Synthesis and dopamine transporter binding affinities of 3α-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes

Article abstract of DOI:10.1016/S0960-894X(02)00464-X

A series of 3α-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine transporter. The unsubstituted analogue 7b (K_i=98 nM) was the most potent compou

Full text of DOI:10.1016/S0960-894X(02)00464-X

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2387–2390
Synthesis and Dopamine Transporter Binding Affinities of
3ꢀ-Benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes
Amy L. Bradley,a Sari Izenwasser,b Dean Wade,b Cheryl Klein-Stevens,c
Naijue Zhuc and Mark L. Trudella,*
aDepartment of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
bDepartment of Psychiatry, University of Miami School of Medicine, Miami, FL 33136, USA
cDepartment of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA
Received 14 March 2002; accepted 24 May 2002
Abstract—A series of 3a-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the
compounds were determined at the dopamine transporter. The unsubstituted analogue 7b (Ki=98 nM) was the most potent com-
pound of the series with binding affinity three-times greater than cocaine and only 5-fold less than GBR-12909. The structure–
activity data for 7a–f suggests that these compounds may be binding at the dopamine transporter in a similar fashion to GBR
12909. # 2002 Elsevier Science Ltd. All rights reserved.
The search for new therapeutic agents for the treatment
of cocaine (1) addiction has led to the study of a number
of structurally unique compounds with varied pharma-
cological profiles.1,2 Although a cocaine antagonist has
yet to be identified, it has been hypothesized that com-
pounds that exhibit high affinity for the dopamine
transporter (DAT) yet have weak agonist activity may
be useful in an agonist-based pharmacotherapy.2,3 The
disubstituted piperazine, GBR 12909 (2) is a selective
high-affinity dopamine transporter ligand.4À6 Studies
have shown that GBR 12909 (2) dissociates very slowly
from the dopamine transporter and attenuates the
increase in the level of extracellular dopamine induced
by cocaine (1).3,7 Although GBR 12909 (2) is self-admin-
istered,8 it has been shown to block cocaine self-admin-
istration behavior in rhesus monkeys,9 and exhibits
non-stimulant properties in humans.7,10,11
It has been demonstrated that the piperidine derivative
3 possessed high affinity for DAT while the benzyl
analogue 4 exhibited high affinity and increased selec-
tivity over serotonin transporters.12,13 However, the
piperidine isomer 5 was found to exhibit significantly
decreased binding affinity.12 More recently it has been
shown that the benztropine-like analogues 6 were found
to exhibit selective high affinity binding with reduced
muscarinic receptor affinity.21
The high binding affinity observed for the tropane ana-
logues 6 is consistent with the structural similarities
between 2 and 3. However, it was of interest to further
investigate the SAR of this class of compounds to
determine whether an isomeric tropane-like analogue
would exhibit a SAR similar to that of the GBR-like
piperidine analogues (4 and 5).
The unique pharmacological activity of 2 has prompted
numerous studies of the structure–activity relationships
(SAR) of disubstituted piperazines and related dis-
ubstituted piperidines in search of high affinity DAT
selective ligands (Fig. 1).12À22 From these studies it has
been shown that the piperazine ring system is not
required for high affinity selective binding to the DAT.
Alternatively, it was envisaged that a tropane-like ana-
logues of compounds 3 and 4 could exhibit binding affinity
more closely aligned with that of the 3a-phenyl tropanes,
a potent class of DAT uptake inhibitors.23 Herein, we
wish to report the synthesis and dopamine transporter
affinity of a series of novel 3a-benzyl-8-(diaryl-methoxy-
ethyl)-8-azabicyclo-[3.2.1]octanes (7a–f).
As illustrated in Scheme 1, the synthesis of the tropane-
like analogues 7 was achieved in straightforward fashion
from 3-tropinone (8). Demethylation of 8 afforded the
*Corresponding author. Tel.: +1-504-280-7337; fax: +1-504-280-
6860; e-mail: mtrudell@uno.edu
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00464-X

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A. L. Bradley et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2387–2390
Figure 1. Cocaine and GBR 12909-related analogues.
ethyl bromides 13a–e were prepared in similar fashion to
procedures previously reported in the literature.4,12 How-
ever, the di(p-methoxyphenyl)-methoxyethyl bromide 13f
was prepared using Williamson conditions (Scheme 2) due
to the apparent lability of the dimethoxybenzhydrol
moiety under acidic conditions.24 The relative stereo-
chemistry of the 3a-benzyl-8-diarylmethoxyethyl-8-aza-
bicyclo[3.2.1]octanes was unequivocally established by
X-ray crystallographic analysis of the oxalate salt of 7a.25
The dopamine transporter (DAT) binding affinity was
determined for the 3a-benzyltropanes 7 by their ability
to displace bound [3H]WIN 35,428 from rat caudate-
putamen tissue.26 The Ki values that are reported in
Table 1, are inhibition constants derived for the unlabeled
ligands. In addition, the Ki values for cocaine (1) and
GBR 12909 (2) that were obtained under similar condi-
tions are reported for comparison.26
The binding affinities at the dopamine transporter of
the 3a-benzyl-8-diaryl-methoxyethyl-8-azabicyclo-[3.2.1]
octanes 7a–f were generally found to be more potent
than cocaine (1) but were 10-fold less potent than GBR-
12909 (2). The most potent analogue of the series was
the unsubsituted compound 7b (Ki=98 nM). This was
somewhat surprising since it has been shown in numer-
ous studies of GBR-related compounds that the
difluoro-analogues usually exhibit comparable binding
affinities (withinÆSEM) for a series of derivatives.4,12,13,21
The least potent derivative was the dichloro compound 7c
(Ki=346 nM). It was noteworthy that the mono-chloro
Scheme 1. (i) ClCO2Et, K2CO3, toluene, reflux. (ii) KH,
C6H5CH2PO(OCH3)2, DMF, 25 ꢀC. (iii) H2, 10% Pd/C, HCl, i-PrOH.
(iv) TMSI, CHCl3. (v) BrCH2CH2OCH(p-X-C6H4)(p-Y-C6H4) (13a–f)
K2CO3, DMF, 50 ꢀC.
Table 1. In vitro binding affinity of 7a–f at the dopamine transporter
ethyl carbonate 9 which was followed by Horner–
Wadsworth–Emmons olefination to provide the benzyl-
idene 10 in 55% overall yield. Hydrogenation of 10 over
10% palladium on carbon furnished the 3a-benzyl-
tropane 11 stereoselectively in 60% yield. Removal of
the ethyl carbamate was achieved with trimethylsilyl
iodide in chloroform to afford the amine 12. Con-
comitant addition of 2-di(p-fluorophenyl)-methoxyethyl
bromide (13a) furnished the tropane-like analogue 7a in
42% overall yield.
Compda
X
Y
Ki (nM)b
1
2
187Æ19c
12Æ31c
144Æ25
98Æ5
7a
7b
7c
7d
7e
7f
F
H
Cl
CH3
H
CH3O
F
H
Cl
CH3
Cl
CH3O
346Æ50
217Æ20
198Æ20
135Æ15
aAll new compounds were tested as the oxalate salt.
bAll values are the mean ÆSEM of three experiments performed in
In addition to the difluorophenyl analogue 7a, a series of
substituted benzhydrol derivatives (7b–f) was prepared in
good yield (Scheme 1). The required 2-di(aryl)methoxy-
triplicate.
cThe Ki values are reproduced from ref 26 and were collected under
identical conditions.

A. L. Bradley et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2387–2390
2389
and the phenyl ring (molecular topology) may be more
important for high affinity binding than the position of
the nitrogen atom. Studies to further elucidate the SAR
of these and related compounds are currently under
investigation and will be reported in due course.
Scheme 2. (i) SOCl2, reflux. (ii) BrCH2CH2OH, K2CO3, benzene.
Acknowledgements
analogue 7e (Ki=198 nM) exhibited intermediate binding
affinity relative to 7b and 7c.
The authors wish to thank the National Institute on
Drug Abuse for the financial support of this research,
DA11528 (MLT) and DA05926 (ALB).
A significant feature of the SAR of compounds 7a–f is the
relative order of binding affinities. For the disubstituted
compounds, the order from most potent to least was
H>F >OCH3 >CH3 >Cl. This trend is similar to that
observed for the GBR piperazine derivatives.4 This
suggests that 3a-benzyl-8-(diaryl-methoxyethyl)-8-aza-
bicyclo[3.2.1]-octanes 7a–f bind to the DAT in a similar
fashion to GBR 12909 (2). Moreover, the equipotent
affinity of the dimethoxy analogue 7f (Ki=135 nM) is in
contrast to the effect of the dimethoxy substitution
reported in the benztropine system (Ki=2000 nM).27
References and Notes
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However, the most striking aspect of this SAR is the
similar potency of 7b relative to the tropane isomer 14
(Ki=99Æ9 nM)28 recently prepared in our laboratories
(Fig. 2). This is quite different than the 23-fold decrease
in binding affinity reported for the piperidine derivative
5 (Ki=595 nM) relative to its isomer 3 (Ki=25 nM).12
The high binding affinity of 7b suggests that the tropane
ring system may be a critical feature for molecular
recognition of these compounds at DAT. The rigid tro-
pane system may hold the diaryl moiety and the phenyl
ring in a conformation suited for high affinity binding.
The proper spatial orientation of the diaryl moiety and
the phenyl ring may overcome the positional effect of
the nitrogen atom observed in the piperidine ana-
logues.12 Similar structural effects have been reported
for the phenyltropanes. The 3-phenyl-oxatropane and
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In summary, the 3a-benzyl-8-(diarylmethoxyethyl)-8-
azabicyclo[3.2.1]octanes 7a–f appear to bind in similar
fashion to GBR 12909 and related analogues at the
dopamine transporter but different than derivatives of
benztropine . The high-binding affinity observed for 7b
suggests that the relative positions of the diaryl moiety
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Figure 2. 3a-(2-Benzhydryloxyethyl)-8-benzyl-8-azabicyclo-[3.2.1]octane
(14).

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A. L. Bradley et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2387–2390
24. Winfield, L.; Trudell, M. L. Unpublished results.
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with the Cambridge Crystallographic Data Center. The coor-
dinates can be obtained upon request from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EB, UK.
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W. D.; Vilner, B. J.; Katz, J. L.; Newman, A. H. J. Med.
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