compounds
20 and 23 containing a thiophene ring as the aromatic
moiety Ar1 were also explored. Analogue 20 displays a
good potency (Ki ) 13.5 nM) for the NET and a lower
selectivity vs the SERT (5-fold) and the DAT (12.5-fold)
in comparison to compound 3. However, analogue 23
exhibits an improved activity (Ki ) 10.3 nM) at the NET
and a fairly good selectivity vs the SERT (50-fold) and
the DAT (37-fold).
a
Reagents and conditions: (a) LiAlH4, THF, 0 °C to room
temperature, 3 h; (b) benzoyl chloride, pyridine, DMAP, room
temperature, 2 h; (c) Bu6Sn2, Pd(PPh3)4, toluene, reflux, 9 h; (d)
I2, CH2Cl2, room temperature, 15 h; (e) 3,4-dichlorophenylboronic
acid, Pd(PPh3)4, Na2CO3, toluene/H2O, reflux.
To prepare the inverse ester 29 (Scheme 9), the
methyl ester 3 was reduced with LiAlH4 to give the
alcohol 28, which was further treated with acetic
anhydride. For the synthesis of the benzoate 31, the
methyl ester 24 was similarly converted to the benzoate
30, which was then subjected to the transformation to
the iodide 2b,31 followed by Suzuki coupling as above
(Scheme 10).
Resu lts a n d Discu ssion
All final compounds were tested for their ability to
inhibit high-affinity reuptake of DA, 5-HT, and NE into
nerve endings (synaptosomes) prepared from brain
regions enriched in transporters for these biogenic
amine neurotransmitters.31,44 The protocols used are
described in the Experimental Section. The uptake data
and selectivity profiles (based on the Ki values) of all
the new compounds prepared are listed in Table 1. For
comparison purposes, data for compound 3 from our
preliminary paper30 and for (-)-cocaine are also in-
cluded. All data are mean values ( SEM from two to
four independent experiments, each consisting of six
drug concentrations in triplicate.
As mentioned above, the introduction of a 3-chloro
substituent into Ar2 resulted in the discovery of 11e, a
NET ligand with good potency (Ki ) 17.5 nM). However,
both of the compounds 27a and 27b with a 3-chloro
substituent in Ar1 display a dramatically decreased
activity at the NET, and their selectivity profiles switch
to selectivity for the SERT vs NET and DAT.
To investigate the influence of the ester group in the
biaryl analogues on transporter potency and selectivity,
we converted compound 3 into the alcohol 28 and the
inverted ester 29. In comparison to the methyl ester 3,
To explore the effect of modifications of Ar2 in lead
compound 3 with different substituents on activity and

Biaryl Analogues of Constrained Tricyclic Tropanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 2001
Ta ble 1. Inhibition of Reuptake at Monoamine Transporters (Ki ( SEM (nM))a
[3H]DA
uptake
Ki (nM)
[3H]5-HT
uptake
Ki (nM)
[3H]-NE
uptake
Ki (nM)
uptake ratio (based on Ki)
compd
substituent
5-HT/DA
NE/DA
NE/5-HT
cocaine
3b
423 ( 147
477 ( 81
841 ( 85
155 ( 0.4
614 ( 105
3394 ( 598
108 ( 3.5
12 ( 1
0.37
1.29
4.04
0.26
0.02
0.05
0.7
0.02
0.01
11a
R1 ) H,
39 ( 7
R2 ) 4-MeO
X ) COOMe
R1 ) H,
11b
11c
11d
11e
11f
11g
11h
11i
377 ( 53
214 ( 5
660 ( 87
1489 ( 142
1260 ( 99
213 ( 51
114 ( 31
22.7 ( 2.1
739 ( 148
17.5 ( 2.2
9.7 ( 2.7
1.75
6.97
3.03
2.4
0.30
0.11
1.77
0.20
0.04
0.58
0.29
0.05
0.37
0.69
0.44
0.02
0.59
0.08
0.04
0.16
1.19
0.06
0.52
0.04
R2 ) 4-I
X ) COOMe
R1 ) H,
R2 ) 4-Me
X ) COOMe
R1 ) H,
417 ( 25
89 ( 12
R2 ) 4-Cl
X ) COOMe
R1 ) H,
R2 ) 3-Cl
X ) COOMe
R1 ) H,
236 ( 76
106 ( 14
1595 ( 201
1053 ( 107
3125 ( 0.01
47 ( 6.6
239 ( 37
1.01
3.62
0.25
0.95
0.71
R2 ) 3, 4-Cl2
X ) COOMe
R1 ) H,
384 ( 59
61 ( 6
R2 ) 3, 5-Cl2
X ) COOMe
R1 ) H,
393 ( 18
466 ( 103
57.9 ( 0.65
1146 ( 185
32.4 ( 1.2
R2 ) 2, 4-Cl2
X ) COOMe
R1 ) H,
1002 ( 60.4
2215 ( 52
909 ( 85
R2 ) 4-NMe2
X ) COOMe
R1 ) H,
11j
R2 ) 4-CF3
X ) COOMe
R1 ) H,
11k
19.3
R2 ) 4-CN
X ) COOMe
E ) COOMe
R ) H,
15
16a
568 ( 97
155 ( 16
149 ( 25
73 ( 5
45.9 ( 10.5
19.8 ( 1.4
0.26
0.47
0.08
0.13
0.31
0.27
E ) COOMe
R ) 5-Me,
E ) COOMe
E ) COOMe
E ) COOMe
R ) H,
16b
674 ( 7
200 ( 10
22.5 ( 4.6
0.30
0.03
0.11
17
18
20
277 ( 48
98 ( 3
179 ( 19
145 ( 33
248 ( 33
71 ( 5
20.5 ( 2.8
13.9 ( 0.7
13.5 ( 2.0
0.52
2.54
0.40
0.07
0.14
0.08
0.14
0.06
0.19
E ) COOMe
R ) 4-MeO,
E ) COOMe
R1 ) 3-Cl,
R2 ) H
23
371 ( 11
531 ( 51
366 ( 35
10.3 ( 0.5
991 ( 139
1.43
0.09
0.03
0.23
0.02
2.71
27a
4259 ( 307
X ) COOMe
R1 ) 3-Cl,
R2 ) 3, 5-Cl2
X ) COOMe
R1 ) H,
27b
28
8742 ( 1843
1298 ( 6
2771 ( 185
1544 ( 242
46 ( 10
>10000
0.32
1.19
0.28
0.17
N/T
0.14
0.35
N/T
N/T
183 ( 8
57( 4
0.12
1.24
R2 ) H
X ) CH2OH
29
R1 ) H,
165 ( 2
R2 ) H
X ) CH2OAc
R1 ) 3-Cl,
R2 ) 3, 4-Cl2
X ) CH2OC(O)Ph
31
5643 ( 332
956 ( 81
>10000
N/T
a
Ki values are mean ( SEM from two to four independent experiments, each consisting of six drug concentrations (in triplicate) that
b
were selected on the basis of preliminary screening experiments to bracket the approximate IC50 value. Data taken from ref 30.

2002 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Zhou et al.
were dissolved in anhydrous DMF (2 mL) and stirred at room
temperature for 20 min under nitrogen. Then the stannane 9
(53.9 mg, 0.11 mmol) in DMF (2 mL) was added, and the
mixture was stirred at 45-55 °C for 16 h. The solvent was
removed under reduced pressure, and the residue was chro-
matographed on silica gel using ethyl acetate/triethylamine
(98/2) or dichloromethane/methanol (98/2) as the eluents to
provide the desired product 11a as a white solid (17.8 mg,
42%). [R]25D +77.4° (c 0.36, CHCl3); 1H NMR (CDCl3): δ 1.41-
1.59 (m, 3H), 2.04-2.28 (m, 3H), 2.42 (t, J ) 3.3 Hz, 1H), 2.73
(dd, J ) 3.0 and 5.8 Hz, 1H), 3.25-3.34 (m, 1H), 3.66 (s, 3H),
3.76-3.82 (m, 1H), 3.85 (s, 3H), 3.95 and 4.08 (ABq, J ) 18.6
Hz, both d with J ) 2.4 Hz, 2H), 6.16 (t, J ) 2.7 Hz, 1H), 6.97
(d, J ) 8.4 Hz, 2H), 7.25 (d, J ) 7.2 Hz, 2H), 7.51 (d, J ) 8.1
Hz, 2H), 7.53 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3): δ 32.0,
32.6, 36.6, 37.4, 48.4, 51.9, 52.4, 53.7, 55.3, 56.2, 114.2, 121.7,
126.6, 127.9, 128.8, 133.2, 135.8, 138.5, 140.5, 159.1, 174.3;
MS m/z (%): 389 (M+, 9), 330 (14), 207 (13), 165 (16), 148 (27),
138 (26), 91 (25), 83 (100), 68 (51). Anal. (C25H27NO3‚0.5HCl)
C, H, N.
a dramatic loss in activity was observed for alcohol 28,
whereas conversion into the inverse ester 29 leads to a
significant gain in activity with a favorable SERT
selectivity vs NET and DAT. Biaryl analogue 31 with a
benzoyloxymethyl moiety derived from the highly potent
and selective SERT ligand 2b displays no NET activity
and a dramatically reduced activity at the SERT. The
methyl ester group would thus appear to be a critical
element for NET activity; however, we have not fully
explored all possible chemical modifications at this site.
In summary, a number of conformationally con-
strained tricyclic tropane derivatives, (Z)-9-(biarylylm-
ethylene)-7-azatricyclo[4.3.1.03,7]decanes with the gen-
eral structure 4, have been synthesized and their
transporter inhibitory activities explored. Most of the
methyl esters exhibit moderate to high inhibitory activ-
ity at the NET but lower activities at the DAT and
SERT. Among them, some potent and selective NET
ligands, such as compounds 11a , 11f, and 23, were
identified. This selectivity profile differs from that of the
monoaryl series, as most members of that series display
excellent potency at and selectivity for the SERT.31 This
finding suggests that the different shape and size of the
lipophilic recognition pocket that encompasses the aryl
ring(s) of these tropanes are major determinants of a
ligand’s transporter activity at either the NET or the
SERT. Some of the compounds in this series may also
be valuable in sorting out the contribution of the
individual transporters to cocaine’s reinforcing proper-
ties.
(1S,3S,6R,10S)-(Z)-9-[4-(4-Iod op h en 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 (11b). Procedure A was followed giving the title
compound as an oil. [R]25 +44.5° (c 0.17, CHCl3); 1H NMR
D
(CDCl3): δ 1.40-1.58 (m, 3H), 2.06-2.30 (m, 3H), 2.45 (t, J )
3.0 Hz, 1H), 2.74 (dd, J ) 3.3 and 5.7 Hz, 1H), 3.26-3.36 (m,
1H), 3.69 (s, 3H), 3.74-3.82 (m, 1H), 3.96 and 4.08 (ABq, J )
18.0 Hz, both d with J ) 2.7 and 2.4 Hz, respectively, 2H),
6.19 (t, J ) 2.7 Hz, 1H), 7.29 (d, J ) 8.1 Hz, 2H), 7.35 (d, J )
8.4 Hz, 2H), 7.54 (d, J ) 8.1 Hz, 2H), 7.78 (d, J ) 8.7 Hz, 2H);
13C NMR (CDCl3): δ 32.0, 32.6, 36.5, 37.4, 48.4, 52.0, 52.4,
53.7, 56.3, 105.2, 121.5, 126.8, 128.8, 128.9, 133.2, 135.8, 137.8,
140.5, 142.4, 174.3; MS m/z (%): 485 (M+, 15), 426 (19), 207
(8), 149 (26), 106 (9), 83 (100), 68 (37). Anal. (C24H24
-
INO2‚0.33H2O) C, H, N.
Rep r esen ta tive P r oced u r e for Su zu k i Cou p lin g (P r o-
ced u r e B): (1S,3S,6R,10S)-(Z)-9-[4-(4-Meth ylp h en yl)ben -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11c). To a mixture of the iodide 13 (42 mg,
0.103 mmol) and Pd(PPh3)4 (5.9 mg, 0.005 mmol) in 1.0 mL of
degassed toluene was added p-tolylboronic acid (15.3 mg, 0.113
mmol), followed by a solution of sodium carbonate (21.8 mg,
0.205 mmol) in 0.5 mL of water. After reflux at 110 °C for 31
h, the reaction mixture was cooled, diluted with CHCl3, and
washed with brine. The organic phase was separated and dried
over Na2SO4. The solvent was removed under reduced pres-
sure, and the residue was chromatographed on silica gel
(preparative TLC) using ethyl acetate/triethylamine (10/1) and
dichloromethane/methanol (95/5) as the eluents to provide the
Exp er im en ta l Section
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 ppm relative to internal TMS. Coupling constants
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. DMF (DriSolv) was ob-
tained from EM Science. Iodide 10a was obtained from the
corresponding bromide.46 2-Iodo-5-phenylthiophene (19) was
prepared from 2-phenylthiophene according to the reported
method.47 The key intermediates 13, 22, 26, and 2b were
synthesized based on previously reported procedures,31,32 while
the catalyst system was optimized with the ligand Ph3As
instead of (o-CH3C6H4)3P.
Rep r esen ta tive P r oced u r e for Ra d ica l Cycliza tion . A
solution of compound 8 (1.00 g, 4.88 mmol) in deoxygenated
anhydrous benzene (100 mL) was heated to 80 °C, and a
solution of tri-n-butylstannane (2.75 mL, 10.2 mmol) and AIBN
(824 mg, 4.92 mmol) in deoxygenated anhydrous benzene (50
mL) was then added via a syringe pump over 8 h. After stirring
at 80 °C for a further 15 h, the mixture was cooled to room
temperature and concentrated under reduced pressure. The
residue was then subjected to column chromatography with
hexanes/ethyl acetate (6/1 to 1/1) as the eluent to give the two
isomers of 9. (Z)-9 was used as the starting material to
synthesize the biaryl analogues.
desired product 11c as a white solid (19.0 mg, 50%). [R]25
D
+72.3° (c 0.92, CHCl3); 1H NMR (CDCl3): δ 1.42-1.60 (m, 3H),
2.02-2.30 (m, 3H), 2.39 (s, 3H), 2.44 (t, J ) 2.7 Hz, 1H), 2.74
(dd, J ) 3.0 and 5.7 Hz, 1H), 3.28-3.36 (m, 1H), 3.66 (s, 3H),
3.78-3.84 (m, 1H), 3.98 and 4.10 (ABq, J ) 18.6 Hz, both d
with J ) 2.4 Hz, 2H), 6.18 (t, J ) 2.7 Hz, 1H), 7.23 (d, J ) 8.4
Hz, 2H), 7.26 (d, J ) 8.4 Hz, 2H), 7.51 (d, J ) 8.4 Hz, 2H),
7.55 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3): δ 21.1, 31.9, 32.5,
36.5, 37.3, 48.3, 51.9, 52.3, 53.8, 56.3, 121.8, 126.7, 126.8, 127.3,
128.6, 128.8, 129.5, 131.9, 137.0, 137.8, 174.2; MS m/z (%): 373
(M+, 23), 314 (31), 277 (64), 199 (15), 156 (15), 83 (100), 68
(33), 51 (30). Anal. (C25H27NO2‚0.2HCl) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[4-(4-Ch lor op h en 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 (11d ). Procedure B was followed, giving the title
compound as an oil. [R]25 +85.4° (c 0.68, CHCl3); 1H NMR
D
(CDCl3): δ 1.44-1.58 (m, 3H), 2.05-2.28 (m, 3H), 2.43 (t, J )
3.3 Hz, 1H), 2.74 (dd, J ) 3.0 and 5.6 Hz, 1H), 3.26-3.34 (m,
1H), 3.66 (s, 3H), 3.78-3.82 (m, 1H), 3.95 and 4.08 (ABq, J )
18.9 Hz, both d with J ) 2.4 Hz, 2H), 6.17 (t, J ) 3.0 Hz, 1H),
7.27 (d, J ) 8.4 Hz, 2H), 7.39 (d, J ) 8.4 Hz, 2H), 7.51 (d, J )
8.4 Hz, 2H), 7.52 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3): δ
32.0, 32.6, 36.5, 37.4, 48.4, 51.9, 52.4, 53.7, 56.3, 121.5, 126.9,
128.1, 128.8, 128.9, 133.3, 136.8, 137.6, 139.1, 141.3, 174.3;
MS m/z (%): 393 (M+, 24), 334 (49), 265 (10), 215 (44), 202
Rep r esen ta tive P r oced u r e for Stille Cou p lin g (P r o-
ced u r e A): (1S,3S,6R,10S)-(Z)-9-[4-(4-Meth oxyp h en yl)-
ben zylid en e]-7-a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxy-
lic Acid Meth yl Ester (11a ). 4-Iodo-4′-methoxybiphenyl (10a )
(50.5 mg, 0.16 mmol), triphenylarsine (26.6 mg, 0.087 mmol),
Pd2(dba)3 (9.9 mg, 10.8 µmol), and CuI (16.5 mg, 0.087 mmol)

Biaryl Analogues of Constrained Tricyclic Tropanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 2003
(45), 189 (42), 165 (37), 149 (100), 141 (46), 115 (30), 108 (47).
Anal. (C24H24ClNO2‚0.25HCl) C, H, N.
NMR (CDCl3): δ 31.8, 32.4, 36.4, 37.2, 40.6, 48.2, 52.0, 52.3,
53.9, 56.3, 112.7, 122.2, 126.1, 127.5, 128.8, 132.0, 132.1, 134.9,
139.1, 149.9, 174.0; MS m/z (%): 403 (M+ + 1, 49), 402 (M+,
21), 344 (20), 320 (72), 262 (27), 235 (46), 201 (85), 171 (100),
165 (52), 150 (47), 130 (89), 117 (75), 105 (56). Anal.
(C26H30N2O2‚0.6HCl) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[4-(3-Ch lor op h en 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 (11e). Procedure B was followed, giving the title
compound as an oil. [R]25 +47.2° (c 1.20, CHCl3); 1H NMR
D
(CDCl3): δ 1.46-1.54 (m, 3H), 2.05-2.28 (m, 3H), 2.43 (t, J )
3.0 Hz, 1H), 2.73 (dd, J ) 2.7 and 5.6 Hz, 1H), 3.28-3.34 (m,
1H), 3.66 (s, 3H), 3.78-3.82 (m, 1H), 3.96 and 4.10 (ABq, J )
19.2 Hz, both d with J ) 2.4 Hz, 2H), 6.17 (t, J ) 2.7 Hz, 1H),
7.27 (d, J ) 8.7 Hz, 2H), 7.31 (d, J ) 7.5 Hz, 1H), 7.36 (dd, J
) 7.5 and 7.8 Hz, 1H), 7.47 (d, J ) 7.8 Hz, 1H), 7.53 (d, J )
8.4 Hz, 2H), 7.58 (s, 1H); 13C NMR (CDCl3): δ 32.0, 32.6, 36.5,
37.4, 48.4, 51.9, 52.4, 53.7, 56.3, 121.5, 125.0, 127.0, 127.2,
127.5, 128.9, 130.0, 134.7, 137.1, 137.4, 141.5, 142.5, 174.3;
MS m/z (%): 393 (M+, 13), 334 (34), 215 (28), 202 (30), 189
(28), 167 (34), 149 (100), 141 (51), 115 (30), 108 (48). Anal.
(C24H24ClNO2‚0.33H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[4-[4-(Tr iflu or om eth yl)ph en yl]ben -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11j). Procedure B was followed, giving the title
1
compound as a white solid. [R]25 +55.9° (c 0.32, CHCl3); H
D
NMR (CDCl3): δ 1.44-1.60 (m, 3H), 2.06-2.26 (m, 3H), 2.45
(t, J ) 3.0 Hz, 1H), 2.75 (dd, J ) 3.0 and 5.8 Hz, 1H), 3.26-
3.36 (m, 1H), 3.67 (s, 3H), 3.80-3.84 (m, 1H), 3.96 and 4.10
(ABq, J ) 18.0 Hz, both d with J ) 2.4 and 2.7 Hz, respectively,
2H), 6.19 (t, J ) 3.0 Hz, 1H), 7.29 (d, J ) 8.4 Hz, 2H), 7.57 (d,
J ) 8.7 Hz, 2H), 7.69 (br s, 4H); 13C NMR (CDCl3): δ 32.0,
32.6, 36.5, 37.4, 48.4, 51.9, 52.3, 53.7, 56.2, 121.4, 125.6, 125.7,
127.1, 127.2, 128.9, 130.1, 137.4, 141.9, 174.3 (CF3 and the
adjacent aromatic C not observed); MS m/z (%): 427 (M+, 52),
368 (100), 299 (18), 285 (24), 259 (43), 215 (42), 202 (36), 189
(39), 174 (64), 164 (66), 152 (46), 141 (60), 115 (42), 106 (46).
Anal. (C25H24F3NO2‚0.5H2O) C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-[4-(3,4-D ic h lo r o p h e n y l)b e n -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11f). Procedure B was followed, giving the title
1
compound as a white solid. [R]25 +80.6° (c 0.74, CHCl3); H
D
NMR (CDCl3): δ 1.42-1.58 (m, 3H), 2.04-2.28 (m, 3H), 2.43
(t, J ) 3.0 Hz, 1H), 2.73 (dd, J ) 2.7 and 5.7 Hz, 1H), 3.24-
3.34 (m, 1H), 3.66 (s, 3H), 3.78-3.82 (m, 1H), 3.95 and 4.07
(ABq, J ) 18.3 Hz, both d with J ) 2.4 and 2.7 Hz, respectively,
2H), 6.16 (t, J ) 2.7 Hz, 1H), 7.28 (d, J ) 8.4 Hz, 2H), 7.42
(dd, J ) 2.1 and 8.4 Hz, 1H), 7.49 (d, J ) 8.4 Hz, 2H), 7.51 (d,
J ) 8.4 Hz, 1H), 7.67 (d, J ) 2.1 Hz, 1H); 13C NMR (CDCl3):
δ 31.9, 32.5, 36.4, 37.4, 48.3, 51.9, 52.3, 53.7, 56.2, 121.3, 126.0,
126.9, 128.6, 128.9, 130.6, 131.2, 132.8, 136.2, 137.3, 140.6,
141.7, 174.2; MS m/z (%): 427 (M+, 12), 368 (34), 215 (33),
202 (29), 189 (41), 184 (35), 166 (49), 148 (100), 141 (63), 120
(41), 106 (48). Anal. (C24H23Cl2NO2‚0.1H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[4-(4-Cya n op h en 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 (11k ). Procedure B was followed, giving the title
compound as an oil. [R]25 +73.6° (c 0.37, CHCl3); 1H NMR
D
(CDCl3): δ 1.44-1.60 (m, 3H), 2.06-2.26 (m, 3H), 2.45 (t, J )
3.3 Hz, 1H), 2.74 (dd, J ) 3.3 and 5.8 Hz, 1H), 3.24-3.34 (m,
1H), 3.66 (s, 3H), 3.78-3.82 (m, 1H), 3.95 and 4.08 (ABq, J )
18.9 Hz, both d with J ) 2.4 and 2.7 Hz, respectively, 2H),
6.18 (t, J ) 3.0 Hz, 1H), 7.30 (d, J ) 8.1 Hz, 2H), 7.56 (d, J )
8.4 Hz, 2H), 7.68 (d, J ) 8.7 Hz, 2H), 7.72 (d, J ) 8.7 Hz, 2H);
13C NMR (CDCl3): δ 32.0, 32.6, 36.4, 37.4, 48.4, 51.9, 52.3,
53.7, 56.3, 110.7, 119.0, 121.3, 127.1, 127.4, 129.0, 132.6, 136.6,
137.9, 142.4, 145.1, 174.3; MS m/z (%): 384 (M+, 60), 325 (100),
256 (21), 242 (29), 227 (29), 216 (54), 192 (50), 162 (76), 152
(36), 141 (66), 115 (47), 106 (43). Anal. (C25H24N2O2‚2/3HCl)
C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-[4-(3,5-D ic h lo r o p h e n y l)b e n -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11g). Procedure B was followed, giving the title
compound as an oil. [R]25 +76.9° (c 0.38, CHCl3); 1H NMR
D
(CDCl3): δ 1.43-1.58 (m, 3H), 2.04-2.28 (m, 3H), 2.44 (t, J )
3.0 Hz, 1H), 2.73 (dd, J ) 2.7 and 5.6 Hz, 1H), 3.26-3.34 (m,
1H), 3.66 (s, 3H), 3.78-3.81 (m, 1H), 3.94 and 4.08 (ABq, J )
19.2 Hz, both d with J ) 2.4 Hz, 2H), 6.17 (t, J ) 2.7 Hz, 1H),
7.27 (d, J ) 8.4 Hz, 2H), 7.32 (dd, J ) 1.8 and 2.1 Hz, 1H),
7.45 (d, J ) 2.1 Hz, 2H), 7.51 (d, J ) 8.7 Hz, 2H); 13C NMR
(CDCl3): δ 32.0, 32.6, 36.5, 37.4, 48.4, 51.9, 52.3, 53.7, 56.3,
121.3, 125.3, 126.9, 127.0, 129.0, 135.3, 136.0, 137.7, 142.1,
143.7, 174.3; MS m/z (%): 427 (M+, 27), 368 (53), 215 (43),
202 (38), 189 (53), 184 (35), 166 (46), 148 (100), 141 (61), 120
(40), 108 (53), 106 (46). Anal. (C24H23Cl2NO2‚0.4HCl) C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-[4-(2,4-D ic h lo r o p h e n y l)b e n -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11h ). Procedure B was followed, giving the
title compound as an oil. [R]25D +79.4° (c 0.80, CHCl3); 1H NMR
(CDCl3): δ 1.42-1.59 (m, 3H), 2.04-2.26 (m, 3H), 2.43 (t, J )
3.3 Hz, 1H), 2.73 (dd, J ) 2.7 and 5.6 Hz, 1H), 3.26-3.34 (m,
1H), 3.67 (s, 3H), 3.78-3.82 (m, 1H), 3.94 and 4.08 (ABq, J )
18.9 Hz, both d with J ) 2.4 Hz, 2H), 6.18 (t, J ) 2.7 Hz, 1H),
7.24-7.29 (m, 4H), 7.37 (d, J ) 8.7 Hz, 2H), 7.48 (d, J ) 1.8
Hz, 1H); 13C NMR (CDCl3): δ 32.0, 32.6, 36.6, 37.4, 48.4, 51.9,
52.3, 53.7, 56.3, 121.5, 127.2, 128.1, 129.4, 129.7, 132.0, 133.2,
133.6, 136.0, 137.0, 138.7, 141.7, 174.3; MS m/z (%): 427 (M+,
7), 368 (11), 215 (31), 202 (24), 189 (36), 179 (12), 166 (26),
(1S ,3S ,6R ,10S )-(Z)-9-[4-(1-P yr r olyl)b 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
Ester (15). Procedure A was followed, giving the title com-
pound as an oil. [R]25D +68.3° (c 0.21, CHCl3); 1H NMR (CDCl3):
δ 1.45-1.58 (m, 3H), 2.02-2.28 (m, 3H), 2.43 (t, J ) 3.0 Hz,
1H), 2.72 (dd, J ) 3.0 and 5.7 Hz, 1H), 3.24-3.34 (m, 1H),
3.66 (s, 3H), 3.78-3.82 (m, 1H), 3.92 and 4.06 (ABq, J ) 19.5
Hz, both d with J ) 2.4 Hz, 2H), 6.14 (t, J ) 3.0 Hz, 1H), 6.34
(dd, J ) 2.1 and 2.4 Hz, 2H), 7.09 (dd, J ) 2.1 and 2.4 Hz,
2H), 7.24 (d, J ) 8.4 Hz, 2H), 7.35 (d, J ) 8.4 Hz, 2H); 13C
NMR (CDCl3): δ 32.0, 32.6, 36.5, 37.3, 48.3, 51.9, 52.3, 53.7,
56.3, 110.4, 119.2, 120.3, 121.1, 129.5, 135.6, 137.0, 157.6,
174.2; MS m/z (%): 348 (M+, 50), 289 (47), 220 (11), 206 (9),
180 (19), 152 (13), 144 (28), 115 (16), 83 (100), 68 (50), 41 (50).
Anal. (C22H24N2O2‚0.75HCl) C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-[4-(2-Th ie n yl)b 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
Ester (16a ). Procedure B was followed, giving the title
compound as a white solid. [R]25 +78.1° (c 0.80, CHCl3); H
1
D
NMR (CDCl3): δ 1.42-1.60 (m, 3H), 2.02-2.08 (m, 1H), 2.08-
2.30 (m, 2H), 2.45 (t, J ) 3.3 Hz, 1H), 2.74 (dd, J ) 2.7 and
5.6 Hz, 1H), 3.28-3.36 (m, 1H), 3.68 (s, 3H), 3.78-3.84 (m,
1H), 3.90 and 4.01 (ABq, J ) 18.9 Hz, both d with J ) 2.4 and
2.7 Hz, respectively, 2H), 6.16 (t, J ) 2.7 Hz, 1H), 7.10 (dd, J
) 3.6 and 3.3 Hz, 1H), 7.23 (d, J ) 8.1 Hz, 2H), 7.29 (d, J )
3.3 Hz, 1H), 7.33 (d, J ) 3.6 Hz, 1H), 7.59 (d, J ) 8.1 Hz, 2H);
13C NMR (CDCl3): δ 32.0, 32.6, 36.5, 37.4, 48.4, 51.9, 52.4,
53.7, 56.2, 121.5, 122.9, 124.7, 125.8, 126.8, 128.0, 128.8, 132.1,
136.6, 141.1, 174.3; MS m/z (%): 365 (M+, 28), 306 (29), 277
(6), 197 (9), 152 (21), 83 (100), 68 (36). Anal. (C22H23NO2S‚
0.2H2O) C, H, N.
148 (100), 141 (54), 120 (35), 108 (48), 106 (37). Anal. (C24H23
-
Cl2NO2‚0.5H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[4-[4-(Dim eth yla m in o)p h en yl]ben -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11i). Procedure B was followed, giving the title
compound as an oil. [R]25 +97.1° (c 0.18, CHCl3); 1H NMR
D
(CDCl3): δ 1.42-1.58 (m, 3H), 2.04-2.26 (m, 3H), 2.42 (t, J )
3.0 Hz, 1H), 2.72 (dd, J ) 2.7 and 5.6 Hz, 1H), 2.99 (s, 6H),
3.26-3.34 (m, 1H), 3.65 (s, 3H), 3.76-3.82 (m, 1H), 3.96 and
4.08 (ABq, J ) 18.0 Hz, both d with J ) 2.4 Hz, 2H), 6.15 (t,
J ) 3.0 Hz, 1H), 6.79 (d, J ) 8.7 Hz, 2H), 7.22 (d, J ) 8.4 Hz,
2H), 7.50 (d, J ) 8.4 Hz, 2H), 7.53 (d, J ) 8.7 Hz, 2H); 13C
(1S,3S,6R,10S)-(Z)-9-[4-(5-Meth yl-2-th ien yl)ben zyliden e]-
7-a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (16b). Procedure B was followed, giving the title
1
compound as a white solid. [R]25 +71.8° (c 0.55, CHCl3); H
D
NMR (CDCl3): δ 1.42-1.60 (m, 3H), 2.04-2.30 (m, 3H), 2.42

2004 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Zhou et al.
(t, J ) 3.0 Hz, 1H), 2.50 (s, 3H), 2.72 (dd, J ) 3.0 and 5.6 Hz,
1H), 3.24-3.34 (m, 1H), 3.65 (s, 3H), 3.78-3.82 (m, 1H), 3.92
and 4.06 (ABq, J ) 18.3 Hz, both d with J ) 2.4 and 2.7 Hz,
respectively, 2H), 6.12 (t, J ) 2.7 Hz, 1H), 6.18 (m, 1H), 7.09
(d, J ) 3.3 Hz, 1H), 7.18 (d, J ) 8.4 Hz, 2H), 7.50 (d, J ) 8.4
Hz, 2H); 13C NMR (CDCl3): δ 15.5, 32.0, 32.6, 36.5, 37.4, 48.4,
51.9, 52.4, 53.7, 56.2, 121.6, 122.7, 125.3, 126.2, 128.8, 132.5,
136.1, 139.4, 140.7, 141.7, 174.3; MS m/z (%): 379 (M+, 17),
320 (32), 237 (12), 211 (24), 187 (18), 160 (100), 152 (38), 141
(26), 118 (21), 106 (21). Anal. (C23H25NO2S‚1HCl‚0.75H2O) C,
H, N.
(1S ,3S ,6R ,10S )-(Z)-9-[4-(3-Th ie n yl)b 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
Ester (17). Procedure B was followed, giving the title com-
pound as a white solid. [R]25D +58.5° (c 0.43, CHCl3); 1H NMR
(CDCl3): δ 1.38-1.56 (m, 3H), 1.98-2.22 (m, 3H), 2.36 (t, J )
3.3 Hz, 1H), 2.66 (dd, J ) 2.7 and 5.7 Hz, 1H), 3.18-3.28 (m,
1H), 3.58 (s, 3H), 3.72-3.76 (m, 1H), 3.88 and 4.01 (ABq, J )
18.6 Hz, both d with J ) 2.1 and 2.4 Hz, respectively, 2H),
6.08 (t, J ) 2.7 Hz, 1H), 7.16 (d, J ) 8.4 Hz, 2H), 7.19 (d, J )
0.9 Hz, 1H), 7.32 (dd, J ) 2.4 and 0.9 Hz, 1H), 7.38 (dd, J )
2.4 and 0.9 Hz, 1H), 7.49 (d, J ) 8.4 Hz, 2H); 13C NMR
(CDCl3): δ 32.0, 32.6, 36.5, 37.4, 48.4, 51.9, 52.4, 53.8, 56.3,
120.1, 121.7, 126.2, 126.4, 128.8, 133.6, 136.3, 140.6, 141.9,
174.3; MS m/z (%): 365 (M+, 4), 307 (19), 223 (10), 197 (24),
173 (16), 165 (28), 153 (100), 141 (20), 115 (25), 106 (19). Anal.
(C22H23NO2S‚0.75HCl) C, H, N.
(1S ,3S ,6R ,10S )-(Z )-9-[4-(2-F u r y l)b e n z y li d e n e ]-7-
a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (18). Procedure B was followed, giving the title com-
pound as a white solid. [R]25D +53.1° (c 0.31, CHCl3); 1H NMR
(CDCl3): δ 1.48-1.62 (m, 3H), 2.08-2.38 (m, 3H), 2.45 (t, J )
3.0 Hz, 1H), 2.75 (dd, J ) 2.7 and 5.6 Hz, 1H), 3.36-3.44 (m,
1H), 3.68 (s, 3H), 3.86-3.94 (m, 1H), 4.01 and 4.22 (ABq, J )
14.1 Hz, both d with J ) 2.4 Hz, 2H), 6.16 (t, J ) 3.0 Hz, 1H),
6.49 (dd, J ) 1.8 and 3.3 Hz, 1H), 6.66 (dd, J ) 0.6 and 3.3
Hz, 1H), 7.22 (d, J ) 8.4 Hz, 2H), 7.48 (dd, J ) 0.6 and 1.8
Hz, 1H), 7.64 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3): δ 31.6,
32.3, 36.2, 37.2, 48.0, 52.0, 52.3, 53.8, 56.3, 105.0, 111.7, 122.3,
123.8, 128.4, 128.7, 131.9, 136.6, 142.1, 153.9, 174.3; MS m/z
(%): 349 (M+, 38), 290 (34), 277 (100), 199 (17), 183 (16), 152
(23), 83 (88), 68 (35). Anal. (C22H23NO3‚0.6H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[(5-P h en yl-2-th ien yl)m eth ylen e]-
7-a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (20). Procedure A was followed, giving the title com-
pound as a white solid. [R]25D +90.6° (c 0.29, CHCl3); 1H NMR
(CDCl3): δ 1.42-1.62 (m, 3H), 2.05-2.20 (m, 1H), 2.20-2.36
(m, 2H), 2.43 (t, J ) 3.3 Hz, 1H), 2.76 (dd, J ) 2.7 and 5.7 Hz,
1H), 3.40-3.45 (m, 1H), 3.59 (s, 3H), 3.80-3.86 (m, 1H), 3.96
(d, J ) 2.4 Hz, 2H), 6.31 (t, J ) 2.7 Hz, 1H), 6.79 (d, J ) 3.9
Hz, 1H), 7.15 (d, J ) 3.6 Hz, 1H), 7.20 (dd, J ) 7.5 and 6.9
Hz, 1H), 7.30 (dd, J ) 7.5 and 6.6 Hz, 2H), 7.51 (d, J ) 7.8
Hz, 2H); 13C NMR (CDCl3): δ 31.5, 32.1, 36.1, 36.4, 47.6, 52.1,
52.2, 53.6, 56.1, 115.7, 123.2, 125.6, 127.3, 127.4, 128.9, 134.2,
136.7, 139.8, 143.9, 173.6; MS m/z (%): 365 (M+, 15), 306 (11),
149 (9), 97 (14), 83 (100), 68 (31), 57 (46). Anal. (C22H23NO2S‚
0.2HCl) C, H, N.
(1S,3S,6R,10S)-(Z)-9-(3-Ch lor o-4-p h en 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 (27a ). Procedure B was followed, using iodide 26 as the
starting material and giving the title compound as an oil. [R]25
D
+73.8° (c 0.21, CHCl3); 1H NMR (CDCl3): δ 1.46-1.62 (m, 3H),
2.06-2.30 (m, 3H), 2.46 (t, J ) 3.0 Hz, 1H), 2.75 (dd, J ) 2.7
and 5.6 Hz, 1H), 3.26-3.38 (m, 1H), 3.70 (s, 3H), 3.76-3.84
(m, 1H), 3.96 and 4.10 (ABq, J ) 18.0 Hz, both d with J ) 2.4
Hz, 2H), 6.13 (t, J ) 2.4 Hz, 1H), 7.16 (dd, J ) 8.1 and 1.8 Hz,
1H), 7.29 (d, J ) 6.6 Hz, 1H), 7.33 (d, J ) 1.8 Hz, 1H), 7.36-
7.48 (m, 5H); 13C NMR (CDCl3): δ 32.0, 32.6, 36.4, 37.4, 48.3,
51.9, 52.3, 53.7, 56.3, 120.5, 126.7, 127.5, 128.0, 129.4, 129.7,
131.2, 132.4, 137.9, 138.0, 139.1, 142.9, 174.3; MS m/z (%): 393
(M+, 8), 334 (19), 149 (17), 91 (11), 83 (97), 68 (36), 44 (100).
Anal. (C24H24ClNO2) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[3-Ch lor o-4-(3,5-d ich lor op h en yl)-
ben zylid en e]-7-a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxy-
lic Acid Meth yl Ester (27b). Procedure B was followed, using
iodide 26 as the starting material and giving the title
compound as an oil. [R]25 +80.2° (c 0.19, CHCl3); 1H NMR
D
(CDCl3): δ 1.44-1.62 (m, 3H), 2.02-2.28 (m, 3H), 2.45 (t, J )
2.7 Hz, 1H), 2.72 (dd, J ) 5.6 and 2.7 Hz, 1H), 3.26-3.34 (m,
1H), 3.67 (s, 3H), 3.74-3.84 (m, 1H), 3.94 and 4.06 (ABq, J )
16.2 Hz, both d with J ) 2.4 Hz, 2H), 6.11 (t, J ) 2.7 Hz, 1H),
7.14 (dd, J ) 7.8 and 1.8 Hz, 1H), 7.24 (d, J ) 7.8 Hz, 1H),
7.27 (d, J ) 1.8 Hz, 1H), 7.30 (d, J ) 1.5 Hz, 1H), 7.31 (d, J )
1.8 Hz, 1H), 7.37 (dd, J ) 1.5 and 1.8 Hz, 1H); 13C NMR
(CDCl3): δ 32.0, 32.6, 36.3, 37.4, 48.3, 52.0, 52.2, 53.7, 56.3,
120.3, 125.4, 126.5, 126.8, 127.6, 128.0, 129.2, 129.8, 130.2,
130.9, 134.5, 141.8, 174.3; MS m/z (%): 461 (M+, 11), 402 (23),
314 (23), 249 (32), 215 (67), 202 (43), 189 (64), 165 (100), 148
(95), 141 (92), 120 (58), 106 (75). Anal. (C24H22Cl3NO2‚0.1HCl)
C, H, N.
(1S,3S,6R,10S)-(Z)-9-(4-Bip h en ylylm et h ylen e)-10-(h y-
d r oxym eth yl)-7-a za tr icyclo[4.3.1.03,7]d eca n e (28). To a
solution of 3 (34 mg, 0.0946 mmol) in 4 mL of THF was added
portionwise LiAlH4 (11 mg, 0.29 mmol), and the mixture was
stirred for 3 h. The reaction mixture was quenched with
concentrated Rochelle salt solution (15 mL) and extracted with
EtOAc (3 × 10 mL). The organic phase was washed with brine
(20 mL), dried over Na2SO4, and concentrated under reduced
pressure. The residue was chromatographed on silica gel using
ethyl acetate/triethylamine (10/1) as the eluent to afford
compound 28 as a white solid (29 mg, 92%). 1H NMR (CDCl3):
δ 1.48-1.68 (m, 3H), 2.02-2.38 (m, 3H), 2.44 (dd, J ) 5.6 and
2.7 Hz, 1H), 2.83 (dd, J ) 5.7 and 3.0 Hz, 1H), 3.28-3.32 (m,
2H), 3.32-3.54 (m, 2H), 3.88 and 4.02 (ABq, J ) 13.2 Hz, both
d with J ) 2.4 and 2.1 Hz, respectively, 2H), 6.25 (t, J ) 2.7
Hz, 1H), 7.26-7.33 (m, 3H), 7.38-7.43 (m, 2H), 7.57-7.62 (m,
4H); 13C NMR (CDCl3): δ 33.1, 33.6, 36.7, 38.3, 48.9, 50.1, 55.6,
59.8, 66.3, 123.5, 127.9, 128.0, 128.5, 130.0, 130.1, 137.9, 140.3,
141.0, 142.1; MS m/z (%): 331 (M+, 44), 314 (16), 300 (48),
205 (22), 191 (18), 178 (18), 165 (33), 149 (17). Anal. (C23H25
-
NO‚0.33H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-10-(Acetoxym eth yl)-9-(4-bip h en ylyl-
m eth ylen e)-7-a za tr icyclo[4.3.1.03,7]d eca n e (29). To a solu-
tion of the alcohol 28 (22 mg, 0.0664 mmol) in pyridine (2 mL)
and acetic anhydride (0.5 mL) was added DMAP (1 mg), and
the reaction mixture was stirred for 2 h. After removal of the
solvent under reduced pressure, the residue was dissolved in
20 mL of EtOAc and washed with a saturated solution of
NaHCO3 (2 × 10 mL). The organic phase was dried over Na2-
SO4 and concentrated under reduced pressure. The residue
was chromatographed on silica gel using ethyl acetate/triethy-
(1S,3S,6R,10S)-(Z)-9-[2-[5-(4-Meth oxyp h en yl)th ien yl]-
m et h ylen e]-7-a za t r icyclo[4.3.1.03,7]d eca n e-10-ca r b oxyl-
ic Acid Meth yl Ester (23). Procedure B was followed, using
iodide 22 as the starting material and giving the title
1
compound as a white solid. [R]25 +83.3° (c 0.23, CHCl3); H
D
NMR (CDCl3): δ 1.46-1.58 (m, 3H), 1.98-2.10 (m, 1H), 2.10-
2.32 (m, 2H), 2.42 (t, J ) 2.7 Hz, 1H), 2.72 (dd, J ) 2.7 and
5.6 Hz, 1H), 3.25-3.34 (m, 1H), 3.65 (s, 3H), 3.76-3.80 (m,
1H), 3.83 (s, 3H), 3.88 and 3.98 (ABq, J ) 18.6 Hz, both d with
J ) 2.4 and 2.7 Hz, respectively, 2H), 6.32 (t, J ) 2.7 Hz, 1H),
6.81 (d, J ) 3.6 Hz, 1H), 6.90 (d, J ) 8.4 Hz, 2H), 7.10 (d, J )
3.6 Hz, 1H), 7.62 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3): δ
32.0, 32.6, 36.5, 36.6, 48.5, 51.9, 52.3, 53.8, 55.3, 56.3, 114.3,
115.2, 122.1, 126.8, 126.9, 133.2, 139.4, 148.8, 148.9, 159.1,
174.1; MS m/z (%): 395 (M+, 48), 336 (30), 255 (24), 228 (23),
203 (28), 184 (28), 168 (100), 151 (47), 115 (32), 108 (26). Anal.
(C23H25NO3S‚0.1HCl) C, H, N.
lamine (10/1) as the eluent to give compound 29 as a white
1
solid (19.7 mg, 79%). [R]25 +167.0° (c 0.51, CHCl3); H NMR
D
(CDCl3): δ 1.42-1.60 (m, 3H), 1.74-1.84 (m, 1H), 2.05 (s, 3H),
2.02-2.28 (m, 3H), 2.38 (dd, J ) 5.6 and 2.7 Hz, 1H), 2.86
(dd, J ) 5.7 and 2.7 Hz, 1H), 3.28-3.36 (m, 1H), 3.92-4.08
(m, 4H), 6.18 (t, J ) 2.7 Hz, 1H), 7.28-7.36 (m, 3H), 7.41-
7.46 (m, 2H), 7.56-7.63 (m, 4H); 13C NMR (CDCl3): δ 20.9,
32.2, 32.8, 36.0, 37.2, 45.3, 48.7, 53.9, 58.2, 67.2, 122.0, 126.9,
127.1, 127.2, 128.8, 136.4, 138.8, 140.6, 140.9, 171.1; MS m/z

Biaryl Analogues of Constrained Tricyclic Tropanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 2005
(%): 373 (M+, 31), 314 (90), 300 (25), 191 (12), 165 (15), 149
(28), 83 (51), 68 (49), 43 (100). Anal. (C25H27NO2‚0.2H2O) C,
H, N.
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variations at the C-2 center provides compounds of subnano-
(1S,3S,6R,10S)-(Z)-10-(Ben zoyloxym eth yl)-9-[3-ch lor o-
4-(3,4-dich lor oph en yl)ben zyliden e]-7-azatr icyclo[4.3.1.03,7]-
d eca n e (31). Procedure B was followed, using iodide 2b as
the starting material and giving the title compound as an oil.
[R]25 +115.6° (c 0.66, CHCl3); 1H NMR (CDCl3): δ 1.48-1.68
D
(m, 3H), 1.92-2.02 (m, 1H), 2.06-2.28 (m, 3H), 2.49 (dd, J )
5.6 and 2.4 Hz, 1H), 2.97 (dd, J ) 5.7 and 2.4 Hz, 1H), 3.28-
3.38 (m, 1H), 3.96 and 4.06 (ABq, J ) 18.6 Hz, both d with J
) 2.7 Hz, 2H), 4.16-4.30 (m, 2H), 6.14 (t, J ) 2.7 Hz, 1H),
7.14 (dd, J ) 8.1 and 1.8 Hz, 1H), 7.25 (d, J ) 8.4 Hz, 1H),
7.31 (d, J ) 1.8 Hz, 1H), 7.41-7.60 (m, 6H), 7.64-7.71 (m,
1H), 8.02 (dd, J ) 8.4 and 1.5 Hz, 1H); 13C NMR (CDCl3): δ
32.2, 32.8, 36.3, 37.1, 45.4, 48.7, 53.9, 58.2, 67.3, 126.8, 128.4,
128.6, 128.9, 129.5, 129.8, 130.0, 130.1, 130.9, 131.3, 131.8,
131.9, 131.9, 132.0, 132.1, 132.2, 133.0, 138.7, 138.9, 143.7,
166.4; MS m/z (%): 537 (M+, 0.5), 416 (4), 277 (41), 199 (19),
183 (16), 155 (14), 152 (12), 105 (100). Anal. (C30H26Cl3NO2‚
0.8H2O) C, H, N.
Syn a p tosom a l Up ta k e of [3H]Dop a m in e, [3H]5-Hy-
d r oxytr yp ta m in e, a n d [3H]Nor ep in ep h r in e. Compounds
were tested as the free base. The effect of candidate compounds
in antagonizing biogenic amine high-affinity uptake was
determined as previously described.17f Striatum, midbrain, and
parietal/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 superna-
tant was centrifuged at 17 500g for 20 min. This P2 synapto-
somal 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). 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 concen-
tration). 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 What-
man 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.
Fluoxetine (10 µM) and desipramine (3 µM), respectively, 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. Even though uptake
is a nonequilibrium process, Ki determinations are thought to
be appropriate estimates of affinity between these compounds
and the biogenic amine transporters because it is likely that
the relatively long (45 min) period of incubation of the drug
before addition of the [3H] amine is adequate time for equi-
librium between the test compound and the biogenic amine
transporter to occur.
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. We thank Dr. Werner
Tueckmantel for proofreading of the manuscript.

2006 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Zhou et al.
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