Synthesis and monoamine transporter affinity of 3α-arylmethoxy-3β-arylnortropanes

Article abstract of DOI:10.1016/j.bmcl.2009.10.087

A series of 3-arylnortrop-2-enes and 3α-arylmethoxy-3β-arylnortropanes were synthesized and evaluated for binding affinity at monoamine transporters. The 3-(3,4-dichlorophenyl)nortrop-2-ene (6e) exhibited high affinity for the SERT (K_i = 0.3 nM

Full text of DOI:10.1016/j.bmcl.2009.10.087

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6865–6868
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and monoamine transporter affinity of
-arylmethoxy-3b-arylnortropanes
3a
Harneet Kaur a, Sari Izenwasser b, Abha Verma a, Dean Wade b, Amy Housman b, Edwin D. Stevens a,
David L. Mobley a, Mark L. Trudell a,
*
a Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
b Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-arylnortrop-2-enes and 3a-arylmethoxy-3b-arylnortropanes were synthesized and evalu-
Received 21 September 2009
Revised 16 October 2009
Accepted 20 October 2009
Available online 23 October 2009
ated for binding affinity at monoamine transporters. The 3-(3,4-dichlorophenyl)nortrop-2-ene (6e)
exhibited high affinity for the SERT (Ki = 0.3 nM). The 3 -arylmethoxy-3b-arylnortropanes were generally
SERT selective with the 3 -(3.4-dichlorophenylmethoxy)-3bphenylnortrop-2-ene (7c) possessing subn-
anomolar potency (Ki = 0.061 nM). However, 3 -(3,4-dichlorophenylmethoxy)-3b-phenylnortrop-2-ene
a
a
a
(7b) exhibited high affinity at all three transporters [(DAT Ki = 22 nM), (SERT Ki = 6 nM) and (NET
Ki = 101 nM)].
Keywords:
Monoamine transporters
Neurotransmitters
Dopamine
Ó 2009 Elsevier Ltd. All rights reserved.
Serotonin
Norepinephrine
Tropanes
Monoaminetransportershavebeentherapeutic targetsfora vari-
ety of neurological diseases and disorders. Drug development strat-
egies have focused upon central nervous system (CNS) monoamine
transporter selective agents. This approach has been highly success-
ful for the development of medications for the treatment of depres-
sion.1,2 Selective serotoninreuptakeinhibitors(SSRIs, e.g., fluoxetine
and paroxetine)3 as well as selective norepinephrine reuptake
inhibitors (SNRIs, e.g., reboxetine)4,5 have been widely prescribed
for patients suffering from this common psychiatric disorder. In
addition, dopamine selective uptake inhibitors have been targets
for the development of therapeutics for cocaine addiction.6–8
Over the past decade, the rationale for the development of new
pharmacotherapies has expanded to target compounds that exhibit
efficacy at multiple monoamine transporter systems. The dual
serotonin/norepinephrine reuptake inhibitors (SNRIs, e.g., venla-
faxine and duloxetine) have been widely accepted as more effica-
cious than SSRIs for the treatment of depression with reduced
side effects.9,10 More recently, pharmacological evidence suggests
that triple monoamine uptake inhibitors (TUIs), targeting dopa-
mine transporters (DAT) as well as serotonin transporters (SERT)
and norepinephrine transporters (NET) may be even more effica-
cious and exhibit improved safety profiles as antidepressants.11
The prototypical TUI, DOV 216,303 was found to be both safe
and effective in Phase II clinical studies on depression.12,13 In addi-
tion to therapeutics for depression, there is increasing evidence
that the reinforcing effects of cocaine may in part be mediated
by the SERT.14–16 In lieu of these findings, dual DAT/SERT uptake
inhibitors have become viable pharmacological targets for cocaine
addiction (Fig. 1).17,18
F
O
CF3
O
OCH2CH3
O
O
O
O
N
N
H
N
H
H
Fluoxetine
Paroxetine
Reboxetine
Cl
Cl
S
O
OH
NH
N
H
N
H
OCH3
DOV 216,303
Duloxetine
Venlafaxine
* Corresponding author. Tel.: +1 504 280 7337.
E-mail address: mtrudell@uno.edu (M.L. Trudell).
Figure 1. Monoamine transporter reuptake inhibitors.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.087

6866
H. Kaur et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6865–6868
Our efforts to develop novel molecular scaffolds targeting
CO2Et
N
monoamine transporter systems have led to the development of
several classes of selective DAT ligands and selective SERT ligands.
There have been numerous studies that have shown that 3-aryltro-
pane derivatives exhibit high affinity and selectivity for the DAT.7,8
More recently, we have reported on a series of piperidine deriva-
tives that exhibit potent and selective affinity for the SERT.19,20 Gi-
ven the somewhat similar structural characteristics of these two
classes of molecules it was of interest to explore the possibility
N
ii
i
O
O
2
3
CO2Et
N
CO2Et
N
iii
of merging the two pharmacophores to develop
monoamine transporter ligands that would have unique profile
of multiple transporter affinity. To this end, the 3 -arylmethoxy-
3b-aryltropane pharmacophore (1) was envisaged. The pharmaco-
phore 1 was designed not only to incorporate the main skeletal
features of the DAT selective tropanes and the SERT selective piper-
idines, but the arylmethoxy moiety common to many of the proto-
typical SSRIs and SNRIs also was envisaged to be an important
structural feature for molecular recognition at monoamine
transporters. Herein we describe the synthesis and monoamine
a class of
X
a
X
OH
5a X = H
4a X = H
4b X = F
4c X = Cl
4d X = CF3
4e X = 3,4-Cl2
5b X = F
5c X = Cl
5d X = CF3
5e X = 3,4-Cl2
iv
v, iv
transporter affinities of a series 3
derivatives (Fig. 2).
a-arylmethoxy-3b-aryl-tropane
H
N
H
N
As illustrated in Scheme 1, the syntheses of the target com-
pounds were envisaged to proceed from commercially available
tropinone (2). Conversion of 2 into the carbamate 3 was achieved
in a traditional fashion using ethyl chloroformate.21,22 The prepa-
ration of 3 was necessary to reduce the basicity and nucleophilic-
ity of the nitrogen atom. This served to facilitate subsequent
chromatography as well as provide a chemical handle for manip-
ulation of potential nitrogen substituents. Introduction of the
substituted 3-aryl group was achieved by addition of a preformed
aryl lithium reagent to the ketone moiety of 3. Initially, a mixture
of the desired alcohol 4 along with the alkene 5 was obtained in
low yields. The formation of the alkene 5 was the result of the
dehydration of 4 that occurred during the acidic work-up. To
minimize this dehydration side-reaction, the work-up was per-
formed under weakly acidic conditions [10% NH4Cl (aq)] at cold
temperatures (5–10 °C). This afforded the alcohols 4 in good
yields (40–65%). Although we were confident that the addition
the aryl ring occurred from the less hindered b-face of the tropi-
none skeleton,22 the relative stereochemistry was confirmed
unequivocally by X-ray crystallography.23 As illustrated in Figure
3 for 4a, the 3-phenyl moiety was shown to occupy the 3b-pseu-
X
X
7
6a X = H
O
6b X = F
6c X = Cl
6d X = CF3
6e X = 3,4-Cl2
Y
Scheme 1. Reagents and conditions: (i) ClCO2Et, K2CO3, toluene, reflux; (ii) X–
C6H4Br, n-BuLi, THF, À78 °C; (iii) TFA, CH2Cl2; (iv) KOH, NH2NH2ÁH2O, HOCH2-
CH2OH, reflux; (v) NaH, DMF, Y–C6H4CH2Br, rt.
do equatorial position and the hydroxy group was in the 3
do axial position.
a-pseu-
The ease in which the alcohols 4 were dehydrated prompted us
to divert our attention toward the synthesis of a series of 3-aryl-
nortrop-2-ene derivatives 6. It was envisaged that these rigid al-
kenes might have
transporters to that of the DOV 216,303. The alkenes 5 could be
a similar binding motif at monoamine
Figure 3. X-ray crystal structure of 4a.
R1
N
R2
X
R1
H
N
N
DAT selective
R1
Ar
O
X
R1
N
O
Y
1
X
SSRI/SNRI
Y
R2
SERT selective
Figure 2. Proposed pharmacophore of novel monoamine uptake inhibitors.

H. Kaur et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6865–6868
6867
Table 1
Monoamine transporter affinity and selectivity.
H
N
H
N
X
X
6
7
O
Y
Compda
Code
X
Y
DAT (Ki, nM)b
SERT (Ki, nM)b
NET (Ki, nM)b
DAT/SERT
NET/DAT
NET/SERT
6a
6b
6c
6d
6e
7a
7b
7c
7e
7f
HK3-203
HK3-245
HK3-241
HK3-267
HK3-263
HK2-151
HK3-77
HK3-45
HK3-87
HK3-35
HK3-135
HK3-105
HK3-119
HK3-49
Cocaine
H
F
Cl
CF3
3,4-Cl2
H
H
H
Cl
Cl
Cl
CF3
3,4-Cl2
3,4-Cl2
1222 87
1056 201
231 14
1494 246
16 1.7
176 26
129 22
2.8 1.0
1.8 0.3
0.30 0.10
247 27
6.1 0.5
0.061 0.024
65 25
0.10 0.02
8.5 1.8
534 34
62 15
1289 54
1989 268
120 41
777 96
20 4.6
NT
6.9
8.2
83
830
53
0.47
3.6
258
2.7
630
46
1.1
1.9
0.52
1.9
1.3
7.3
1.5
43
432
67
H
Cl
3,4-Cl2
H
Cl
3,4-Cl2
H
H
117 19
22
16
8
1
101
0
4.6
62
10
17
16,300
26
23,700
246
10
20
543
11
996 53
1718 18
172 70
63
7
2370 367
2093 1210
5435 2570
1232 438
2552 326
3192 877
38
7g
7h
7i
390 28
1390 141
716 52
2930 70
237 33
5.4
3.9
1.7
0.87
12
2.6
11
601
0.83
7j
3,4-Cl2
4.7 0.3
286 38c
a
b
c
All compounds were tested as the oxalate salts. NT: Not tested.
All values are the mean SEM of three experiments preformed in triplicate.
Value taken from Ref. 26.
prepared directly from the crude reaction mixtures containing 4,
by stirring the concentrated residues in dichloromethane contain-
ing 1 equiv of trifluoroacetic acid. This furnished the alkenes 5 in
good overall yields ranging from 35% to 60%. Since many of the po-
tent monoamine uptake inhibitors (SSRIs, SNRIs and TUIs) possess
a NH moiety, it was determined that the tropane nitrogen atom
would be converted into a secondary amine as well. Hydrazine
mediated removal of the carbamate moiety gave the ( )-3-arylnor-
trop-2-enes 6 in 85–95% yield.
SERT ligand of the series was 7c (SERT Ki = 0.061 nM), which also
exhibited the highest affinity for the DAT (DAT Ki = 16 nM) of the
series. However, despite the high DAT and SERT affinity of 7c, the
dichloro derivative 7f was the most SERT selective ligand with
DAT/SERT = 630 and NET/SERT = 23,700. It is noteworthy that the
mono chloro derivative 7b exhibited good affinity for all three
monoamine transporters. Despite being somewhat SERT selective,
7b exhibited transporter selectivity that is similar to other re-
ported monoamine TUIs.11,12
To complete the synthesis of an initial series of target com-
pounds for biological evaluation, the alcohols 4 were alkylated
with a variety of substituted benzyl bromides to afford the corre-
In comparing the two classes of compounds 6 and 7, it is inter-
esting to note that the structure–activity relationships of the aryl
group of the rigid tropene 6 are more closely aligned with the
sponding 3a-arylmethoxy derivatives. Subsequent removal of the
3a-arylmethoxy group of 7 than the 3b-aryl group. This is most
carbamate protecting group gave the target secondary amines 7.
Binding affinities for the dopamine, serotonin and norepineph-
rine transporters were determined by the ability of the drug to dis-
place the radiolabeled ligands [3H]WIN 35,428, [3H]citalopram,
and [3H]nisoxetine, respectively, from the monoamine transporters
in rat brain tissue using previously reported assays.19,20,24 The
binding affinities of all compounds listed in Table 1 were initially
determined for the DAT and SERT. The compounds that exhibited
either DAT or SERT binding affinities with Ki values <100 nM were
then evaluated at norepinephrine transporters to determine a
monoamine transporter selectivity profile. The monoamine trans-
porter binding affinities of the 3-arylnortrop-2-enes 6 were consis-
tent with a previous report that described the SERT selectivity of a
series of 3-aryltrop-2-ene derivatives.25 The nortropenes 6 exhib-
ited selectivity for SERT over both DAT and NET. The 3,4-dichloro
congener 6e (SERT Ki = 0.3 nM) was the most potent of the nortrop-
enes at SERT. However, 6e was not the most SERT selective nortro-
pene of the series (e.g., 6d). In fact, 6e exhibited high affinity at all
three monoamine transporters with DAT and NET affinities nearly
equipotent (NET/DAT = 1.3).
evident when comparing the effects of the 3,4-dichlorophenyl moi-
ety on SERT affinity of 6e with that of 7c and 7i. When the 3,4-
dichlorophenyl moiety occupies the 3a-position (7c), the SERT
affinity is high but when the 3,4-dichlorophenyl moiety occupies
the 3b-position (7i), SERT affinity is significantly reduced. This
trend is also evident for the mono chloro derivatives 6c, 7b and
7e. For predicted favorable solvated conformers of 6e, 7c and 7i
(Fig. 4)27 the alignment of the 3
a-arylmethoxy group of 7c with
the aryl group of 6e is similar for the boat conformer, while there
is no overlap between these two aryl moieties for the chair con-
former. This suggests that it is the boat conformer of 7c that exhib-
its high affinity for the SERT.
The 3a-arylmethoxy-3b-arylnortropanes 7 were found to exhi-
bit some similar trends in transporter affinity to those of the nor-
tropenes 6. As expected the congeners 7 were generally SERT
selective and exhibited high affinity for SERT. The most potent
Figure 4. Superimposed predicted favorable solvated conformers of 6e (red), 7c
(blue) and 7i (yellow).

6868
H. Kaur et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6865–6868
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the unsubstituted 3b-phenyl derivatives 7a–7c, exhibited good to
high affinity for DAT. However, substitution of the 3b-aryl moiety
afforded compounds with diminished affinity at the DAT. Finally,
only the monochloro congener 7b exhibited good NET binding
affinity suggesting that the target pharmacophore 1 may be predis-
posed toward the development of dual DAT/SERT selective ligands.
In conclusion, we have synthesized a novel class of monoamine
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transporter ligands. In general, the 3a-arylmethoxy-3b-arylnortro-
panes 7 exhibited potent affinity and high selectivity for the SERT.
However, several derivatives were found to have good affinity for
the DAT as well, and the chloro congener 7b exhibited high affinity
at all three transporters. Based upon this preliminary study, the
3a-arylmethoxy-3b-aryl-nortropane scaffold seems to be well sui-
ted for the development of new compounds that display a broad
spectrum of monoamine transporter selectivity.
Acknowledgments
18. Jin, C.; Navarro, H. A.; Carroll, F. I. J. Med. Chem. 2008, 51, 8048.
19. Lomenzo, S. A.; Rhoden, J. B.; Izenwasser, S.; Wade, D.; Kopajtic, T.; Katz, J. B.;
Trudell, M. L. J. Med. Chem. 2005, 48, 1336.
20. Rhoden, J.; Bouvet, M.; Izenwasser, S.; Wade, D.; Lomenzo, S. A.; Trudell, M. L.
Bioorg. Med. Chem. 2005, 13, 5623.
21. Bradley, A. L.; Izenwasser, S.; Wade, D.; Klein-Stevens, C.; Zhu, N.; Trudell, M. L.
Bioorg. Med. Chem. Lett. 2002, 12, 2387.
22. Paul, N. M.; Taylor, M.; Kumar, R.; Deschamps, J. R.; Luedtke, R. R.; Newman, A.
H. J. Med. Chem. 2008, 51, 6095.
We thank Dr. Amy Hauck Newman at the NIDA Intramural Re-
search Program, Baltimore, Maryland for the assistance provided to
Harneet Kaur in the aftermath of Hurricane Katrina. This research
was supported by the National Institute on Drug Abuse
(DA11528) and the Louisiana Optical Network Initiative Institute
(DLM), supported by the Louisiana Board of Regents Post-Katrina
Support Fund Initiative grant LEQSF(2007-12)-ENH-PKSFI-PRS-01.
23. CCDC 748234 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
24. Zhang, S.; Izenwasser, S.; Wade, D.; Xu, L.; Trudell, M. L. Bioorg. Med. Chem.
2006, 14, 7943.
Supplementary data
25. Krunic, A.; Mariappan, S.; Reith, M. E. A.; Dunn, W. J. Bioorg. Med. Chem. Lett.
2005, 15, 5488.
26. Kulkarni, S. S.; Grundt, P.; Kopajtic, T.; Katz, J. L.; Newman, A. H. J. Med. Chem.
2004, 47, 3388.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.10.087.
27. Structures in Figure 4 were generated using OpenEye Scientific Software’s
Omega for conformers and OEChem for shape overlays, and the images were
generated with PyMol (Delano Scientific LLC).
References and notes
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