1-Naphthyl and 4-indolyl arylalkylamines as selective monoamine reuptake inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.11.022

A series of enantiomerically pure 1-naphthyl and 4-indolyl arylalkylamines were prepared and evaluated for their binding affinities to the monoamine transporters. The two series of enantiomers displayed considerable differences in binding selectivity betw

Full text of DOI:10.1016/j.bmcl.2008.11.022

Bioorganic & Medicinal Chemistry Letters 19 (2009) 58–61
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1-Naphthyl and 4-indolyl arylalkylamines as selective monoamine
reuptake inhibitors
a,c,
James R. Manning a, Tammy Sexton b, Steven R. Childers b, , Huw M. L. Davies
*
*
a Department of Chemistry, University at Buffalo, The State University of New York, 1515 Dickey Road, Buffalo, NY 14260-3000, USA
b Department of Physiology/Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA
c Department of Chemistry, Emory University, Atlanta, GA 30322, 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 enantiomerically pure 1-naphthyl and 4-indolyl arylalkylamines were prepared and evaluated
for their binding affinities to the monoamine transporters. The two series of enantiomers displayed con-
siderable differences in binding selectivity between the monoamine transporters, leading to the design of
(S)-4-(3,4-dichlorophenyl)-4-(1H-indol-4-yl)-N-methylbutan-1-amine as a potent inhibitor for the dopa-
mine and serotonin transporters.
Received 10 September 2008
Revised 31 October 2008
Accepted 10 November 2008
Available online 13 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Monoamine transporters
Dopamine
Serotonin
Norepinephrine
C–H activation
Rhodium catalysis
Asymmetric synthesis
3-Aryloxy-3-arylpropanamines can be designed to be selective
monoamine reuptake inhibitors and have become one of the most
widely used classes of antidepressants. The most established mem-
ber of this class is the selective serotonin transporter (SERT) inhib-
itor, fluoxetine1 (1). More recently, it has been recognized that
compounds with different selectivities at the monoamine trans-
porters can also show beneficial antidepressant efficacy. A range
of newer analogs have been developed such as nisoxetine2 (2)
and atomoxetine3 (3) that are norepinephrine transporter (NET)
inhibitors and (+)-S-duloxetine4 (4), which is a mixed SERT/NET
inhibitor. In addition to the antidepressant utility of selective
monoamine transporter inhibitors, interest has been shown in
developing potential medications for cocaine addiction using long
acting dopamine transporter (DAT) inhibitors or less selective
monoamine transporter inhibitors.5 In many of the studies, the
use of bicyclic aromatic ring systems, particularly naphthyl, has re-
sulted in significantly more potent inhibitors than analogs contain-
ing a monocyclic aromatic ring6 (Table 1).
line,8 ritalin9 and venlafaxine.10 We have developed an effective
method for the synthesis of 1,1-diarylbutenoates, and due to our
interest in the incorporation of bicyclic aromatic rings into CNS
agents, we have extended the chemistry to the synthesis of 1-
naphthyl11 and 4-indolyl derivatives.12 The 4-indolyl system is
especially worth exploring because normally functionalization at
the 4-position in indoles is quite challenging.12 In this letter, we
use these transformations to generate enantioselectively 1-naph-
thyl and 4-indolyl arylalkylamines (5 and 6, Fig. 1) and demon-
strate that selective monoamine reuptake inhibitors can be
generated using these scaffolds.
The key step for the asymmetric synthesis of the 1-naphthyl
and 4-indolyl arylalkylamines is the combined C–H activation/
Cope rearrangement using 4-acetoxy-1,2-dihydronaphthalene (8)
or 4-acetoxy-6,7-dihydroindole (10) as substrates (Scheme 1). A
subsequent elimination of acetic acid generates directly 1,1-diaryl-
butenoates with very high asymmetric induction (>98% ee). In this
study, the second aryl group was chosen to be either 2-thiophenyl,
in analogy to the structure of duloxetine, and 3,4-dichlorophenyl,
which has been shown to be a useful pharmacophore for generat-
ing potent dopamine transporter inhibitors.5c,6a The reaction of the
aryldiazoacetate 9 with 8, catalyzed by the chiral dirhodium cata-
lyst Rh2(S-DOSP)4 generated a diarylbutenoate that was directly
hydrogenated with Wilkinson’s catalyst to form the butanoate
11b. A representative example of the synthesis of 11 is shown in
Scheme 1. In this case of the 2-thiophenyl derivative the reaction
For some time, we have been engaged in a research program di-
rected towards the development of novel asymmetric methods for
the synthesis of the most common classes of monoamine reuptake
inhibitors. These have included 3b-aryltropanes,6c,e 4-arylindan-
amines,7 as well as commercial therapeutic agents, such as sertra-
* Corresponding authors.
E-mail address: hmdavie@emory.edu (H.M.L. Davies).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.022

J. R. Manning et al. / Bioorg. Med. Chem. Lett. 19 (2009) 58–61
59
Table 1
Ar
NHMe
Ar
NHMe
n
Monoamine transporter binding affinities of 1–4
n
N
H
S
6
5
O
N
H
Figure 1. 1-Naphthyl and 4-indolyl derivatives (5 and 6).
O
N
H
O
N
O
N
H
H
OMe
Me
is best conducted with the 5-bromothiophenylvinyldiazoacetate 7
followed by removal of the bromine during the hydrogenation by
using a more reactive catalyst, palladium on charcoal, to form
the butanoate 11a. Similar reactions starting from 10 generated
the indole derivatives 12a and 12b. The opposite enantiomeric ser-
ies of 11–12 (ent-11–12) were obtained by conducting the first
reactions with Rh2(R-DOSP)4 as catalyst.13
The resulting diarylbutenoates 11a,b and 12a,b were readily
converted to diarylalkylamines 13–16a,b using standard synthetic
methods as illustrated in Scheme 2. The diarylpropylamines 13a,b
CF3
1 (Fluoxetine)
2 (Nisoxetine)
SERT Ki (nM)
4 (
S
-Duloxetine)
3 (Atomoxetine)
NET Ki (nM)
Compound
DAT IC50 (nM)
( )-1
( )-2
( )-3
S-4
48
2000
6
4
16
16
6000
—
2000
370
660
277
1500
4.6
R-4
8.8
OAc
1.
CO2Me
S
N2
8
Rh2(S-DOSP)4
CO2Me
S
2. H2 (45 psi)
Pd/C, NaOAc
7
Br
11a
64% yield
>98% ee
Cl
OAc
Cl
1.
CO2Me
N2
8
Cl
Cl
Rh2(S-DOSP)4
CO2Me
2. H2 (45 psi)
RhCl(PPh3)3
11b
9
78% yield
>98% ee
OAc
1.
CO2Me
N
S
N2
10
Boc
Rh2(S-DOSP)4
CO2Me
S
N
2. H2 (45 psi)
Pd/C, NaOAc
Boc
12a
7
Br
73% yield
>98% ee
Cl
OAc
1.
Cl
CO2Me
N2
N
10
Boc
Cl
Cl
Rh2(S-DOSP)4
CO2Me
N
2. H2 (45 psi)
RhCl(PPh3)3
Boc
12b
9
43% yield
>98% ee
Scheme 1. Asymmetric synthesis of naphth-1-ylbutanoates and indol-4-ylbutanoates 11–12.

60
J. R. Manning et al. / Bioorg. Med. Chem. Lett. 19 (2009) 58–61
and 15a,b were obtained by using a Curtius rearrangement14 to de-
H
N
HCl
Ar
Ar
CO2Me
crease the carbon chain, while the diarylbutylamines 14a,b and
16a,b, were obtained by a reductive amination procedure.15 The
enantiomeric series of these eight compounds, ent-13–16a,b,
was also prepared.
a, b, c, d, e
The 16 diarylalkylamine derivatives were evaluated for their
binding affinities at the three monoamine transporters.16 A consid-
erable difference was seen between the 2-thiophenyl- (entries 1–
8) and the 3,4-dichlorophenyl series (entries 9–16). In the case of
the naphthyl-thiophenyl alkylamines, the DAT binding was not
very strong (230–466 nM) and not especially influenced by which
enantiomer was bound. The binding affinities were also not greatly
influenced by the tether length as the diarylpropylamines were
roughly equipotent to the diarylbutylamines (compare entries 1
and 2 with entries 3 and 4). In contrast, the enantiomers had sig-
nificantly different SERT and NET binding affinities in which 13a
and 14a had the greatest binding affinity for SERT (12.1 and
9.3 nM, respectively), while the enantiomers ent-13a and ent-
14a have the greatest binding affinities to NET (52.1 and
7.92 nM, respectively). Consequently 13a and 14a are moderately
selective for SERT (by a factor of about 10) while ent-13a has
roughly equal binding affinities towards both SERT and NET and
ent-14a is moderately selective for NET. In the case of the indolyl
thiophenylalkylamines 15a and 16a, the selectivity trends were
slightly different as the ent series (ent-15a and ent-16a) was 2–
14 times more potent a binder than the enantiomeric series at all
of the transporters (entries 5–8) Table 2.
11a,b
13a,b
Ar
Ar
Ar
HCl
Ar
Ar
Ar
CO2Me
N
H
d, f, g, e
a, h, d, e
i, j, g, k, e
11a,b
12a,b
12a,b
14a,b
15a,b
16a,b
H
CO2Me
N
HCl
N
N
H
Boc
HCl
CO2Me
N
H
N
N
H
Boc
Scheme 2. Synthesis of 13–16. Reagents and condition: (a) LiOH, THF/H2O; (b)
DPPA, Et3N, CH3CN; H3Oþ; (c) ClCO2Me, K2CO3, DCM/H2O; (d) LAH, THF; (e) 1.0 M
HCl in Et2O; (f) PCC, DCM; (g) Ti(OiPr)4, MeNH2; NaBH4; (h) DPPA, Et3N, CH3CN;
MeOH; (i) DIBAL-H, THF; (j) for Ar = thiophen-2-yl, Dess–Martin; for Ar = 3,4-
dichlorophenyl, f; (k) for Ar = thiophen-2-yl, d; for Ar = 3,4-dichlorophenyl, TFA.
The 3,4-dichlorophenyl moiety is well known to enhance bind-
ing to the dopamine transporter5c,6a and this was very much the
trend that was observed in entries 9–16. In the case of the 3,4-
dichlorophenyl naphthyl series 13b and 14b, the NET binding
Table 2
Monoamine transporter binding affinities of compounds 13–16
a
Entry
Structure
Compound
n
SERT Kia (nM)
NET Kia (nM)
DAT IC50 (nM)
1
2
3
4
13a
Ent-13a
14a
1
1
2
2
12.1 ( 2.3)
30.2 ( 8.6)
9.5 ( 1.7)
39.7 ( 6.2)
139 ( 20)
52.1 ( 6.8)
109 ( 10)
7.9 ( 1.1)
230 ( 27)
309 ( 26)
405 ( 40)
466 ( 69)
H
N
HCl
n
S
Ent-14a
H
N
HCl
5
6
7
8
15a
Ent-15a
16a
1
1
2
2
166 ( 15)
31.9 ( 3.6)
271 ( 70)
72.9 ( 7.9)
102 ( 23)
13.8 ( 2.5)
79.7 ( 8.5)
9.0 ( 1.6)
572 ( 103)
292 ( 89)
957 ( 85)
318 ( 43)
n
S
Ent-16a
N
H
Cl
Cl
H
N
HCl
9
13b
Ent-13b
14b
1
1
2
2
86 ( 25)
1630 ( 240)
1640 ( 320)
>10000
35.8 ( 4.5)
9.7 ( 1.3)
209 ( 41.0)
61.2 ( 6.9)
10
11
12
5.3 ( 1.7)
49.9 ( 6.9)
4.1 ( 1.8)
n
n
Ent-14b
2480 ( 590)
Cl
Cl
H
N
HCl
13
14
15
16
15b
Ent-15b
16b
1
1
2
2
3.63 ( 0.41)
1.68 ( 0.18)
2.72 ( 0.51)
0.82 ( 0.31)
35.4 ( 1.9)
95 ( 12)
360 ( 96)
4840 ( 540)
14.9 ( 0.77)
7.21 ( 0.53)
14.3 ( 3.6)
3.8 ( 1.2)
Ent-16b
N
H
a
Values are means of three experiments, standard deviation is given in parentheses.

J. R. Manning et al. / Bioorg. Med. Chem. Lett. 19 (2009) 58–61
61
11. Davies, H. M. L.; Yang, J.; Manning, J. R. Tetrahedron: Asymmetry 2006, 17, 665.
12. Davies, H. M. L.; Manning, J. R. J. Am. Chem. Soc. 2006, 128, 1060.
13. The absolute stereochemistry of the naphthyl series was assigned by analogy
to a compound that was used in the formal synthesis of sertraline.11 The
absolute stereochemistry of the indole series was assigned by analogy to a
compound whose absolute stereochemistry was determined by X-ray
crystallography.12
14. Sasmal, S.; Geyer, A.; Maier, M. E. J. Org. Chem. 2002, 67, 6260.
15. Kumpaty, H. J.; Williamson, J. S.; Bhattacharyya, S. Synth. Commun. 2003, 33,
1411.
16. Transporter binding studies: Affinities of analogs at dopamine transport sites are
determined by displacement of [125I]RTI-55 binding in membranes from rat
striatum.17 Frozen brains from Sprague–Dawley rats are obtained
commercially and striata are dissected on ice. Tissue is homogenized in
10 vol of RTI-55 assay buffer (0.32 M sucrose, 10 mM sodium phosphate buffer,
pH 7.4) with a Polytron, and centrifuged three times at 48,000g for 10 min,
with fresh buffer resuspension for each centrifugation. Assay tubes contain
0.5 mg (original wet weight) of membranes, 0.01 nM [125I]RTI-55, and various
concentrations of unlabeled drugs dissolved in RTI-55 assay buffer in a final
volume of 2 ml. Tubes are incubated for 50 min at 25 °C, and the reaction is
terminated by rapid filtration with 3ꢀ 5 ml of cold Tris buffer through
Whatman GF/B glass fiber filters pre-soaked in Tris buffer containing 0.1% BSA
was not influenced by the enantiomers but for DAT and SERT, the
ent series was considerably more potent (about 3–4 times more
potent at DAT and 12–16 times more potent at SERT. The trends
were slightly different for the 3,4-dichlorophenyl indolyl alkyla-
mine series because the ent series was most potent for DAT and
SERT binding while the opposite is seen for NET binding. As a con-
sequence of these trends, ent-16b has strong binding to DAT and
SERT (3.83 and 0.815 nM, respectively) and a 1000-fold selectivity
compared to the NET binding affinity.
In summary these studies illustrate the subtle differences in
selectivities between enantiomeric series for binding to the mono-
amine transporters. The 4-substituted indoles, 15 and 16, repre-
sent an interesting series of compounds because they are
relatively potent and contain a substitution pattern that has not
been previously greatly explored.
Acknowledgments
for at least 1 h. Non-specific binding is determined in the presence of 1 lM WF-
23.Affinities of analogs at 5-HT transport sites are determined by displacement
of [3H]citalopram binding in membranes from rat frontal cortex.18 Tissue is
obtained from frozen rat brains as described above, homogenized in 10 vol of
citalopram assay buffer (50 mM Tris–HCl, 120 mM NaCl, 5 mM KCl, pH 7.4)
with a Polytron, and centrifuged two times at 48,000g for 10 min, with fresh
buffer resuspension for each centrifugation. Assay tubes contain 50 mg
(original wet weight) of membranes, 0.4 nM [3H]citalopram, and various
concentrations of unlabeled drugs dissolved in citalopram assay buffer in a
final volume of 2 ml. Tubes are incubated for 60 min at 25 °C, and the reaction
is terminated by rapid filtration with 3ꢀ 4 ml of cold Tris buffer through
Whatman GF/B glass fiber filters pre-soaked in Tris buffer containing 0.1% BSA
This work was partially supported by Grants DA-06634 and DA-
15225 from the National Institute on Drug Abuse. J.R.M. thanks the
National Institutes of Health for a Ruth L. Kirschstein predoctoral
fellowship (DA-019287).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.11.022.
for at least 1 h. Non-specific binding is determined in the presence of 10 lM
fluoxetine.Binding of analogs at NE transport sites is determined by
displacement of [3H]nisoxetine binding.19 Whole rat brains (minus
cerebellum) are homogenized in 30 vol of 120 mM NaCl, 5 mM KCl, 50 mM
Tris–HCl, pH 7.4, and centrifuged at 48,000g for 10 min. The membranes are
resuspended in nisoxetine assay buffer (300 mM NaCl, 5 mM KCl, 50 mM Tris–
HCl, pH 7.4) and centrifuged again before final resuspension in volumes of
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(0.7 nM) together with unlabeled drugs dissolved in nisoxetine assay buffer
to a final volume of 1 ml. Tubes are incubated for 40 min at 25 °C, and the
reaction is terminated by rapid filtration with 3ꢀ 4 ml of cold Tris buffer
through Whatman GF/B glass fiber filters which have been pre-soaked in Tris
buffer containing 0.1% BSA for at least 1 h. Non-specific binding is determined
in the presence of 1 lM desipramine.In [3H]citalopram and [3H]nisoxetine
binding assays, radioactivity is determined by liquid scintillation
spectrophotometry (efficiency: 50%) after eluting filters overnight in 5 ml of
Ecolite scintillation fluid (ICN). IC50 values are calculated from displacement
curves using 7–10 concentrations of unlabeled analogs. Because binding of
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[3H]paroxetine and [3H]nisoxetine binding assays, Ki values are calculated
using the Cheng–Prusoff equation.21 All data are mean values SEM of at least
three separate experiments, each of which is conducted in triplicate.
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