3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters

Article abstract of DOI:10.1016/j.bmcl.2013.05.071

A series of 3-aryl-3-arylmethoxy-azetidines were synthesized and evaluated for binding affinities at dopamine and serotonin transporters. The 3-aryl-3-arylmethoxyazetidines were generally SERT selective with the dichloro substituted congener 7c (K_i = 1.0 nM) and the tetrachloro substituted derivative 7i (K_i = 1.3 nM) possessing low nanomolar affinity for the SERT. The 3-(3,4-dichlorophenyl-3-phenylmethoxyazetidine (7g) exhibited moderate affinity at both DAT and SERT transporters and suggests that substitution of the aryl rings can be used to tune the mononamine transporter affinity.

Full text of DOI:10.1016/j.bmcl.2013.05.071

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4404–4407
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands
for monoamine transporters
Amber Thaxton a, Sari Izenwasser b, Dean Wade b, Edwin D. Stevens a, David L. Mobley c, Vivian Jaber a,
Stacey A. Lomenzo 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
c Department of Pharmaceutical Sciences, University of California-Irvine, Irvine, CA 92697, 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-aryl-3-arylmethoxy-azetidines were synthesized and evaluated for binding affinities at
dopamine and serotonin transporters. The 3-aryl-3-arylmethoxyazetidines were generally SERT selective
with the dichloro substituted congener 7c (Ki = 1.0 nM) and the tetrachloro substituted derivative 7i
(Ki = 1.3 nM) possessing low nanomolar affinity for the SERT. The 3-(3,4-dichlorophenyl-3-phen-
ylmethoxyazetidine (7g) exhibited moderate affinity at both DAT and SERT transporters and suggests
that substitution of the aryl rings can be used to tune the mononamine transporter affinity.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 3 April 2013
Revised 15 May 2013
Accepted 20 May 2013
Available online 29 May 2013
Keywords:
Azetidines
Serotonin transporters
Dopamine transporters
To date there are no pharmacological therapies for psychostim-
ulant-dependence or the adverse side effects associated with crav-
medications capable of restoring dopaminergic and serotonergic
tone to disrupted neuronal systems. In this vein, both releaser-type
drugs or uptake inhibitors could be developed.5,6 To date, dopa-
mine/norepinephrine uptake inhibitors (e.g., buproprion, methyl-
phenidate), SSRIs (e.g., fluoxetine, paraoxetine) and SNRIs (e.g.,
duloxetine) and NRIs (e.g., reboxetine) have been widely pre-
scribed for depression, ADHD and obesity and have good safety re-
cords.7–11 This would suggest that a dual uptake inhibitor could be
a promising pharmacological target for the treatment of psycho-
stimulant addiction.
Our efforts to develop novel molecular scaffolds targeting mono-
amine transporter systems have led to the discovery of the 3a-aryl-
methoxy-3b-aryltropanes (1) as a unique class of monoamine
transporter ligands that possess tunable affinity for dopamine and
serotonin transporters.12 This has prompted a broader examination
of the structure-activity relationships of this molecular scaffold in
ing and withdrawal.
A variety of medications have been
investigated as potential treatment strategies, however, none have
been identified as having significant promise.1 The failure of these
drugs to be effective may be due to the limited scope of action, tar-
geting single monoaminergic systems. To date there is mounting
evidence that in addition to dopaminergic systems, brain seroto-
nergic systems also modulate responses in psychostimulant-in-
duced behaviors.2–4 A single dopaminergic or serotonergic agent
may not adequately attenuate the behavioral effects associated
with psychostimulant abuse. It has been suggested by Rothman
and co-workers that the development of an appropriately cali-
brated dual acting DAT/SERT agent may be more effective as a
medication than an agent selective for a single transporter.5 This
model of psychostimulant addiction suggests that drug-induced
dopamine and serotonin dysfunction contribute to the withdrawal
symptoms, drug craving, and relapse. The model further postulates
that decreased levels of synaptic dopamine during stimulant with-
drawal are the source of anhedonia and psychomotor retardation.
Moreover, decreased levels of synaptic serotonin results in depres-
sion, obsession, and lack of impulse control. Based upon this ratio-
nale, it should be possible to treat stimulant addicts that exhibit
depleted synaptic levels of dopamine and serotonin with
⇑
Corresponding author. Tel.: +1 504 280 7337; fax: +1 504 280 6860.
E-mail address: mtrudell@uno.edu (M.L. Trudell).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.05.071

A. Thaxton et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4404–4407
4405
search of compounds with dual affinity for dopamine and serotonin
transporters. It was of interest to explore condensed ring systems
that would accommodate the pharmacophore requirements while
reducing the overall molecular weight and lipophilicity inherent
to the tropane derivatives. To this end, we identified the 3-aryl-
methoxy-3-arylazetidines (2) as viable targets for synthesis and
biological evaluation at monoamine transporters.
The azetidine ring system has recently become an attractive
molecular scaffold for the development of CNS active com-
pounds.13 Preliminary computational studies revealed that the
replacement of the tropane ring system with an azetidine scaffold
would lead to significant decrease in molecular weight and lipo-
philicity (cLogP values, Table 1).14 In addition, superposition of
the of predicted favorable solvated conformers of
1 and 2
(Fig. 1)15 suggested that the azetidine scaffold would lead to a
favorable alignment of the major structural elements of the two
compounds.
As illustrated in Scheme 1, the syntheses of a series of chlori-
nated target compounds were achieved from commercially avail-
able N-Boc-3-azetidinone (3). The chlorinated derivatives were
selected as initial targets since the corresponding tropane ana-
logues (1a–c, Table 1) had demonstrated a broad range of DAT/
SERT selectivity. Introduction of the substituted 3-aryl group was
achieved by addition of a preformed aryl lithium reagent to the ke-
tone moiety of 3.16 To minimize degradation the azetidine ring the
work-up was performed under weakly acidic conditions [10%
NH4Cl (aq.)] at cold temperatures (5–10 °C). This afforded the alco-
hols 4 in high yields (86–94%).
To complete the synthesis of the initial series of target com-
pounds, the alcohols 4 were alkylated with a variety of substituted
benzyl bromides using phase-transfer conditions to furnish the
N-Boc-3-arylmethoxy-3-aryl-azetidines (5). Typically the azeti-
dines 5 were not isolated and purified but rather converted into
the 3-arylmethoxy-3-arylazetidine hydrochloride salts 6 or the
N-methyl-3-arylmethoxy-3-arylazetidine salts 7. Treatment of 5
with 2 M HCl in EtOAc at room temperature afforded the
corresponding hydrochloride salts 6 in 21–64% overall yield.
Alternatively, the N-methyl derivatives 7 were prepared in
18–55% overall yield by heating 5 with 1 M lithium aluminum
Figure 1. Superimposed predicted favorable solvated conformers of 1 (green) and 2
(cyan).
hydride in THF at 65 °C. After work-up with Glauber’s salt the
N-methyl derivatives were treated with 2 M HCl in EtOAc at room
temperature to give the hydrochloride salts. In general, we found
that direct conversion of the azetidine bases to the hydrochloride
salts gave stable solid compounds. In the few exceptions that solid
hydrochloride salts were not formed, the acidic oils were treated
with sodium carbonate solution and the resulting azetidine free
base was converted into the oxalate salt. Many of the salts gave
crystalline compounds which allowed the structure to be
confirmed unequivocally by X-ray crystallography (Fig. 2, 6a).17
Binding affinities for the dopamine and serotonin transporters
were determined by the ability of the drug to displace the radiola-
beled ligands [3H]WIN 35,428 and [3H]citalopram, respectively,
from the monoamine transporters in rat brain tissue using
previously reported assays.18 The monoamine transporter binding
Table 1
Monoamine transporter affinity and selectivity
Cmpda
Code
R1
R2
R3
cLogPb
DATc (Ki, nM)
SERTc (Ki, nM)
DAT/SERT
1ad
1bd
1cd
6a
6be
6ce
6d
6e
6f
6g
6h
6i
7a
7b
7c
HK2–151
HK3–77
HK3–45
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
3.67
4.27
4.87
3.02
3.63
4.23
3.63
4.23
4.83
4.23
4.83
5.44
3.40
4.01
4.61
4.01
4.61
5.22
4.61
5.22
5.82
117 19
22 8.0
16 1.0
247 27
6.1 0.50
0.061 0.024
1230 70
2590 20
7.3 0.70
825 8.0
3.5 0.20
8.1 3.2
208 8.0
2.9 0.30
4.2 0.30
73 9.4
4.0 0.3
1.0 0.20
39 7.0
7.8 3.3
3.0 1.1
23 1.6
0.47
3.6
258
4.0
1.4
390
3.9
1100
470
6.3
1000
870
24
980
1210
36
490
330
27
4-Cl
3,4-Cl2
H
4-Cl
34-Cl2
H
4-Cl
3,4-Cl2
H
4-Cl
3,4-Cl2
H
4-Cl
3,4-Cl2
H
4-Cl
3,4-Cl2
H
ANT-I-35
ANT-I-74
ANT-I-57
ANT-I-129
ANT-I-87
ANT-I-92
ANT-I-110
ANT-I-126
ANT-I-108
ANT-I-47
ANT-I-73
ANT-I-72
ANT-I-85
ANT-I-84
ANT-I-125
ANT-I-133
ANT-I-124
ANT-I-106
4860 450
3610 25
2820 110
3180 360
3830 42
3770 320
1300 86
3020 340
3670 30
1730 320
3910 280
1210 69
1410 107
2030 600
976 61
4-Cl
4-Cl
4-Cl
3,4-Cl2
3,4-Cl2
3,4-Cl2
H
H
H
7d
7e
7f
7g
7h
7i
4-Cl
4-Cl
4-Cl
3,4-Cl2
3,4-Cl2
3,4-Cl2
620 140
2290 513
436 66
4-Cl
3,4-Cl2
4.8 2.2
1.3 0.0
630
340
a
b
c
Compounds were tested as the hydrochloride salts unless otherwise noted.
See Ref. 13.
All values are the mean SEM of three experiments preformed in triplicate.
Data taken from Ref. 12.
d
e
Compound was tested as the oxalate salt.

4406
A. Thaxton et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4404–4407
of N-methyl 3-arylmethoxy-3-aryl-azetidines 7 also exhibited high
affinity for the SERT. The N-methyl analogues typically exhibited
higher affinity at the SERT than the corresponding unsubstituted
analogues 6. The dichloro substituted congener 7c (Ki = 1.0 nM)
and the tetrachloro substituted derivative 7i (Ki = 1.3 nM) were
the most potent analogues of the entire series. However, the NH
analogues 6e and 6h exhibited similar SERT affinity to the corre-
sponding N-methyl analogues 7e and 7h, while the DAT affinities
of 6e and 6h were not similarly affected. Overall, N-methyl, 3,4-di-
chloro analogue 7c exhibited the greatest selectivity for SERT (DAT/
SERT = 1210) of all the azetidine derivatives.
Inspection of the SAR of the azetidines 6 and 7, revealed that
for compounds with the 3,4-dichlorophenyl group attached as
the 3-aryl substituent (e.g., 6g and 7g) the relative DAT affinity
was improved and the DAT/SERT selectivity was decreased. A
similar effect had been observed for a series of meperidine deriv-
atives.19 However, if the 3-arylmethoxy moiety possessed
a
chloro substituent (e.g., 6h and 7h) then the DAT affinity de-
creased and the SERT selectivity dominated. Alternatively, if the
3-arylmethoxy moiety possessed the 3,4-dichloro substituent pat-
tern (e.g., 6c and 7c) then the ligand exhibited high SERT affinity.
However, when both aryl groups possessed the 3,4-dichloro-
phenyl moiety there was little improvement in affinity or selec-
tivity. The effect of the 3-(3,4-chlorophenyl-methoxy) moiety on
SERT affinity and selectivity is consistent with the SAR observed
Scheme 1. Reagents and conditions: (i) R2-C6H4Br, n-BuLi, THF, À78 °C. (ii) R3-
C6H4CH2Br, Bu4NBr, 4 N NaOH/CH2Cl2, reflux. (iii) 2 M HCl/EtOAc, rt. (iv) LiAlH4,
THF, 65 °C.
for the 3a
-arylmethoxy-3b-aryltropanes.12 Among the tropane
congeners, the 3b-(3,4-chlorophenylmethoxy) derivatives (e.g.,
1c) typically exhibited some of the highest SERT affinity and
selectivity for the class of ligands.
affinities of the 3-arylmethoxy-3-aryl-azetidines (6) were generally
selective for the SERT over the DAT exhibiting nanomolar affinity
for the SERT and micromolar affinity for the DAT. The dichloro
substituted congeners 6e (Ki = 3.5 nM) and 6h (Ki = 2.9 nM) were
the most potent of the azetidines at SERT. The binding affinities
Of the azetidine derivatives, 7g exhibited a binding profile
which most closely approached that of a dual DAT/SERT uptake
inhibitor (DAT/SERT = 27) while maintaining nanomolar affinity
at both transporters. Although SERT selective, the moderate affinity
for the DAT observed for 7g (Ki = 620 nM) was encouraging. While
the SAR of the azetidines did not mirror the SAR of the tropanes, it
was clear that substitution of the aryl rings can be used to tune the
monoamine transporter affinity and suggests that the proper sub-
stitution of the aryl rings might lead to a potent DAT/SERT dual
inhibitor.
In conclusion, we have synthesized a novel class of azetidine-
based monoamine transporter ligands. In general, the 3-aryl-3-
arylmethoxyazetidines 6 and 7 exhibited high affinity for the SERT
and were generally selective for the SERT over the DAT. However, it
is clear that DAT affinity can be improved with the proper substi-
tution of the 3-aryl ring. Based upon these preliminary studies,
the azetidine scaffold seems to be suitable replacement for the tro-
pane scaffold and the 3-aryl-3-arylmethoxy-azetidines are well
suited for the development of new compounds that display a broad
spectrum of multi-targeted monoamine transporter affinity and
selectivity.
Acknowledgments
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.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.bmcl.2013.05.071. These data include MOL files and InChiKeys
of the most important compounds described in this article.
Figure 2. X-ray crystal structure of 6a.

A. Thaxton et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4404–4407
4407
13. Lowe, J. T.; Lee, M. D., IV; Akella, L. B.; Davoine, E.; Donckele, E. J.; Durak, L.;
Duvall, J. R.; Gerard, B.; Holson, E. B.; Joliton, A.; Kesavan, S.; Lemercier, B. C.;
Liu, H.; Marié, J.-C.; Mulrooney, C. A.; Muncipinto, G.; Welzel-O’Shea, M.;
Panko, L. M.; Rowley, A.; Suh, B.-C.; Thomas, M.; Wagner, F. F.; Wei, J.; Foley, M.
A.; Marcaurelle, L. A. J. Org. Chem. 2012, 77, 7187.
14. cLogP values were calculated for the free base using software from
Collaborative Drug Discovery, Inc. at www.collaborativedrug.com.
15. Structures in Figure 1 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).
16. Sonesson, C.; Swanson, L.; Pettersson, F. WO 2,010,058,017A1, 2010; Chem.
Abstr. 2010, 152, 591844. Sonesson, C.; Swanson, L.; Pettersson, F. WO
2,010,058,020 A1, 2010; Chem. Abstr. 2010, 152, 591843.
17. CCDC 930712 contains the supplementary crystallographic data for this Letter.
These data can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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