Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: Discovery of a potential clinical candidate for treatment of methamphetamine abuse

Article abstract of DOI:10.1039/c3md20374c

A series of N-substituted lobelane analogues was synthesized and evaluated for their [³H]dihydrotetrabenazine binding affinity at the vesicular monoamine transporter and for their inhibition of vesicular [ ³H]dopamine uptake. Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had been identified as a potential clinical candidate for the treatment of methamphetamine abuse.

Full text of DOI:10.1039/c3md20374c

MedChemComm
View Article Online
View Journal | View Issue
CONCISE ARTICLE
Exploring the effect of N-substitution in nor-lobelane on
the interaction with VMAT2: discovery of a potential
clinical candidate for treatment of methamphetamine
abuse
Cite this: Med. Chem. Commun., 2013,
4, 564
Guangrong Zheng,a David B. Horton,b Narsimha Reddy Penthala,a Justin R. Nickell,b
b
b
b
a
*
John P. Culver, Agripina G. Deaciuc, Linda P. Dwoskin and Peter A. Crooks
Received 18th December 2012
Accepted 21st January 2013
A
series of N-substituted lobelane analogues was synthesized and evaluated for their [3H]
dihydrotetrabenazine binding affinity at the vesicular monoamine transporter and for their inhibition of
vesicular [3H]dopamine uptake. Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had
been identified as a potential clinical candidate for the treatment of methamphetamine abuse.
DOI: 10.1039/c3md20374c
www.rsc.org/medchemcomm
The rewarding and reinforcing effects of methamphetamine site on VMAT2 and inhibits DA uptake at VMAT2 at a concen-
(METH) are believed to be through its interaction with the tration that does not interact with DAT and the serotonin
vesicular monoamine transporter-2 (VMAT2) and the dopamine transporter (SERT).8 However, lobeline is also a nicotinic
(DA) transporter (DAT), resulting in elevated synaptic DA acetylcholine receptor (nAChR) ligand exhibiting high affinity at
concentrations.1 The involvement of VMAT2 in the mechanism the a4b2* subtype.8 Thus, the involvement of nAChRs as part of
of METH addiction is demonstrated also by the reduced drug- the mechanism by which lobeline inhibits the behavioral effects
seeking behavior exhibited by heterozygous VMAT2 knockout of METH cannot be ruled out. Structural modication of the
mice compared to wild-type mice in condition place preference lobeline molecule identied lobelane (2, Fig. 1) as a compound
(CPP) experiments.2 Thus, VMAT2 has been considered as a of interest. Compared to lobeline, lobelane has negligible
potential target for development of treatments for METH activity at nAChRs, but has increased potency and selectivity in
abuse.3
inhibiting VMAT2 function.9,10 Importantly, lobelane also dose-
Over the past decade, a research focus in our laboratories has dependently decreases METH self-administration (SA) in rats
been the discovery and development of novel therapeutic agents without altering food-maintained responding.11 Collectively,
that target VMAT2.4 The validation of VMAT2 as a therapeutic these results suggest that VMAT2 is a valid target for METH
target for METH abuse was based on (ꢀ)-lobeline (1, Fig. 1), a abuse.
natural alkaloid from Lobelia inata. Lobeline inhibits METH-
To identify analogues with higher potency and selectivity in
evoked DA release from rat striatal slices and attenuates METH- inhibiting VMAT2 function, extensive structure–activity rela-
induced behavioral effects in rats.5–7 The inhibitory effects of tionship (SAR) studies have been carried out based on the
lobeline on METH are thought to result from its interaction lobelane scaffold, including structural modications of the
with VMAT2. Lobeline binds to the tetrabenazine (TBZ) binding piperidine ring, the two phenyl rings, and the ethylene linkers
bridging the piperidine ring and the phenyl rings.4,9,12 These
modications have also included changing the chirality of the
piperidinyl C-2 and C-6 stereo centers, altering the positions of
the two phenethyl substituents on the piperidine ring, replacing
the piperidine ring with other aza-heterocyclic ring systems,
adding various substituent groups on the phenyl rings, and
varying the distance between the piperidine ring and the two
phenyl rings.4,9,12 A number of lead compounds have been
Fig. 1 Structures of lobeline 1, lobelane 2, and lobelane analogues.
identied based on these modications; however, similar to
lobelane, most of these analogues also exhibit low water solu-
bility, which limits in vivo evaluation of their pharmacological
properties. In addition, despite their high potency in the in vitro
aDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas
for Medical Sciences, Little Rock, AR 72205, USA. E-mail: pacrooks@uams.edu; Fax:
+1-501-686-6057; Tel: +1-501-686-6495
VMAT2 assays, in vivo preliminary screens indicate that these
bDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky,
lead compounds have limited efficacy in inhibiting METH SA in
Lexington, KY 40536, USA
564 | Med. Chem. Commun., 2013, 4, 564–568
This journal is ª The Royal Society of Chemistry 2013

View Article Online
Concise Article
MedChemComm
rats (unpublished results). We reasoned that poor pharmaco-
Analogues 6–13, 14a, and 14b were synthesized starting from
kinetic (PK) properties of these analogues might be responsible the common intermediate, nor-lobelane (3), which was prepared
for the low in vivo efficacy.
as previously reported (Schemes 1 and 2).12a N-Alkylation of 3
In the present study, we focused on structural modications with methyl bromoacetate or chloroacetonitrile afforded
that would increase the hydrophilicity of these lobelane analogues 6 and 8, respectively. Reduction of 6 and 8 with DIBAL-
analogues by introducing polar functional groups into the H furnished the corresponding amino alcohol analogue 7 and
lobelane molecule. During our previous SAR studies, we the diamino analogue 9. 9 was converted into analogue 10 by N-
observed that the N-methyl group of lobelane is not required for methylation under the treatment of NaBH3CN/(CH2O)n and to
VMAT2 binding and inhibition, since nor-lobelane (3, Fig. 1) guanidino analogue 11 by reacting with N,N0-di-(tert-butoxy-
has equal potency to lobelane (Table 1).10 In addition, replace- carbonyl)thiourea, followed by treatment with CF3COOH to
ment of the N-methyl group with an N-ethyl (compound 4) or an remove the two BOC protective groups. Conversion of 3 to the
N-n-propyl group (compound 5)12a only slightly decreased the corresponding hydrazino compound 12 was accomplished by a
inhibitory effect of [3H]DA uptake at VMAT2 when compared to two-step procedure, i.e., N-nitrosation and a subsequent LAH
lobelane (Table 1). These preliminary results indicate that reduction. Without further purication aer work-up, the
modications to the N-methyl group can be tolerated. Herein, unstable compound 12 was converted into analogue 13 using the
we further investigate the structural modication of the N- same N-methylation procedure as described for analogue 10
methyl group of lobelane and its analogues.
(Scheme 1). Analogues 14a and 14b, which contain an N-1,2(R)-
dihydroxypropyl group and N-1,2(S)-dihydroxypropyl group,
respectively, were prepared by reacting nor-lobelane with S-gly-
cidol or R-glycidol, respectively (Scheme 2).
Table
1
Analogue inhibition of [3H]DTBZ binding to rat synaptic vesicle
membranes and inhibition of [3H]DA uptake into rat striatal synaptic vesicles
Phenyl ring modied nor-lobelane analogues 15–25 were
synthesized as previously reported.12a 15a–25a and 15b–22b
were synthesized by applying the same method for the synthesis
of analogues 14a and 14b, from their corresponding precursors,
15–25 (Scheme 2, Table 2). Similarly, analogue 28a, a homo-
logue of 19a, was prepared from the corresponding nor-
compound 28. 28 was synthesized by initial Kumada coupling13
[3H]DTBZ
VMAT2 [3H]DA uptake
Compd.
Ki ꢁ SEM (mM)a
Ki ꢁ SEM (mM)a
1
2
3
4
5
6
7
8
2.76 ꢁ 0.64b
0.97 ꢁ 0.00b
2.31 ꢁ 0.21b
3.41 ꢁ 0.67c
1.87 ꢁ 0.25c
4.4 ꢁ 0.76
0.47 ꢁ 0.045b
0.045 ꢁ 0.002b
0.044 ꢁ 0.008b
0.060 ꢁ 0.005
0.087 ꢁ 0.04
0.34 ꢁ 0.13
between
2,6-dibromopyridine
(26)
and
4-methoxy-
benzylmagnesium chloride to form compound 27, followed by
catalytic hydrogenation over Adams catalyst (PtO2) (Scheme 3).
The ability of the above analogues14 to interact with VMAT2
was assessed by determining their inhibition of [3H]dihydrote-
trabenazine ([3H]DTBZ) binding to rat brain vesicle
membranes, and their inhibition of [3H]DA uptake into rat
striatal synaptic vesicles.10 The results are summarized in
Tables 1 and 2.
1.43 ꢁ 0.136
22.57 ꢁ 0.23
5.59 ꢁ 0.94
9.59 ꢁ 1.47
3.49 ꢁ 0.63
>100
0.17 ꢁ 0.01
4.49 ꢁ 0.35
9
0.51 ꢁ 0.089
0.18 ꢁ 0.024
0.68 ꢁ 0.18
10
11
13
0.054 ꢁ 0.042
a
Each Ki value represents data from at least three independent
experiments, evaluated in duplicate. Data taken from ref. 10. Data
taken from ref. 12b.
b
c
Scheme 1 Reagents and conditions: (a) BrCH2COOMe, K2CO3, CH3CN, reflux, 72 h, 77%; (b) DIBAL-H, toluene, 0 ꢂC, 1 h, 83% for 7, 79% for 9; (c) ClCH2CN, K2CO3, NaI,
CH3CN, reflux, 96 h, 66%; (d) NaCNBH3, (CH2O)n, HOAc, MeOH, rt, 4 h, 60% for 10, 35% for 13; (e) i. N,N0-di-(tert-butoxycarbonyl) thiourea, DMF, rt, 18 h, 58%; (ii)
CF3COOH, CH2Cl2, rt, 30 min, 74%; (f) (i) NaNO2, HOAc, MeOH/H2O, 0 ꢂC-reflux, 20 h, 82%; (ii) LAH, THF, reflux, 1 h, 33%.
This journal is ª The Royal Society of Chemistry 2013
Med. Chem. Commun., 2013, 4, 564–568 | 565

View Article Online
MedChemComm
Concise Article
replaced by an N,N-dimethylhydrazino group, was the most
potent analogue in this series, inhibiting [3H]DA uptake at
VMAT2, being equipotent to lobelane. Analogue 8, in which the
N-methyl group is replaced by an N-acetonitrile group, dis-
played 100-fold lower potency in inhibiting [3H]DA uptake at
VMAT2 compared to lobelane. The rest of the analogues in this
series were 4–19 fold less potent compared to lobelane in the
same assay. Interestingly, the most potent inhibitor of DA
uptake at VMAT2, 13, exhibited no affinity at the [3H]DTBZ
binding site, indicating that DA uptake at VMAT2 is not via
interaction with the DTBZ recognition binding site on VMAT2.
For this series of analogues, there is no correlation between
affinity for the VMAT2 binding site and inhibition of DA uptake
at VMAT2, which is in consistent with our previously reported
studies on other lobelane analogues.10,15
Scheme 2 Synthesis of analogues containing N-1,2-dihydroxypropyl group.
Initial structural exploration of N-substitution patterns
based on lobelane led to analogues 6–13 (Table 1), 14a, and 14b
(Table 2). Compound 13, in which the N-methyl group is
Table 2 Analogue inhibition of [3H]DTBZ binding to rat synaptic vesicle membranes and inhibition of [3H]DA uptake into rat striatal synaptic vesicles
Compd.
Ar
[3H]DTBZ Ki ꢁ SEMa (mM)
VMAT2 [3H]DA uptake Ki ꢁ SEMa (mM)
14a
14b
0.56 ꢁ 0.08
1.28 ꢁ 0.13
0.19 ꢁ 0.05
0.86 ꢁ 0.12
15a
15b
1.30 ꢁ 0.05
5.61 ꢁ 0.62
0.16 ꢁ 0.04
0.76 ꢁ 0.04
16a
16b
1.00 ꢁ 0.16
1.08 ꢁ 0.38
0.19 ꢁ 0.06
1.03 ꢁ 0.16
17a
17b
1.04 ꢁ 0.73
1.87 ꢁ 0.69
0.49 ꢁ 0.06
0.79 ꢁ 0.08
18a
18b
0.46 ꢁ 0.22
2.73 ꢁ 0.68
0.14 ꢁ 0.02
0.52 ꢁ 0.04
19a
19b
8.29 ꢁ 2.79
7.74 ꢁ 2.34
0.029 ꢁ 0.008
0.18 ꢁ 0.04
20a
20b
10.4 ꢁ 0.65
13.9 ꢁ 0.38
0.14 ꢁ 0.04
0.09 ꢁ 0.04
21a
21b
0.31 ꢁ 0.07
0.13 ꢁ 0.07
0.03 ꢁ 0.002
0.08 ꢁ 0.01
22a
22b
> 100
90.2 ꢁ 9.70
0.79 ꢁ 0.23
2.25 ꢁ 1.30
23
23a
1.75 ꢁ 0.36
0.023 ꢁ 0.006
0.060 ꢁ 0.006
0.53 ꢁ 0.053
24
24a
0.93 ꢁ 0.22
0.21 ꢁ 0.02
0.039 ꢁ 0.002
0.16 ꢁ 0.035
25
25a
5.24 ꢁ 1.81
0.62 ꢁ 0.10
0.043 ꢁ 0.003
0.104 ꢁ 0.004
28
28a
—
13.1 ꢁ 7.4
91 ꢁ 40
0.048 ꢁ 0.005
0.57 ꢁ 0.05
a
Each Ki value represents data from at least three independent experiments, evaluated in duplicate; The data of 14a–22a and 14b–22b were taken
from ref. 16.
566 | Med. Chem. Commun., 2013, 4, 564–568
This journal is ª The Royal Society of Chemistry 2013

View Article Online
Concise Article
MedChemComm
characterizing the PK prole of this molecule and results will be
reported in due course.
We have continued the structural optimization studies based
on 19a. These studies include modifying the substituents on the
two phenyl rings to improve metabolic stability (analogues 23a–
25a, Table 2) and modifying the two ethylene linkers bridging
the phenyl rings and the central piperidine ring (analogue 28a).
Further evaluation and modication of these compounds is
ongoing currently.
Scheme 3 Reagents and conditions: (a) MeOPhCH2MgCl, NiCl2(dppp), THF, rt,
18 h, 97%; (b) H2, PtO2, HOAc, 50 psi, rt, 36 h, 84%; (c) (S)-glycidol, EtOH, reflux,
48 h, 76%.
Conclusions
In summary, a series of lobelane analogues, in which the
Compound 14a, which bears an N-1,2(R)-dihydroxypropyl N-methyl group of lobelane has been replaced by various
group, was chosen for further structural optimization based on hydrophilic moieties, has been synthesized and evaluated in the
preliminary data from in vivo screens (decrease in METH SA in [3H]DTBZ binding assay and the vesicular [3H]DA uptake assay.
rats). We incorporated the chiral N-1,2-dihydroxypropyl moiety Compound 19a, which contains an N-1,2(R)-dihydroxypropyl
into a series of phenyl ring substituted lobelane analogues, group, has been identied as a potential clinical candidate for
including 15–22 and their corresponding N-methylated the treatment of METH abuse.
analogues. Compared to compound 14a, these analogues
exhibited equal or improved binding affinity and potency for
Acknowledgements
inhibiting [3H]DA uptake at VMAT2, as shown in our previous
study.15 Accordingly, analogues 15a–22a, which contain the N- This research was supported by NIH grant R01DA13519,
1,2(R)-dihydroxypropyl group, and 15b–22b, which contain the U01DA13519, T32DA01617, and TR000117.
N-1,2(S)-dihydroxypropyl group, were synthesized and evaluated
(Scheme 2 and Table 2). SAR on this series of analogues was
discussed recently.16 In general, analogues containing N-1,2-
Notes and references
dihydroxypropyl moieties analogues exhibited lower potencies
for inhibiting [3H]DA uptake at VMAT2 compared to their
corresponding N-methyl analogues. There are no apparent
preferences in terms of [3H]DTBZ binding affinities between N-
1,2(R)-dihydroxypropyl containing analogues and their corre-
sponding N-1,2(S)-dihydroxypropyl containing enantiomers.
N-1,2(R)-Dihydroxypropyl containing analogues generally had a
higher potency at the [3H]DA uptake assay than their corre-
sponding S-enantiomers, with the exception of an equi-potent
pair of analogues, 20a and 20b. Analogue 19a (Ki ¼ 29 nM) had
the highest potency of the series inhibiting [3H]DA uptake into
synaptic vesicles, and was chosen for further neurochemical
and behavioral studies.
1 D. Sulzer, M. S. Sonders, N. W. Poulsen and A. Galli, Prog.
Neurobiol., 2005, 75, 406.
2 N. Takahashi, L. L. Miner, I. Sora, H. Ujike, R. S. Revay,
V. Kostic, V. Jackson-Lewis, S. Przedborski and G. R. Uhl,
Proc. Natl. Acad. Sci. U. S. A., 1997, 94, 9938.
3 (a) G. Zheng, L. P. Dwoskin and P. A. Crooks, AAPS J., 2006, 8,
E682; (b) L. P. Dwoskin and P. A. Crooks, Biochem.
Pharmacol., 2002, 63, 89.
4 P. A. Crooks, G. Zheng, A. P. Vartak, J. P. Culver, F. Zheng,
D. B. Horton and L. P. Dwoskin, Curr. Top. Med. Chem.,
2011, 11, 1103.
5 D. K. Miller, P. A. Crooks, L. Teng, J. M. Witkin, P. Munzar,
S. R. Goldberg, J. B. Acri and L. P. Dwoskin, J. Pharmacol.
Exp. Ther., 2001, 296, 1023.
Studies showed that 19a had the best pharmacological
prole in this series,16 including over 50-fold selectivity for
VMAT2 over DAT, SERT, and nAChRs; and decreasing METH-
evoked DA release from vesicles and striatal slices without
intrinsic activity. 19a was also shown to have great selectivity
over a series of off-target receptors/proteins (unpublished data).
Our recent studies have demonstrated that 19a effectively
decreases METH SA and CPP in rats without altering food-
maintained responding. In addition, tolerance to these effects is
not observed aer repeated dosing of 19a.17 Importantly, 19a is
predicted to have low abuse liability, since it is not self-
6 S. B. Harrod, L. P. Dwoskin, P. A. Crooks, J. E. Klebaur and
M. T. Bardo, J. Pharmacol. Exp. Ther., 2001, 298, 172.
7 S. B. Harrod, L. P. Dwoskin, T. A. Green, B. J. Gehrke and
M. T. Bardo, Psychopharmacology, 2003, 165, 397.
8 (a) L. Teng, P. A. Crooks, P. K. Sonsalla and L. P. Dwoskin, J.
Pharmacol. Exp. Ther., 1997, 280, 1432; (b) L. Teng,
P. A. Crooks, P. K. Sonsalla and L. P. Dwoskin, J.
Neurochem., 1998, 71, 258.
9 G. Zheng, L. P. Dwoskin, A. G. Deaciuc, S. D. Norrholm and
P. A. Crooks, J. Med. Chem., 2005, 48, 5551.
administered and does not produce CPP.17 Compared to lobe- 10 J. R. Nickell, S. Krishnamurthy, S. Norrholm, G. Deaciuc,
line and lobelane, 19a exhibited a signicantly increased
K. B. Siripurapu, G. Zheng, P. A. Crooks and L. P. Dwoskin,
duration of action to inhibit METH SA within a behavioral
J. Pharmacol. Exp. Ther., 2010, 332, 612.
session. In this respect, we reasoned that 19a likely has a better 11 N. M. Neugebauer, S. B. Harrod, D. J. Stairs, P. A. Crooks,
PK prole than lobeline and lobelane due to the introduction of
the hydrophilic N-1,2-dihydroxypropyl moiety. We are currently
L. P. Dwoskin and M. T. Bardo, Eur. J. Pharmacol., 2007,
571, 33.
This journal is ª The Royal Society of Chemistry 2013
Med. Chem. Commun., 2013, 4, 564–568 | 567

View Article Online
MedChemComm
Concise Article
12 (a) G. Zheng, L. P. Dwoskin, A. G. Deaciuc, J. Zhu, M. D. Jones
and P. A. Crooks, Bioorg. Med. Chem., 2005, 13, 3899; (b)
G. Zheng, L. P. Dwoskin, A. G. Deaciuc and P. A. Crooks,
Bioorg. Med. Chem. Lett., 2005, 15, 4463; (c) G. Zheng,
L. P. Dwoskin, A. G. Deaciuc and P. A. Crooks, Bioorg. Med.
Chem. Lett., 2008, 18, 6509; (d) A. P. Vartak, J. R. Nickell,
J. Chaqkutip, L. P. Dwoskin and P. A. Crooks, J. Med.
Chem., 2009, 52, 7878.
36.7, 33.3, 26.6, 24.0 ppm; EI-MS m/z 335 (M ꢀ 1)+;
1
compound 10, H NMR (300 MHz, CDCl3) d 7.15–7.32 (m,
10H); 2.55–2.75 (m, 8H), 2.37 (t, J ¼ 8.1 Hz, 2H), 2.22 (s,
6H), 1.85–2.00 (m, 2H), 1.78 (m, 1H), 1.50–1.72 (m, 4H),
1.33–1.45 (m, 3H) ppm; 13C NMR (75 MHz, CDCl3) d 142.4,
128.5, 128.4, 125.8, 62.5, 60.0, 46.1, 43.6, 36.2, 33.1, 27.0,
24.4 ppm; EI-MS m/z 364 (M+); compound 13, 1H NMR
(300 MHz, CDCl3) d 7.15–7.35 (m, 10H); 2.66–2.80 (m, 2H),
2.54 (s, 6H), 2.40–2.60 (m, 4H), 1.95–2.10 (m, 2H), 1.78–
1.90 (m, 2H), 1.58–1.75 (m, 4H), 1.23–1.38 (m, 2H) ppm;
13C NMR (75 MHz, CDCl3) d 143.3, 128.5, 128.4, 125.6,
61.1, 40.9, 36.7, 32.3, 31.9, 24.1 ppm; EI-MS m/z 336 (M+);
13 M. Kumada, Pure Appl. Chem., 1980, 52, 669.
14 Selected spectra data: compound 6, 1H NMR (300 MHz,
CDCl3) d 7.12–7.32 (m, 10H); 3.65 (s, 3H), 3.35 (s, 2H), 2.77
(m, 2H), 2.68 (t, J ¼ 8.1 Hz, 4H), 1.77–1.90 (m, 3H), 1.50–
1.65 (m, 4H), 1.20–1.40 (m, 3H) ppm; 13C NMR (75 MHz,
CDCl3) d 173.3, 142.6, 128.5, 128.4, 125.8, 67.8, 51.8, 46.3,
36.5, 32.6, 27.4, 24.9 ppm; EI-MS m/z 365 (M+); compound
7, 1H NMR (300 MHz, CDCl3) d 7.14–7.34 (m, 10H); 3.50
(br s, 2H), 2.50–2.78 (m, 8H), 1.95–2.05 (m, 2H), 1.52–1.65
(m, 4H), 1.32–1.45 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3)
d 141.9, 128.53, 128.50, 126.0, 62.6, 60.5, 46.9, 36.0, 33.5,
1
compound 19a, H NMR (300 MHz, CDCl3) d 7.07 (dd, J ¼
8.4, 2.1 Hz, 4H), 6.82 (d, J ¼ 8.4 Hz, 4H), 3.78 (s, 6H), 1.22–
1.63 (m, 7H), 3.70 (dd, J ¼ 11.4, 3.3 Hz, 1H), 3.45–3.54 (m,
1H), 3.37 (dd, J ¼ 11.4, 3.9 Hz, 1H), 1.72–1.92 (m, 3H),
2.42–2.74 (m, 8H) ppm; 13C NMR (75 MHz, CDCl3) d 157.8,
134.2, 134.1, 129.4, 114.0, 68.2, 64.9, 63.1, 61.6, 55.5, 46.5,
36.5, 36.2, 32.8, 32.7, 26.6, 25.9, 23.1 ppm; LC-ESI-MS m/z
428 (M+1)+. All compounds are estimated >95% pure based
on GC-MS or LC-MS data.
1
26.2, 23.1 ppm; EI-MS m/z 336 (M ꢀ 1)+; compound 8, H
NMR (300 MHz, CDCl3) d 7.15–7.33 (m, 10H); 3.67 (s,
2H),2.68 (t, J ¼ 8.4 Hz, 4H), 2.52 (m, 2H), 1.62–1.92 (m, 15 J. R. Nickell, G. Zheng, G. Deaciuc, P. A. Crooks and
8H), 1.30–1.52 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) d
L. P. Dwoskin, J. Pharmacol. Exp. Ther., 2011, 336, 724.
142.1, 128.5, 128.3, 126.0, 115.5, 59.9, 36.3, 35.7, 31.0, 30.2, 16 D. B. Horton, K. B. Siripurapu, G. Zheng, P. A. Crooks and
1
24.3 ppm; EI-MS m/z 332 (M+); compound 9, H NMR (300
L. P. Dwoskin, J. Pharmacol. Exp. Ther., 2011, 339, 286.
MHz, CDCl3) d 7.05–7.30 (m, 10H); 2.40–2.75 (m, 10H), 17 J. S. Beckmann, E. D. Denehy, G. Zheng, P. A. Crooks,
1.78–1.95 (m, 2H), 1.30–1.65 (m, 8H) ppm; 13C NMR (75
MHz, CDCl3) d 142.5, 128.4, 128.3, 125.7, 62.1, 49.0, 43.1,
L. P. Dwoskin and M. T. Bardo, Psychopharmacology, 2012,
220, 395.
568 | Med. Chem. Commun., 2013, 4, 564–568
This journal is ª The Royal Society of Chemistry 2013