Synthesis of dopamine transporter selective 3-{2-(diarylmethoxyethylidene)}-8-alkylaryl-8-azabicyclo[3.2.1]octanes

Article abstract of DOI:10.1016/S0960-894X(02)01051-X

A series of 3-{2-(diarylmethoxyethylidene)}-8-alkylaryl-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine and serotonin transporters. The 8-phenylpropyl analogues 8a (K_i=4.1 n

Full text of DOI:10.1016/S0960-894X(02)01051-X

Bioorganic & Medicinal Chemistry Letters 13 (2003) 629–632
Synthesis of Dopamine Transporter Selective
3-{2-(Diarylmethoxyethylidene)}-8-alkylaryl-8-
azabicyclo[3.2.1]octanes
Amy L. Bradley,a Sari Izenwasser,b Dean Wade,b Shaine Cararasa 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
Received 25 October 2002; accepted 25 November 2002
Abstract—A series of 3-{2-(diarylmethoxyethylidene)}-8-alkylaryl-8-azabicyclo[3.2.1]octanes was synthesized and the binding affi-
nities of the compounds were determined at the dopamine and serotonin transporters. The 8-phenylpropyl analogues 8a
(Ki=4.1 nM) and 8b (Ki=3.7 nM) were the most potent compounds of the series with binding affinities 3 times greater than GBR-
12909. In addition, 8a (SERT/DAT=327) was over 300-fold more selective for the dopamine transporter than the serotonin
transporter.
# 2003 Elsevier Science Ltd. All rights reserved.
The disubstituted piperazine GBR 12909 (1) is a selec-
tive high-affinity dopamine transporter ligand and
selective dopamine uptake inhibitor.1ꢀ3 Behavioral
studies with GBR 12909 and related derivatives have
shown potential for the development of an agonist-
based therapeutic agent for cocaine addiction. Although
GBR 12909 is self-administered,4 it has been shown to
suppress cocaine self-administration behavior in rhesus
monkeys,5 and exhibit non-stimulant properties in
humans.6ꢀ8
Because of the unique pharmacological activity of GBR
12909, it has served as a template for the synthesis of
high-affinity selective dopamine transporter ligands.9ꢀ18
From these studies it has been shown that the piper-
azine ring system is not required for high-affinity selec-
tive binding to the DAT. Novel piperidine-based and
tropane-based derivatives of 1 have been synthesized
and shown to possess moderate to high affinity for the
dopamine transporter (DAT) with improved selectivity
over the serotonin transporter (SERT).9
Recently, a GBR-benztropine hybrid analogue 2, was
reported by Rice and coworkers to be a potent and
selective DAT ligand.15 The pharmacological profile of
2 (DAT affinity, uptake inhibition and transporter
selectivity) was reported to be more like the GBR com-
pounds than benztropine. Therefore it was of interest to
further investigate the ethylidenyl-8-azabicyclo[3.2.1]-
octane ring system as a scaffold for the design of analo-
gues of GBR 12909. Herein, we wish to report the
synthesis, dopamine transporter and serotonin trans-
porter affinity of several 3-{2-(diarylmethoxyethyl-
idene)}-8-alkyl-aryl-8-azabicyclo[3.2.1]octanes.
As illustrated in Scheme 1, the synthesis of the target 3-
ethylidenyl-8-azabicyclo[3.2.1]octane ring system was
achieved conveniently from tropinone (3). The deme-
thylation/carbonylation of 3 with ethyl chloroformate
furnished the ethyl carbamate 4 in 95% yield. It was
*Corresponding author. Tel.: +1-504-280-7337; fax: +1-504-280-
6860; e-mail: mtrudell@uno.edu
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(02)01051-X

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A. L. Bradley et al. / Bioorg. Med. Chem. Lett. 13 (2003) 629–632
tropine analogues afforded the corresponding
benzhydryl ethers 7 in good yields (60–80%).20 The
carbamate group was removed with hydrazine hydrate
and the resulting amine was then alkylated with 3-phe-
nylpropyl bromide and benzyl bromide to afford the
desired 3-ethylidenyl-8-azabicyclo[3.2.1]octane analo-
gues 8 and 9.
In addition to the ethylidene analogues 8 and 9, a series
of the 3a-analogues 11–13 (Scheme 2) were also pre-
pared. The 3a-analogues were synthesized by hydro-
genation of the ester 5 over palladium on carbon to
afford the 3a-ester 10 in 90% yield as a single isomer
(Scheme 2). Subsequent conversion of 10 into the 3-{2-
(diarylmethoxyethyl)} - 8 - methyl - 8 - aza - bicyclo[3.2.1]
octanes (11) was achieved via a similar synthetic
sequence to that established above. However, the final
step of the synthesis, introduction of the N-methyl
group, was achieved by reduction of the carbamate
moiety with lithium aluminum hydride to give the N-
methyl analogue 11. The 3-{2-(diarylmethoxyethyl)}-8-
(3-phenylpropyl)-8-azabicyclo[3.2.1]octanes (12) and the
3-{2-(diarylmethoxyethyl)}-8-benzyl-8-aza-bicyclo[3.2.1]
octanes (13) were prepared from the ester 10 in similar
fashion to the ethylidene derivatives (Scheme 2).
Scheme 1. (i) ClCO2Et, K2CO3, toluene, Á; (ii) (CH3O)2-
POCH2CO2CH3, DBU, LiCl, CH3CN,ꢁ25 ꢁC; (iii) LiAlH4, THF, 0 ꢁC;
HOCH2CH2OH; (vi) RBr, K2CO3, DMF.
.
(iv) ClCH2CH2OCH(p-X-C6H4)2, 145 C; (v) NH2NH2 H2O, KOH,
The dopamine transporter (DAT) binding affinities and
the serotonin transporter (SERT) binding affinities were
determined for the GBR-analogues by their ability to
displace bound [3H]WIN 35,428 and [3H]citalopram
from rat caudate-putamen tissue.21,22 The Ki values that
are reported in Table 1, are inhibition constants derived
for the unlabeled ligands. In addition, the Ki value for
GBR 12909 (1) binding to DAT that was obtained
under identical conditions is reported for comparison.21
important to remove the methyl group early in the syn-
thetic sequence since preliminary studies had indicated
that demethylation of late intermediates was proble-
matic.19 Subsequent olefination of 4 with trimethylphos-
phoroacetate afforded the ethylidene ester 5 in 80%
yield. Selective reduction of the ester 5 with lithium
aluminum hydride gave the alcohol 6 in 86% yield. The
benzhydryl ether moiety was then introduced by heating
the corresponding substituted benzhydryl chloride and
the alcohol 6 neat at 145 ꢁC. This melt procedure ori-
ginally reported by Newman for the synthesis of benz-
Table 1. DAT and SERT binding affinities
Compda
X
Ki (nMꢂSEM)b
DAT
SERT
SERT/DAT
1
12ꢂ1.9c
4.1ꢂ0.6
3.7ꢂ0.4
48ꢂ5
35d
327
152
113
281
8a
8b
9a
9b
H
F
H
F
1340ꢂ230
562ꢂ200
5420ꢂ74
2220ꢂ740
7.9ꢂ0.5
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
13c
13d
14
H
F
Cl
Cl, H
H
F
Cl
Cl, H
H
F
Cl
Cl, H
F
58ꢂ9
31ꢂ3
14,100ꢂ200
2470ꢂ300
1160ꢂ140
3430ꢂ280
750ꢂ41
243
80
64
71
42
24
4
12
48
251
9
18ꢂ4
48ꢂ14
18ꢂ2
7.4ꢂ3
50ꢂ12
30ꢂ3
175ꢂ23
177ꢂ46
374ꢂ12
99ꢂ9
4780ꢂ190
1430ꢂ230
822ꢂ175
1940ꢂ345
651ꢂ7
5.7ꢂ1.4
91ꢂ16
82ꢂ11
20ꢂ5
24
33
27
15
F
30ꢂ6
809ꢂ110
aAll synthesized compounds were tested as the oxalate salt.
bAll values are the mean ꢂ SEM of three experiments performed in
triplicate.
Scheme 2. (i) H2, 10% Pd/C, CH3OH; (ii) LiAlH4, THF, 0 ꢁC; (iii)
ClCH2CH2OCH(p-X-C6H4)2, 145 ꢁC; (iv) LiAlH4, THF, 25 ꢁC; (v)
.
NH2NH2 H2O, KOH, HOCH2CH2OH; (vi) RBr, K2CO3, DMF.
cThe Ki value is reproduced from ref 21 and was collected under
identical conditions.
dThe SERT/DAT value is reproduced from ref 15.

A. L. Bradley et al. / Bioorg. Med. Chem. Lett. 13 (2003) 629–632
631
The ethylidene derivatives 8 and 9 were evaluated as
racemic mixtures15 and demonstrated high affinity for
the DAT. The N-phenylpropyl analogues 8a
(Ki=4.1 nM) and 8b (Ki=3.7 nM) were the most potent
compounds of this study. Both analogues were 4-fold
more potent at DAT than GBR 12909 (1).21 Although
direct comparison of the binding affinities of 8a and 8b
with 2 is not possible since the Ki-values were measured
in different assays, it is possible to indirectly compare
relative potencies based upon the binding affinities of
GBR 12909 in both assays. The N-methyl analogue 2
(Ki=19 nM) was reported to be 5-fold less potent than
GBR 12909 in the [125I]RTI-55 binding assay.15 There-
fore, the relative potency of the N-phenylpropyl ethyli-
denes 8a and 8b can be considered to be significantly
greater than the N-methyl analogue 2.
12 were generally more potent than the corresponding
N-methyl congeners. The difluoro derivative 12b
(Ki=7.4 nM) exhibited DAT potency equal to that of
the ethylidene derivative 8a. Only the dichloro analogue
12c (Ki=50 nM) was found to have diminished binding
affinity relative to the N-methyl derivatives.
The N-benzyl compounds 13 were generally found to
have diminished DAT binding affinity relative to the N-
phenylpropyl analogues and the ethylidene derivatives.
Only the difluoro derivative 13b (Ki=5.7 nM) possessed
high affinity for the DAT. In fact 13b was the most
potent compound of the 3a-analogues and was equipo-
tent with the ethylidene derivatives 8b and 9b.
Of the 3a-derivatives only the N-methyl analogue 11a
(SERT/DAT=243) and the N-benzyl analogue 13b
(SERT/DAT=251) exhibited transporter selectivity of a
similar magnitude to the ethylidene derivatives.
Although 11a was as selective for the DAT, the binding
affinity was 10-fold less than 8a and this was consistent
with previous results reported for this compound.15
However, 13b was as potent and selective as the corre-
sponding ethylidene derivative 9b. Moreover, 13b was 8-
fold more selective than the N-phenylpropyl congener
12b. The observed increase in selectivity of 13b over 12b
is believed to be due to the N-benzyl group. Dutta and
coworkers have reported similar SAR for GBR-related
piperidine derivatives.14,23,24 However, surprisingly the
DAT selectivity determined for 13b was not observed
for the desfluoro and chloro N-benzyl compounds
13a,c,d.
The ethylidene analogues also exhibited high selectivity
for binding at the DAT over the SERT, with 8a (SERT/
DAT=327) nearly 10-fold more selective than GBR
12909 (1). To our knowledge, 8a is one of the most
selective DAT ligands reported to date. The binding
affinities of the N-benzyl ethylidene detivatives 9 were
diminished relative to 8. The largest decrease was
observed for the desfluoro analogue 9a. However, it is
noteworthy that despite reduced DAT binding affinity
the difluoro analogue 9b (SERT/DAT=281) exhibited
high selectivity for the dopamine transporter over the
serotonin transporter.
The high potency and high DAT selectivity observed for
the ethylidene analogues prompted further investigation
of the corresponding saturated 3a-derivatives. Although
Rice and coworkers had previously reported on several
3a-tropane derivatives (11a, 11b, 12a and 12b),15 it was
felt that evaluation of these compounds as well as new
analogues along with the ethylidene derivatives in the
similar assays would permit a more accurate assessment
of the effect of unsaturation at C3 of the 3-ethylidenyl-
8-azabicyclo[3.2.1]octane ring system. For the N-methyl
3a-analogues 11, the dichloro derivative 11c
(Ki=18 nM) was determined to be the most potent
derivative albeit the least selective of the series (SERT/
DAT=64). The desfluoro and difluoro N-methyl 3a-
derivatives, 11a and 11b, exhibited moderate affinity at
DAT. The DAT and SERT binding affinities of 11a and
11b were consistent with the previously reported SAR.15
The binding affinities of the N-phenylpropyl derivatives
The high DAT affinity and selectivity observed for
the N-benzyl 3a-analogue 13b led to a brief investi-
gation of potentially less lipophilic analogues and
pro-drug precusors.11 The hydroxylated N-benzyl
derivatives 14 and 15 were prepared from 10 in
straightforward fashion (Scheme 3). The 300-OH com-
pound 14 and 400-OH compound 15 exhibited decreased
DAT binding affinity and increased SERT binding affi-
nity (Table 1) relative to 13b. As a result, the hydro-
xylated analogues 14 and 15 were much less selective for
the DAT than 13b.
Comparison of the racemic ethylidene derivatives 8 and
9 with the achiral 3a-derivatives 11–13 revealed that in
general sp2-hybridization of the C3-carbon atom
imparted greater binding affinity for the DAT while
decreasing affinity for SERT. The N-phenylpropyl ana-
logue 8a was the most selective compound of the study
and was nearly 10-fold more selective than the corre-
sponding 3a-analogue 12a. Consistent with the SAR of
the GBR-related compounds, the difluoro derivative 8b
was less selective than the desfluoro compound 8a but
was still 5-fold more selective than the corresponding
3a-derivative 12b.
Overall, the 3-{2-(diarylmethoxyethylidene)}-8-alky-
laryl-8-azabicyclo[3.2.1]octanes exhibited higher affinity
and selectivity for the DAT than GBR 12909 and most
related-analogues reported to date. It is evident that
3-ethylidenyl-8-azabicyclo-[3.2.1]octane ring system
Scheme 3. (i) H2, 10% Pd/C, CH3OH; (ii) LiAlH4, THF, 0 ꢁC; (iii)
ClCH2CH2OCH(p-F-C6H4)2, 145 ꢁC; (iv) NH2NH2 H2O, KOH,
.
HOCH2CH2OH; (v) HOC6H4CHO, NaBH(OAc)3, ClCH2CH2Cl, rt.

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A. L. Bradley et al. / Bioorg. Med. Chem. Lett. 13 (2003) 629–632
is an important structural feature of these com-
pounds for selective molecular recognition at the
DAT. While the N-benzyl group appeared to lead to
the DAT selective compound 13b in the 3a-series the
effect was not as significant in the 3-ethylidenyl-8-
azabicyclo[3.2.1]octane series. This suggests that the
observed SERT/DAT selectivity of 8 and 9 is due to
either a conformational effect of the rigid 3-ethylidenyl-
8-azabicyclo[3.2.1] octane ring system or a stereo-
chemical effect inherent to unsaturation at C3. Efforts
to resolve the 3-ethylidenyl-8-azabicyclo[3.2.1]octane
enantiomers are currently under investigation. The
results of this study and additional studies to further
elucidate the SAR of these compounds will be reported
in due course.
8. Sogaard, U.; Michalow, J.; Butler, B.; Lund Laursen, A.;
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Acknowledgements
16. Winfield, L.; Izenwasser, S.; Wade, D.; Trudell, M. L.
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The authors wish to thank the National Institute on
Drug Abuse for the financial support of this research,
DA11528 (M.L.T.) and DA05926 (A.L.B.).
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