Deconstructing 14-phenylpropyloxymetopon: Minimal requirements for binding to mu opioid receptors

Article abstract of DOI:10.1016/j.bmc.2012.05.006

A series of phenylpropyloxyethylamines and cinnamyloxyethylamines were synthesized as deconstructed analogs of 14-phenylpropyloxymetopon and analyzed for opioid receptor binding affinity. Using the Conformationally Sampled Pharmacophore modeling approach, we discovered a series of compounds lacking a tyrosine mimetic, historically considered essential for μ opioid binding. Based on the binding studies, we have identified the optimal analogs to be N-methyl-N-phenylpropyl-2-(3-phenylpropoxy)ethanamine, with 1520 nM, and 2-(cinnamyloxy)-N-methyl-N-phenethylethanamine with 1680 nM affinity for the μ opioid receptor. These partial opioid structure analogs will serve as the novel lead compounds for future optimization studies.

Full text of DOI:10.1016/j.bmc.2012.05.006

Bioorganic & Medicinal Chemistry 20 (2012) 4556–4563
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Deconstructing 14-phenylpropyloxymetopon: Minimal requirements
for binding to mu opioid receptors
Lidiya Stavitskaya a, , Jihyun Shim a, , Jason R. Healy b, Rae R. Matsumoto b, Alexander D. MacKerell Jr. a,
,
⇑
Andrew Coop a,
⇑
a Dept. of Phar. Sci., Univ. of MD, School of Pharmacy, 20 N. Pine Street, Baltimore, MD, 21201, USA
b Dept. of Basic Pharm. Sci., WVU, PO Box 9500, 2037 Health Sci. North, Morgantown, WV 26506, 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 phenylpropyloxyethylamines and cinnamyloxyethylamines were synthesized as deconstructed
analogs of 14-phenylpropyloxymetopon and analyzed for opioid receptor binding affinity. Using the Con-
formationally Sampled Pharmacophore modeling approach, we discovered a series of compounds lacking
Received 20 February 2012
Revised 27 April 2012
Accepted 4 May 2012
Available online 11 May 2012
a tyrosine mimetic, historically considered essential for
have identified the optimal analogs to be N-methyl-N-phenylpropyl-2-(3-phenylpropoxy)ethanamine,
with 1520 nM, and 2-(cinnamyloxy)-N-methyl-N-phenethylethanamine with 1680 nM affinity for the
l opioid binding. Based on the binding studies, we
l
Keywords:
Opioid
opioid receptor. These partial opioid structure analogs will serve as the novel lead compounds for future
optimization studies.
Phenylpropyloxyethylamine
Conformationally sampled pharmacophore
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Tremendous effort has been put towards the development of
novel opioids lacking side effects that are commonly seen in opioid
The
l
opioid agonist morphine (I) is the standard for severe
treatment.11 Lack of tolerance and physical dependence has been
observed after repeated treatment with 14-methoxymetopon (II,
Fig. 1), a member of the alkoxymorphinan opioid series.12 Studies
also showed that II has reduced constipation13 as compared to I
and respiratory depression as compared to sufentanil14 and has
pain management.1,2 Despite the ability of I to treat severe pain,
there are significant side effects which often cause undermedica-
tion in clinical settings. Such effects are tolerance, dependence,3
constipation, nausea, and respiratory depression.4,5
Opioid therapy is often accompanied by additional medications
been characterized as a l selective opioid with 500-fold greater
to treat or prevent some of the undesirable side effects.6 One of the
systemic antinociceptive potency than I.13,12 Upon superaspinal
administration, II can elicit potency of up to one million-fold great-
er than morphine.13 Another derivative that belongs to the 14-alk-
oxymorpinan family is the 14-phenylpropyloxymetopon (III,
Fig. 1), an agonist which is even more potent than II (24000-fold
higher in the tail flick assay and 8500-fold higher in the hot plate
assay as compared to I).15 Although III is unsuitable for clinical
use due to its extreme potency, it can serve as a lead compound
for structural development of a novel opioid skeleton.
most problematic side effects associated with the
l opioids is con-
stipation,7 which becomes more severe as the dosage increases due
to analgesic tolerance.3 Though, constipation can be managed using
laxatives and stool softeners during the initial stages of therapy,
they are less effective during chronic use of opioid therapy.6 Re-
cently, peripherally- restricted
l opioid receptor antagonists, alv-
imopan,8 and methylnaltrexone bromide, have been approved
by the FDA for treatment of opioid induced constipation. These
agents do not cross the blood brain barrier (BBB), thus avoiding
the antagonist effect in the CNS while reversing the unwanted side
effects in the gastrointestinal tract (GI).8,9 A significant limitation to
chronic use of alvimopan is the increased risk of a heart attack.8,10
Moreover, methylnaltrexone must be administered subcutaneously
as it exhibits poor oral bioavailability.9 Another problem associated
with co-administration of these drugs with opioid agonists is that it
adds to the regimen of drugs already taken by the patients.
9
The structure of III is comprised of 6 rings: aromatic A, cyclohex-
yls B and C, piperidine D, epoxy E, and an aromatic ring coming off
position 14 (Fig. 1).15 Our current work aimed to deconstruct III in
an effort to develop a novel opioid class that exhibits high affinity
at the
l opioid receptor. Our hypothesis is that opioid activity can
be achieved in the presence of a basic amine and a phenylpropyloxy
group alone. By removing fundamental rings A–E, the skeleton will
be able to adopt an alternate binding mode with the receptor, there-
by potentially causing alternate receptor trafficking events16 and
post-receptor mechanisms, all of which are involved in the develop-
ment of tolerance.3 To test our hypothesis, phenylpropyloxyethyl-
amine (IV, Fig. 1) and analogs with flexible and ring-constrained
⇑
Corresponding authors.
E-mail address: acoop@rx.umaryland.edu (A. Coop).
Contributed equally to the work.
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2012.05.006

L. Stavitskaya et al. / Bioorg. Med. Chem. 20 (2012) 4556–4563
4557
NCH3
NCH3
OCH3
NCH3
I
II
III
IV
D
H
O
B
N
A
C
O
E
O
O
O
HO
OH
HO
O
HO
O
CH3
CH3
Morphine
14-Methoxymetopon
14-Phenylpropyloxymetopon
Phenylpropyloxyethylamine
Figure 1. Opioids used for hypothesis and the proposed analog.
N-substituents were synthesized, characterized, and pharmacolog-
ically evaluated. Specifically, the synthesis of phenylpropyloxyeth-
ylamines containing N,N-dimethyl, diethyl, dipropyl, and dibutyl,
as well as pyrrolidine, pyridine, and azepane substituents is de-
scribed. In addition, a cinnamyloxyethylamine series containing
identical N-substituents was generated in an effort to understand
the effect of saturation in this group. In order to investigate
differences and similarities in increasing affinities11 between the
morphinans and this series, N-benzyl, N-phenethyl and N-phenyl-
propyl analogs were synthesized. The results show that the novel
Specifically, N-allyl, N-phenethyl, and N-phenylpropyl tended to
yield high affinity while the N-benzyl groups tended to yield low
affinity at the
29), 35 (8, 30), 36 (9, 30), 37 (8, 31), 38 (9, 31), 39 (8, 32), and
40 (9, 32) were synthesized in order to investigate the differences
and similarities that compounds without the traditional rings have
within this series.
l
opioid receptor.11 Compounds 33 (8, 29), 34 (9,
2.2. Molecular modeling studies
series of compounds differ in their affinity for the
Additionally, we discovered a series of compounds lacking a tyro-
sine mimetic, historically considered essential for
l
opioid receptor.
The novel series of compounds consist of an aromatic moiety,
similar to that of morphine and its analogs. To investigate if the
aromatic moiety on compounds 17 and 18 mimic the aromatic
moiety coming off position 14 on 14-cinnamyloxymetopon, and
not the A-ring on morphine, the conformationally sampled phar-
macophore (CSP)18–22 modeling approach was applied and phar-
macophore models were designed. The CSP method, developed
by MacKerell and coworkers, is a novel approach for ligand-based
drug design.19–22 This method maximizes the probability of inclu-
sion of the bioactive conformation for model development by con-
sidering all the energetically accessible conformations of each
ligand in the set rather than individual low energy conformers tra-
ditionally used. The CSP method has been previously used to pre-
dict the affinity and efficacy of the peptidic and nonpeptidic d
opioids20–22 as well as to a number of conjugated bile acids,18,19
with many of the compounds studied being highly flexible. Consid-
ering that the studied compounds also have a high degree of con-
formational freedom, the CSP method was performed in order to
ensure that conformational flexibility of the ligands was properly
taken into account during model development.
For the analysis, only the first replica corresponding to room
temperature was used from which 2500 conformations were ob-
tained. The 1D probability distribution of distances between the
basic nitrogen (N) and the centroid of the aromatic moieties (X
and Y) of compounds 17 and 18, are displayed in Figure 2. As
expected, there is a significant overlap for the YN distances (Table
1) of the molecules indicated in red (14-COM), blue (17), and ma-
genta (18) and no evident overlap is observed with compound 17
and the A-ring (XN: indicated in green). However, when the OC val-
ues are analyzed for compound 18 (Table 1), a small amount of
overlap occurs indicating that, although the aromatic moiety on
phenylpropyloxyethylamines does not have large overlap with
A-ring (OC = 0.0024), some overlap is possible.
l opioid binding.
2. Results and discussion
2.1. Chemistry
In our initial studies, N,N-dimethyl-2-(3-phenylpropoxy)ethan-
amine (3), 2-(cinnamyloxy)-N,N-dimethylethanamine (5), and 1-
(2-(3-phenylpropoxy)ethyl)pyrrolidine (7) were synthesized and
characterized following literature procedures17 as shown in Scheme
1. The appropriate chloroethylamines 2, 6 were treated with the
alcohols 1, 4 in the presence of NaH and heated at 50 °C for 3 h. Com-
pounds 3, 5 and 7 were successfully synthesized in moderate yields
(3, 40%; 5, 17%; 7, 22%). Due to the hygroscopic nature of the salts,
the final products remained in oil form.
To improve the yield of amino ethers and use a less hazardous
compound than NaH, an alternate approach was developed and
utilized for subsequent reactions. Potassium hydroxide proved to
be a good substitute for NaH, and reactions were found to proceed
well, with less side-products, at room temperature. Targets 13–18,
20, and 21 (Scheme 2) were prepared following the new procedure.
Compound 13 was attained from starting materials 8 and 10; 14
from 9 and 10; 15 from 8 and 11; 16 from 9 and 11; 17 from 8
and 12; 18 from 9 and 12; 20 from 8 and 19; and 21 from 9 and
19. The final products were converted into oxalic salts using
diethyl ether and oxalic acid. All of the compounds were synthe-
sized in moderate 22–37% yields.
To investigate the effect of constrained N-substituents, targets
24–28 were synthesized (Scheme 3) following the same procedure
as developed for the alkyl analogs. Compound 24 was prepared
from 4 and 6; 25 from 1 and 22; 26 from 4 and 22; 27 from 9
and 23; and 28 from 8 and 23.
Additionally, the similar approach was utilized to determine the
1D probability distribution of maximum distances between the aro-
matic moieties on the N-arylalkyl series (compounds 33–38) and the
The N-arylalkyl and N-diallyl series (Scheme 4) was selected
based on the established SAR of increasing affinity in opioids.
1
2
1
2
R1
NaH
DMF
R1
OH
Cl
O
+
% yield
2 R1 = dimethylamine
6 R1 = pyrrolidine
3 1,2 = CH2-CH2, R1 = dimethylamine 40
1 1,2 = CH2-CH2
4 1,2 = CH=CH
5 1,2 = CH=CH, R1= dimethylamine 17
7 1,2 = CH2-CH2, R1 = pyrrolidine
22
Scheme 1. Synthesis of analogs 3, 5 and 7 and their yields.

4558
L. Stavitskaya et al. / Bioorg. Med. Chem. 20 (2012) 4556–4563
( )n
N
( )n
N
1
2
1
2
KOH
DMF
( )n
( )n
Br
HO
HO
O
10 n = 0
11 n = 1
% yield
+
8
9
13 1,2 = CH=CH, n = 0
14 1,2 = CH2-CH2, n = 0
15 1,2 = CH=CH, n = 1
16 1,2 = CH2-CH2, n = 1
17 1,2 = CH=CH, n = 2
18 1,2 = CH2-CH2, n = 2
22
36
33
40
24
37
1,2 = CH=CH
1,2 = CH2-CH2
12
n = 2
N
O
19
20 1,2 = CH=CH (amide) 22
21 1,2 = CH2-CH2(amide) 29
Scheme 2. Synthesis of N,N-dialkyl analogs and their yields.
1
2
1
2
KOH
DMF
N
N
( )n
( )n
R1
R2
O
+
% yield
24 1,2 = CH=CH, n = 0 21
4 1,2 = CH=CH, R1 = OH
1 1,2 = CH2-CH2, R1 = OH
8 1,2 = CH=CH, R1 = Br
9 1,2 = CH2-CH2, R1 = Br
6
n = 0 R2 = Cl
22 n = 1 R2 = Cl
23 n = 2 R2 = OH
25 1,2 = CH2-CH2, n = 1 14
26 1,2 = CH=CH, n = 1
27 1,2 = CH2-CH2, n = 2 37
28 1,2 = CH=CH, n = 2 22
34
Scheme 3. Synthesis of pyrrolidine, piperdine and azepane containing analogs and their yields.
R3
N
R3
N
1
2
1
2
KOH
DMF
O
R2
R1
R4
R2
+
% yield
33
34
4 1,2 = CH=CH, R1 = OH 29
1,2 = CH=CH, R2 = CH2Ph, R3 = CH3
1,2 = CH2-CH2, R2 = CH2Ph, R3 = CH3
20
32
R2= CH2Ph, R3=CH3, R4=OH
R2= (CH2)2Ph, R3=CH3, R4=Cl
R22, R3= CH2CH=3CH2,3R4=Cl
30
31
32
1 1,2 = CH2-CH2, R1 = OH
R = (CH ) Ph, R =CH , R =Cl 35
8
9
1,2 = CH=CH, R2 = (CH2)2Ph, R3 = CH3 19
1,2 = CH2-CH2, R2 = (CH2)2Ph, R3=CH3 34
1,2 = CH=CH, R1 = Br
1,2 = CH2-CH2, R1 = Br
2
3
4
36
37
38
1,2 = CH=CH, R2 = (CH2)3Ph, R3= CH3
19
1,2 = CH2-CH2, R2 = (CH2)3Ph, R3=CH3 27
39 1,2 = CH=CH, R2,R3 = CH2CH=CH2
40 1,2 = CH2-CH2, R2,R3 = CH2CH=CH2
23
22
Scheme 4. Synthesis of N-arylalkyl and N-diallyl analogs and their yields.
Y
NCH3
O
X
O
HO
O
CH3
14-Cinnamyloxymetopon (14-COM)
Y
Y
O
N
compound 17
O
N
compound 18
Figure 2. 1D probability distribution of distances between the basic nitrogen (N) and the aromatic moieties (X, Y) of compounds 17 and 18. Green represents the probability
distribution of the XN distance on the 14-cinnamyloxymetopon (14-COM); red the YN on the 14-cinnamyloxymetopon; blue the YN on 17 and magenta the YN on 18.
basic nitrogen and compared to the distribution between the aro-
matic A-ring and the basic nitrogen on morphine. Results displayed
in Figure 3 illustrate that the distance distribution between the aro-
matic ring coming off the oxygen position (‘Left’ phenyl) and the
nitrogen on the phenylpropyloxyethylamines had some overlap
with the conformations that are sampled by the aromatic A-ring
and the basic nitrogen on morphine in the vicinity of 5–6 Å. The ex-
tent of overlap is quantified based on the OC values in Table 2. Thus,
while the probability is low, it is possible for the aromatic rings in
33–38 to assume a conformation of the A-ring relative to the basic
N similar to that in morphine. It is more likely when considering
morphine analogues which possess more flexible distances between
aromatic ring and basic nitrogen such as tramadol and tapentadol
(Fig. S1, Supplementary data). However, the cinnamyl analogs are

L. Stavitskaya et al. / Bioorg. Med. Chem. 20 (2012) 4556–4563
4559
Table 1
Table 2
Overlap coefficients for compounds 17 and 18
Overlap coefficients for compounds 33–38
Compd
OC with respect to XN
of 14-COM
OC with respect to YN
of 14-COM
Compd OC with respect to morphine A-ring
‘Left’ Phenyla
‘Right’ phenyla
17
18
0
0.6838
0.7648
33
34
35
36
37
38
0
0.0002
0.0002
0.025
0.0158
0.0344
0.0426
0.0024
0.0204
0
0.0172
0
0.0126
less likely to mimic the A-ring as they are less flexible and therefore
sample a narrower range of conformations.
a
‘Left’ and ‘Right’ refer to the rings relative to the basic N as shown in Figures 3
and 4.
Similar to the above results, the N-benzyl derivatives (‘Right’
phenyl) have only a very small amount of overlap with the mor-
phine A-ring probability distribution (Fig. 4, Table 2). In contrast,
more overlap in the conformational sampling between the basic
nitrogen and the aromatic ring on the N-phenethyl and N-phenyl-
propyl is observed with that of the A-ring on morphine. These re-
sults indicate that the aromatic moiety on compounds 35–38 may
be mimicking the A-ring.
The N-arylalkyl and N-diallyl analogs were selectively synthe-
sized motivated by established opioid SAR.11 From the results in
Table 3, it appears that the second aromatic ring is important for
binding. Among the N-arylalkyl analogs, compounds 35 and 38 dis-
played the highest affinity for the
1520 nM, respectively), weak affinity for d (6850 and 6650 nM,
respectively), and negligible (>10,000 nM) affinity for . The N-
benzyl analogs (33, 34), which tend to yield lower affinity as com-
pared to N-phenethyl and N-phenylpropyl substituents (in the
established opioid SAR)11 displayed similar binding affinity for
l opioid binding site (1680 and
j
2.3. Opioid receptor binding
Opioid binding studies for the compounds were performed at all
three opioid receptors (l, d, j) via a displacement assay, following
the
l opioid receptor (2760–3040 nM) as the N-phenethyl and N-
standard procedures.23 The phenylpropyloxyethylamine and cinn-
amyloxyethylamine analogs showed low to negligible (>10,000
phenylpropyl analogs (35–38, 1520–6450 nM), while the N-diallyl
analogs showed no activity at either receptor type (data not
shown). The present results on differing N-arylalkyl analogs pro-
vided evidence that the current series does not possess the typical
opioid SAR profile for the N-aryl alkyl analogs.
nM) affinity at the
compounds possessing <10,000 nM binding affinity. The N-dibutyl
analogs (17, 18) in the N-dialkyl series both displayed similar weak
binding affinity (2490 nM) for the
l opioid receptor. Table 3 contains data for
l receptor and negligible
(>10,000 nM) affinity for the d receptor, independent of the level
of the unsaturation.
3. Conclusion
N-heterocycles were examined to delineate the effect of confor-
mational freedom of these substituents on opioid activity. From
our results, it appears that constraining the flexible chains in the
N-dialkyl analogs to give ring-constrained N-heterocyclic analogs
(7, 24–27) is not favorable for interaction with the opioid receptors
and results in negligible binding affinity in the displacement assays
(data not shown).
A
series of phenylpropyloxyethylamines with differing N-
substituents were synthesized to test the hypothesis that opioid
activity can be achieved in the presence of a basic amine and a phe-
nylpropyloxy group alone. The phenylpropyloxyethylamines are
capable of binding to the
weak affinity while maintaining negligible affinity for
l opioid receptor, possessing a fairly
j and d
NCH3
O
HO
OH
Morphine
N
O
33
N
N
O
34
O
35
N
N
N
O
36
O
37
O
38
Figure 3. 1D probability distribution of distances between the basic nitrogen and the aromatic moiety coming off the oxygen on compounds 33–38 and the aromatic A-ring
on morphine.

4560
L. Stavitskaya et al. / Bioorg. Med. Chem. 20 (2012) 4556–4563
NCH3
O
HO
OH
N
Morphine
O
33
N
N
O
34
O
35
N
N
N
O
36
O
37
O
38
Figure 4. 1D probability distribution of distances between the basic nitrogen and the aromatic moiety coming off the nitrogen on compounds 33–38 and the aromatic A-ring
on morphine.
MD simulations were performed with a 2 fs integration time step
using the Leap-Frog integrator26 with covalent bonds involving
hydrogen atoms constrained to their equilibrium bond length by
the SHAKE algorithm.27 Aqueous solvation was treated using the
generalized born continuum solvent model,28 with non-bond inter-
actions truncated at 18 Å with smoothing over the region 16–18 Å
using a switching function.29 For conformational sampling, the mol-
ecules were subjected to Temperature Replica Exchange-Molecular
Dynamic (TREX-MD) simulations.30 TREX-MD is an efficient sam-
pling method used to overcome local minima and to sample diverse
conformational space.30 TREX-MD performs a range of independent
MD simulations (replicas) in which each replica is under different
temperatures, representing systemofdifferentdegreesof kineticen-
ergy to overcome energy barriers.30 Exchanges of conformations
occuring between the adjacent simulations are selected according
to the Metropolis criterion,31, such that exchanges that lead to a low-
er energy are always accepted and the exchanges leading a higher
energy are conditionally accepted. In this study, 8 replicas with
exponential scaling of temperatures between 300–400 K (300, 313,
326, 339, 354, 368, 384, 400 K) were used. MD simulations on each
replica were carried out for 5 ns using Langevin dynamics32 in impli-
cit solvent using the GBMV (generalized born using molecular vol-
ume) method.33 Exchanges were attempted every 0.5 ps. To
confirm that the simulation was sampling distinctive conforma-
tions, the probability of geometric distributions was compared with
increasing simulation time. For example, the probability distribu-
tion of distances between basic nitrogen and aromatic ring of 5
was calculated over 0.5 ns intervals. Overlap between the probabil-
ity distributions at 4.5 and 5 ns reached 99% and a significant shift in
the population was not observed. Therefore 5 ns sampling was
deemed converged enough to perform further model development.
Distance probability distributions were calculated with a bin size
of 0.1 Å. To measure the degree of overlap in the probability distribu-
tions between compounds the overlap coefficient (OC) was calcu-
lated. Given two probability distributions, the OC is obtained using
equiv 1
Table 3
Opioid receptor binding affinities
Compd
Ki SEM (nM)
[3H] DPDPE (d)
[3H] DAMGO (
l
)
[3H] U69,593 (
j)
17
18
33
34
35
36
37
2490 206
2490 165
3040 250
2760 146
1680 155
2310 193
6450 315
1520 175
0.46 0.12
>10,000
>10,000
>10,000
>10,000
6850 453
8530 669
>10,000
6650 405
11 1.1
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
1.07 0.06
38
Naltrexone
The affinity results showed that the optimal N-substituents include N-phenethyl
and N-phenylpropyl. Overall, there was no noticeable trend between the saturated
and unsaturated derivatives in the phenylpropyloxyethylamine series. None of the
compounds exhibited sufficient affinity to enable the determination of their
efficacy.
receptors. Based on the opioid binding studies, we have identified
the optimal analogs in the current series to be 38, with 1520 nM,
and 35, with 1680 nM affinity for the
tional analysis based on the CSP modeling approach showed that
although the aromatic rings in the novel series have only minimal
spatial overlap with the A-ring, their mimicking the A-ring cannot
be totally excluded. Nonetheless, compounds 35 and 38 will serve
as the novel lead compounds for further optimization studies that
will focus on restricting the conformation via reintroduction of the
opioid rings B, D and C.
l opioid receptor. Conforma-
4. Methods
4.1. Computational methods
Compounds were modeled using the program CHARMM24 with
the CHARMM General Force Field25 (CGenFF) parameters. Energy
minimizations were performed using the steepest descent and
X
adopted basis Newton-Raphson (ABNR) to
a RMS force of
minðPi; QiÞ
ð1Þ
10ꢀ6 kcal/mol Å in vacuum with infinite non-bond interaction lists.
i

L. Stavitskaya et al. / Bioorg. Med. Chem. 20 (2012) 4556–4563
4561
where, i is any descriptors such as distance between two pharmaco-
phoric points and Pi and Qi are the normalized probabilities of com-
pounds P and Q.
by formation of oxalate salt from ether. Yield 57%, (1.10 g); mp
120–121 °C
1H NMR (D2O) d 7.36–7.42 (m, 2H), d 7.27–7.35 (m, 3H), d 3.77–
3.81 (m, 2H), d 3.56–3.61 (m, 2H), d 3.33–3.38 (m, 2H), d 2.90–2.93
(m, 6H), d 2.69–2.75 (m, 2H), d 1.91–1.98 (m, 2H); MS ESI m/z = 208
(M+H+); Anal. (C13H21NO (C2H2O4)1) C, H, N.
4.2. Opioid binding assay
2-(Cinnamyloxy)-N,N-dimethylethanamine (5) was prepared th-
rough alkylation of cinnamyl alcohol, 4 (3.74 g 27.9 mmol) with
2-(dimethylamino)ethylchloride hydrochloride, 2 (1 g, 9.30 mmol)
following both method 1 and 2 described above. Yield 17% (0.32 g);
1H NMR (D2O) d 7.54 (d, 3.50 Hz, 2H), d 7.42–7.49 (m, 3H), d 6.75–
6.80 (m, 1H), d 6.39–6.46 (m, 1H), d 4.29 (d, 3.33 Hz, 2H), d 3.88 (t,
5.25 Hz, 2H), d 3.41 (t, 4.90 Hz, 2H), d 2.91–2.96 (m, 6H); MS ESI m/
z = 206 (M+H+); Anal. (C13H19NO (C2H2O4)1) C, H, N.
Opioid binding studies for the compounds were performed at all
three opioid receptors (l, d, j) via a displacement assay, following
standard procedures.23 Briefly,
l opioid receptor membrane protein
were labeled with 1.3 nM [3H]DAMGO (53.4 Ci/mmol). d Opioid
receptor membrane protein were labeled with 1.2 nM [3H]DPDPE
(45 Ci/mmol).
with 1.7 nM [3H]U69,593 (42.7 Ci/mmol). Nonspecific binding was
defined as the radioactivity bound in the presence of 1
j Opioid receptor membrane protein were labeled
lM
1-(2-(3-Phenylpropoxy)ethyl)pyrrolidine (7) was prepared throu-
gh alkylation of 3-phenyl1-propanol, 1 (2.01 mL, 15.0 mmol) with
1-(2-Chloroethyl)pyrrolidine hydrochloride (1 g, 7.4 8 mmol) fol-
lowing both method 1 and 2 described above. Yield 22% (0.38
g);1H NMR (D2O) d 7.41 (t, 7.67 Hz, 2H), d 7.27–7.35 (m, 3H), d
3.76–3.80 (m, 2H), d 3.64–3.70 (m, 2H), d 3.58 (t, 6.61 Hz, 2H), d
3.39 (t, 4.84 Hz, 2H), d 3.09–3.18 (m, 2H), d 2.71 (t, 7.44 Hz, 2H),
unlabelled DAMGO, DPDPE and U69,593 for the respective sub-
types. Competition binding studies were performed using 12 con-
centrations of each test compound and were incubated for 1 h at
25 °C. Reactions were terminated by rapid vacuum filtration
through GF/B glass fiber filters previously soaked in 0.5% polyethyl-
eneimine. Bound radioactivity was quantified by liquid scintillation
counting. Affinities (Ki) were calculated using the Cheng-Prusoff
equation.
d
2.11–2.21 (m, 2H), d 1.91–2.07 (m, 4H); MS ESI m/z = 234
(M+H+); Anal. (C15H23NO (C2H2O4)1) C, H, N.
2-(Cinnamyloxy)-N,N-diethylethanamine (13) was prepared
through alkylation of 2-(diethylamino)ethanol, 10 (1.14 mL,
8.53 mmol) with cinnamyl bromide, 8 (1.85 g, 9.39 mmol) in pres-
ence of KOH (1.19 g, 21.3 mmol) following method 2 described
previously. Yield 22% (0.44 g); 1H NMR (D2O) d 7.54 (d, 3.94 Hz,
2H), d 7.44 (t, 7.42 Hz, 2H), d 7.35–7.41 (m, 1H), d 6.74–6.80 (m,
1H), d 6.38–6.46 (m, 1H), d 4.27 (d, 3.48 Hz, 2H), d 3.87 (t,
4.87 Hz, 2H), d 3.40 (t, 4,87 Hz, 2H), d 3.22–3.36 (m, 4H), d 1.31
(t, 7.19 Hz, 6H); MS ESI m/z = 234 (M+H+); Anal. (C15H23NO
(C2H2O4)1) C, H, N.
N,N-Diethyl-2-(3-phenylpropoxy)ethanamine (14) was prepared
through alkylation of 2-(diethylamino)ethanol, 10 (1.14 mL, 8.53
mmol) with 1-bromo-3-phenylpropane, 9 (1.43 mL, 9.39 mmol)
in presence of KOH (1.19 g, 21.3 mmol) following method 2 de-
scribed previously. Yield 36% (0.72 g); 1H NMR (D2O) d 7.39 (t,
7.37 Hz, 2H), d 7.26–7.35 (m, 3H), d 3.76–3.81 (m, 2H), d 3.58 (t,
6.47 Hz, 2H), d 3.19–3.37 (m, 6H), d 2.71 (t, 7.37 Hz, 2H), d 1.90–
1.98 (m, 2H), d 1.30 (t, 7.19 Hz, 6H); MS ESI m/z = 236 (M+H+);
Anal. (C15H25NO (C2H2O4)1) C, H, N.
2-(Dipropylamino)ethanol ( 11) A mixture of dipropylamine
(1.35 mL, 9.88 mmol), 2-chloroethanol (0.86 mL, 9.88 mmol) and
K2CO3 (13.7 g, 99 mmol) in DMF (20 mL/g) was vigorously stirred
at room temperature under N2. After completion, H2O was added
and extracted with Et2O. The combined organic layers were
washed with brine solution and dried over Na2SO4. After removal
of the solvent under reduced pressure, the crude product was puri-
fied by column chromatography (silica gel, 1–3% CHCl3/MeOH/1%
NH4OH). Yield 78% (1.12 g); MS ESI m/z = 146 (M+H+).
2-(Cinnamyloxy)-N,N-diethylethanamine (15) was prepared th-
rough alkylation of 2-(dipropylamino)ethanol, 11 (0.80 g, 5.51
mmol) with cinnamyl bromide, 8 (1.09 g, 5.51 mmol) in presence
of KOH (0.46 g, 8.26 mmol) following method 2 described previ-
ously. Yield 33% (0.48 g); 1H NMR (D2O) d 7.49–7.54 (m, 2H), d
7.43 (t, 7.57 Hz, 2H), d 7.31 (m, 1H), d 6.71–6.77 (m, 1H), d 6.35–
6.44 (m, 1H), d 4.25 (d, 3.53 Hz, 2H), d 3.87 (t, 4.44 Hz, 2H), d
3.41 (t, 4.70 Hz, 2H), d 3.08–3.21 (m, 4H), d 1.66–1.77 (m, 4H), d
0.94 (t, 7.31 Hz, 6H); MS ESI m/z = 262 (M+H+); Anal. (C17H27NO
(C2H2O4)1 (H2O)0.75) C, H, N.
4.3. Experimental methods
All reagents and solvents were purchased from Sigma–Aldrich
unless stated otherwise and used without further purification. All
reactions were carried out under an atmosphere of nitrogen. Thin
layer chromatography was performed on silica 60 F254 plated
(Analtech). All compounds were purified using standard tech-
niques (crystallization, etc) and characterized using standard spec-
troscopic methods such as 1H NMR (Varian Inova 500 MHz) and MS
(ThermoFinnigan LCQ Classic). Elemental analysis was performed
by atlantic microlabs.
4.3.1. Experimental procedures
N,N-Dimethyl-2-(3-phenylpropyloxy)ethanamine
Method 1: solution of 3-phenyl1-propanol,
(3).
(5.99 mL,
A
1
44.6 mmol) in dry DMF was added to a stirring solution of 2.39 g
(104 mmol) of NaH at room temperature. After 30 min, 1.60 g
(14.9 mmol) of 2-(dimethylamino)ethylchloride hydrochloride, 2
was added in small portions over a 30 min period. The resulting
mixture was allowed to stir for another 3 h at 50 °C and 30 min
at room temperature. After completion, the reaction mixture was
quenched with ethanol and the solvent was removed under re-
duced pressure. The crude product was dissolved in H2O and ex-
tracted with Et2O. The product was then extracted into 6 M HCl
from Et2O. The solution was basified to pH 12–13 with 5 M NaOH
(aq) and extract with Et2O. The combined organic layers were
washed with brine solution and dried over Na2SO4. After removal
of the solvent under reduced pressure, the crude product was puri-
fied by column chromatography (silica gel, 5% CHCl3/MeOH/1%
NH4OH) followed by formation of oxalate salt from ether. Yield
40% (1.23 g); mp 120–121 °C
Method 2: To obtain target 3, alcohol 1 (1.25 mL, 9.30 mmol)
was reacted with 2 (1 g, 9.30 mmol) in the presence of KOH
(2.5 equiv, 1.30 g) in DMF (20 mL/g). The reaction mixture was al-
lowed to stir overnight at room temperature. After completion, the
crude reaction mixture was dissolved in H2O and extracted with
Et2O. The product was then extracted into 6 M HCl from Et2O.
The solution was basified to pH 12–13 with 5 M NaOH (aq) and ex-
tract with Et2O. The combined organic layers were washed with
brine solution and dried over Na2SO4. After removal of the solvent
under reduced pressure, the crude product was purified by column
chromatography (silica gel, 5% CHCl3/MeOH/1% NH4OH) followed
N,N-Diethyl-2-(3-phenylpropoxy)ethanamine (16) was prepared
through alkylation of 2-(dipropylamino)ethanol, 11 (0.8 g, 5.51
mmol) with 1-bromo-3-phenylpropane, 9 (0.84 mL, 5.51 mmol)
in presence of KOH (0.46 g, 8.26 mmol) following method 2
described previously. Yield 40% (0.58 g); 1H NMR (D2O) d 7.37 (t,

4562
L. Stavitskaya et al. / Bioorg. Med. Chem. 20 (2012) 4556–4563
6.98 Hz, 2H), d 7.25–7.33 (m, 3H), d 3.75–3.81 (m, 2H), d 3.53–3.59
(m, 2H), d 3.33–3.38 (m, 2H), d 3.07–3.20 (m, 4H), d 2.70 (t, 7.46 Hz,
2H), d 1.88–1.97 (m, 2H), d 1.66–1.77 (m, 4H), d 0.96 (t, 6.98 Hz,
6H); MS ESI m/z = 264 (M+H+); Anal. (C17H29NO (C2H2O4)1) C, H, N.
2-(Cinnamyloxy)-N,N-dibutylethanamine (17) was prepared
through alkylation of 2-(dibutylamino)ethanol, 12 (1.16 g, 5.77
mmol) with cinnamyl bromide, 8 (1.25 g, 6.35 mmol) in presence
of KOH (0.81 g, 14.43 mmol) following method 2 described previ-
ously. Yield 24% (0.40 g); 1H NMR (D2O) d 7.53 (d, 3.65 Hz, 2H), d
7.43 (t, 7.57 Hz, 2H), d 7.33–7.38 (m, 1H), d 6.72–6.78 (m, 1H), d
6.37–6.44 (m, 1H), d 4.24 (d, 3.13 Hz, 2H), d 3.84–3.88 (m, 2H), d
3.41 (t, 4.83 Hz, 2H), d 3.12–3.25 (m, 4H), d 1.64–1.73 (m, 4H), d
0.92 (t, 7.31 Hz, 6H); MS ESI m/z = 290 (M+H+); Anal. (C19H31NO
(C2H2O4)1 (H2O)0.25) C, H, N.
N,N-Dibutyl-2-(3-phenylpropoxy)ethanamine (18) was prepared
through alkylation of 2-(dibutylamino)ethanol, 12 (1.16 mL, 5.77
mmol) with 1-bromo-3-phenylpropane, 9 (0.96 mL, 6.35 mmol)
in presence of KOH (0.81 g, 14.43 mmol) following method 2
described previously Yield 37% (0.62 g); 1H NMR (D2O) d7.39 (t,
7.50 Hz, 2H), d 7.26–7.35 (m, 3H), d 3.76–3.82 (m, 2H), d 3.58 (t,
6.52 Hz, 2H), d 3.34–3.40 (m, 2H), d 3.12–3.26 (m, 4H), d 2.72 (t,
7.50 Hz, 2H), d 1.90–1.97 (m, 2H), d 1.63–1.74 (m, 4H), d 1.33–
1.43 (m, 4H), d 0.90–0.98 (m, 6H); MS ESI m/z = 292 (M+H+); Anal.
(C19H33NO (C2H2O4)1) C, H, N.
2-(Cinnamyloxy)-N,N-diethylacetamide (20) was prepared
through alkylation of N,N-diethyl-2-hydroxyacetamide, 19 (1.00
mL, 7.62 mmol) with cinnamyl bromide, 8 (1.65 g, 8.39 mmol) in
presence of KOH (1.07 g, 19.06 mmol) following method 2 de-
scribed previously. Yield 22% (0.42 g);; 1H NMR (D2O) d 7.39 (d,
3.74 Hz, 2H), d 7.32 (t, 7.65 Hz, 2H), d 7.22–7.28, (m, 1H), d 6.60–
6.66 (m, 1H), d 6.27–6.35 (m, 1H), d 4.24–4.28 (m, 2H), d 4.19 (s,
2H), d 3.39 (q, 7.12 Hz, 2H), d 3.31 (q, 7.12 Hz, 2H), d 1.11–1.22
(m, 6H); MS ESI m/z = 248 (M+H+); Anal. (C15H21NO) C, H, N.
N,N-Diethyl-2-(3-phenylpropoxy)acetamide (21) was prepared
through alkylation of N,N-diethyl-2-hydroxyacetamide, 19 (1.00
mL, 7.62 mmol) with 1-bromo-3-phenylpropane, 9 (1.27 mL, 8.39
mmol) in presence of KOH (1.07 g, 19.1 mmol) following method
2 described previously. Yield 29% (0.55 g); 1H NMR (D2O) d 7.91–
7.98 (m, 2H), d 7.81–7.89 (m, 3H), d 4.20 (t, 6.49 Hz, 2H), d 3.96–
4.08 (m, 4H), d 3.38 (t, 7.79 Hz, 2H), d 2.52–2.66 (m, 2H), d 2.29
(s, 2H), d 1.76–1.89 (m, 6H); MS ESI m/z = 250 (M+H+); Anal.
(C15H23NO) C, H, N.
1-(2-(Cinnamyloxy)ethyl)pyrrolidine (24) was prepared through
alkylation of cinnamyl alcohol, 4 (3.01 g, 22.5 mmol) with 1-(2-
Chloroethyl)pyrrolidine hydrochloride, 6 (1.00 g, 7.48 mmol) in
presence of KOH (1.05 g, 18.71 mmol) following method 2 de-
scribed previously. Yield 21%; 1H NMR (D2O) d 7.55 (d, 10.79 Hz,
2H), d 7.46 (t, 7.73 Hz, 2H), d 7.39 (t, 7.33 Hz, 1H), d 6.76–6.82
(m, 1H), d 6.40–6.48 (m, 1H), d 4.29 (d, 3.05 Hz, 2H), d 3.88 (t,
16.90 Hz, 2H), d 3.67–3.76 (m, 2H), d 3.44–3.49 (m, 2H), d 3.11–
3.21 (m, 2H), d 2.11–2.23 (m, 2H), d 1.98–2.09 (m, 2H); MS ESI
m/z = 232 (M+H+); Anal. (C13H21NO (C2H2O4)1 (H2O)0.25) C, H, N.
scribed previously. Yield 34% (0.57 g); 1H NMR (D2O) d 7.53 (d,
3.86 Hz, 1H), d 7.43 (t, 7.61 Hz, 2H), d 7.37 (t, 7.17 Hz, 1H), d
6.73–6.79 (m, 1H), d 6.38–6.45 (m, 1H), d 4.26 (d, 3.20 Hz, 2H), d
3.88 (t, 4.97 Hz, 2H), d 3.57 (d, 6.40 Hz, 2H), d 3.35 (t, 4.85 Hz,
2H), d 2.99 (t, 12.35 Hz, 2H), d 1.94 (d, 7.50 Hz, 2H), d 1.69–1.85
(m, 3H), d 1.43–1.54 (m, 1H); MS ESI m/z = 246 (M+H+); Anal.
(C16H25NO (C2H2O4)1 (H2O)0.25) C, H, N.
1-(2-(3-Phenylpropoxy)ethyl)azepane (27). was prepared through
alkylation of 2-(1-azepanyl)ethanol, 23 (1 g, 6.98 mmol) with 1-
bromo-3-phenylpropane, 9 (1.17 mL, 7.68 mmol)in presence of
KOH (0.98 g, 17.5 mmol) following method 2 described previously.
Yield 37% (0.68 g); 1H NMR (D2O) d 7.36–7.43 (m, 2H), d 7.26–7.36
(m, 3H), d 3.77–3.83 (m, 2H), d 3.58 (t, 6.10 Hz, 2H), d 3.45–3.53 (m,
2H), d 3.33–3.39 (m, 2H), d 3.19–3.27 (m, 2H), d 2.72 (t, 7.09 Hz,
2H), d 1.64–2.00 (m, 10H); MS ESI m/z = 262 (M+H+); Anal.
(C17H27NO (C2H2O4)1) C, H, N.
1-(2-(Cinnamyloxy)ethyl)azepane ( 28) was prepared through
alkylation of 2-(1-azepanyl)ethanol, 23 (1.00 g, 6.98 mmol) with
cinnamyl bromide, 8 (1.51 g, 7.68 mmol) in presence of KOH
(0.98 g, 17.45 mmol) following method 2 described previously.
Yield 22% (0.39 g); 1H NMR (D2O) d 7.49–7.54 (m, 2H), d 7.43 (t,
7.40 Hz, 2H), d 7.37 (t, 7.40 Hz, 1H), d 6.71–6.78 (m, 1H), d 6.36–
6.44 (m, 1H), d 4.22–4.26 (m, 2H), d 3.87 (t, 4.81 Hz, 2H), d 3.46–
3.53 (m, 2H), d 3.39 (t, 4.81 Hz, 2H), d 3.18–3.27 (m, 2H), d 1.77–
1.95 (m, 4H), d 1.61–1.74 (m, 4H); MS ESI m/z = 260 (M+H+); Anal.
(C17H25NO (C2H2O4)1) C, H, N.
N-Benzyl-2-(cinnamyloxy)-N-methylethanamine (33) was pre-
pared through alkylation of N-benzyl-N-methylethanolamine, 29
(0.99 mL, 6.05 mmol) with cinnamyl bromide, 8 (1.31 g, 6.66
mmol) in presence of KOH (0.85 g, 15.1 mmol) following method
2 described previously. Yield 20% (0.34 g); 1H NMR (D2O) d 7.47–
7.55 (m, 7H), d 7.43 (t, 7.48 Hz, 2H), d 7.32–7.38 (m, 1H), d 6.67–
6.73 (m, 1H), d 6.32–6.40 (m, 1H), d 4.26–4.50 (m, 2H), d 4.15–
4.24 (m, 2H), d 3.80–3.92 (m, 2H), d 3.26–3.54 (m, 2H), d 2.88 (s,
3H); MS ESI m/z = 282 (M+H+); Anal. (C19H23NO (C2H2O4)1) C, H, N
N-Benzyl-N-methyl-2-(3-phenylpropoxy)ethanamine (34) was
prepared through alkylation of N-benzyl-N-methylethanolamine,
29 (0.99 mL, 6.05 mmol) with 1-bromo-3-phenylpropane, 9 (1.01
mL, 6.05 mmol) in presence of KOH (0.85 g, 15.13 mmol) following
method 2 described previously. Yield 32% (0.55 g);1H NMR (D2O) d
7.22–7.58 (m, 10H), d 4.37–4.47 (m, 1H), d 4.23–4.35 (m, 1H), d
3.69–3.87 (m, 2H), d 3.38–3.59 (m, 3H), d 3.21–3.33 (m, 1H), d
2.80–2.90 (m, 3H), d 2.66 (t, 7.09 Hz, 2H), d 1.84–1.93 (m, 2H));
MS ESI m/z = 284 (M+H+); Anal. (C19H25NO (C2H2O4)1) C, H, N.
2-(Methyl(phenethyl)amino)ethanol (30) A mixture of (2-bromo-
ethyl)benzene (5.48 mL, 39.9 mmol), 2-chloroethanol (1.08 mL,
13.3 mmol), and K2CO3 (18.4 g, 133 mmol) in DMF (20 mL/g) was
vigorously stirred at room temperature under N2. After completion,
H2O was added and extracted with Et2O. The combined organic
layers were washed with brine solution and dried over Na2SO4.
After removal of the solvent under reduced pressure, the crude
product was purified by column chromatography (silica gel, 1–3%
CHCl3/MeOH/1% NH4OH). Yield 64% (1.53 g); MS ESI m/z = 180
(M+H+).
1-(2-(3-Phenylpropoxy)ethyl)piperidine
( 25) was prepared
through alkylation of 3-phenyl1-propanol, 1 (0.92 mL, 6.77 mmol)
with 1-(2-chloroethyl)piperidine hydrochloride, 22 (1 g, 6.77
mmol) in presence of KOH (0.95 g, 17.0 mmol) following method
2 described previously. Yield 14% (0.24 g); 1H NMR (D2O) d 7.41
(t, 7.43 Hz, 2H), d 7.29–7.36 (m, 3H), d 3.82 (t, 5.04 Hz, 2H), d
3.59 (t, 6.44 Hz, 2H), d 3.56 (d, 3.56 Hz, 2H), d 3.32 (t, 5.04 Hz,
2H), d 3.00 (t, 12.87 Hz, 2H), d 2.76 (t, 7.57 Hz, 2H), d 1.92–2.00
(m, 4H), d 1.71–1.88 (m, 3H), d 1.46–1.55 (m, 1H); MS ESI m/
z = 248 (M+H+); Anal. (C16H23NO (C2H2O4)1) C, H, N.
1-(2-(Cinnamyloxy)ethyl)piperidine (26) was prepared through
alkylation of cinnamyl alcohol, 4 (1.82 g, 13.55 mmol) with 1-(2-
chloroethyl)piperidine hydrochloride, 22 (1.00 g, 6.77 mmol) in
presence of KOH (0.95 g, 16.93 mmol) following method 2 de-
2-(Cinnamyloxy)-N-methyl-N-phenethylethanamine (35) was
prepared through alkylation of 2-(methyl(phenethyl)amino)etha-
nol, 30 (0.75 g, 4.18 mmol) with cinnamyl bromide, 8 (2.47 g,
12.6 mmol) in presence of KOH (0.59 g, 10.5 mmol) following
method 2 described above. Yield 19%; 1H NMR (D2O) d 7.16–7.4o
(m, 10H), d 6.57–6.63 (m, 1H), d 6.26–6.33 (m, 1H), d 4.18 (d,
2.97 Hz, 2H), d 3.62–3.69 (m, 2H), d 2.82–2.88 (m, 2H), d 2.73–
2.80 (m, 4H), d 2.44 (s, 3H); MS ESI m/z = 296 (M+H+); Anal.
(C20H25NO (C2H2O4)1 (H2O)0.5) C, H, N.
N-Methyl-N-phenethyl-2-(3-phenylpropoxy)ethanamine (36) was
prepared through alkylation of 2-(methyl(phenethyl)amino)etha-
nol, 30 (0.75 g, 4.18 mmol) with 1-bromo-3-phenylpropane, 9

L. Stavitskaya et al. / Bioorg. Med. Chem. 20 (2012) 4556–4563
4563
(1.91 mL, 12.6 mmol) in presence of KOH (0.59 g, 10.46 mmol)
following method 2 described previously. Yield 34% (0.42 g); 1H
NMR (D2O) d 7.31–7.43 (m, 6H), d 7.23–7.30 (m, 4H), d 3.78 (t,
4.47 Hz, 2H), d 3.44–3.60 (m, 4H), d 3.28–3.43 (m, 2H), d 3.02–
3.16 (m, 2H), d 2.94 (s, 3H), d 2.66 (t, 7.45 Hz, 2H), d 1.84–1.93
(m, 2H); MS ESI m/z = 298 (M+H+); Anal. (C20H27NO (C2H2O4)1) C,
H, N.
2-(Methyl(3-phenylpropyl)amino)ethanol ( 31) A mixture of 1-
bromo-3-phenylpropane, 9 (6.07 mL, 39.9 mmol), 2-chloroethanol
(1.08 mL, 13.31 mmol), and K2CO3 (18.4 g, 133 mmol) in DMF
(20 mL/g) was vigorously stirred at room temperature under N2.
After completion, H2O was added and extracted with Et2O. The
combined organic layers were washed with brine solution and
dried over Na2SO4. After removal of the solvent under reduced
pressure, the crude product was purified by column chromatogra-
phy (silica gel, 1–3% CHCl3/MeOH/1% NH4OH). Yield 71% (1.83 g);
MS ESI m/z = 194 (M+H+).
3.32–3.37 (m, 2H), d 2.70 (t, 7.52 Hz, 2H), d 1.87–1.96 (m, 2H);
MS ESI m/z = 260 (M+H+); Anal. (C17H25NO (C2H2O4)1) C, H, N.
Acknowledgements
This work was supported by the National Institute on Drug
Abuse, National Institutes of Health (NIDA, NIH) (DA013583) and
the University of Maryland Computer-Aided Drug Design Center.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2012.05.006.
References and notes
1. Zieglgansberger, W.; Tolle, T. R.; Zimprich, A.; Hollt, V.; Spanagel, R. Pain Brain
1995, 22, 439.
2-(Cinnamyloxy)-N-methyl-N-phenylpropylethanamine (37) was
prepared through alkylation of 2-(methyl(3-phenylpropyl)amino)
ethanol, 31 (1.0 g, 5.17 mmol) with cinnamyl bromide, 8 (3.06 g,
15.52 mmol) in presence of KOH (7.26 g, 12.93 mmol) following
method 2 described previously. Yield 19% (0.30 g); 1H NMR (D2O)
d 7.15–7.40 (m, 10H), d 6.57–6.63 (m, 1H), d 6.25–6.34 (m, 1H), d
4.14–4.18 (m, 2H), d 3.57 (t, 6.23 Hz, 2H), d 2.60–2.66 (m, 4H), d
2.42–2.48 (m, 2H), d 2.30 (s, 3H), d 1.79–1.87 (m, 2H); MS ESI m/
z = 310 (M+H+); Anal. (C21H27NO (C2H2O4)1) C, H, N.
N-Methyl-N-phenylpropyl-2-(3-phenylpropoxy)ethanamine (38)
was prepared through alkylation of 2-(methyl(3-phenylpro-
pyl)amino)ethanol, 31 (1.00 g, 5.17 mmol) with 1-bromo-3-phe-
nylpropane, 9 (2.36 mL, 15.52 mmol) in presence of KOH (0.73 g,
12.9 mmol) following method 2 described previously. Yield 27%
(0.44 g); 1H NMR (D2O) d 7.26–7.32 (m, 4H), d 7.15–7.25 (m, 6H),
d 3.66 (t, 4.88 Hz, 2H), d 3.42 (t, 6.21, 2H), d 3.28 (s, 2H), d 3.09
(s, 2H), d 2.79 (s, 3H), d 2.59–2.65 (m, 4H), d 1.96 (q, 7.84 Hz,
2H), d 1.76–1.84 (m, 2H); MS ESI m/z = 312 (M+H+); Anal.
(C21H29NO (C2H2O4)1 (H2O)0.25) C, H, N.
2-(Diallylamino)ethanol (32) A mixture of diallylamine (1.27 mL,
10.29 mmol), 2-chloroethanol (0.89 mL, 10.29 mmol), and K2CO3
(14.2 g, 103 mmol) in DMF (20 mL/g) was vigorously stirred at
room temperature under N2. After completion, H2O was added
and extracted with Et2O. The combined organic layers were
washed with brine solution and dried over Na2SO4. After removal
of the solvent under reduced pressure, the crude product was puri-
fied by column chromatography (silica gel, 1–3% CHCl3/MeOH/1%
NH4OH). Yield 49% (0.71 g); MS ESI m/z = 142 (M+H+).
2-(Cinnamyloxy)-N,N-diallylethanamine (39) was prepared
through alkylation of 2-(diallylamino)ethanol, 32 (2.00 g, 14.2
mmol) with cinnamyl bromide, 8 (2.79 g, 14.2 mmol) in presence
of KOH (1.19 g, 21.2 mmol) following method 2 described above.
Yield 22% (0.84 g); 1H NMR (D2O) d 7.52 (d, 3.54 Hz, 2H), d 7.42
(t, 7.58 Hz, 2H), d 7.32–7.37 (m, 1H), d 6.72–6.78 (m, 1H), d 6.35–
6.46 (m, 1H), d 5.86–6.00 (m, 2H), d 5.56–5.65 (m, 4H), d 4.22–
4.29 (m, 2H), d 3.80–3.91 (m, 6H), d 3.39–3.44 (m, 2H); MS ESI
m/z = 258 (M+H+); Anal. (C17H23NO (C2H2O4)1) C, H, N.
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N,N-Diallyl-2-(3-phenylpropoxy)ethanamine (40) was prepared
through alkylation of 2-(diallylamino)ethanol, 32 (0.71 g, 5.03
mmol) with 1-bromo-3-phenylpropane, 9 (0.76 mL, 5.03 mmol)
in presence of KOH (0.42 g, 7.54 mmol) following method 2
described previously. Yield 22% (0.29 g); 1H NMR (D2O) d 7.38 (t,
7.36 Hz, 2H), d 7.23–7.33 (m, 3H), d 5.86–5.97 (m, 2H), d 5.56–
5.65 (m, 4H), d 3.75–3.85 (m, 6H), d 3.56 (t, 6.56 Hz, 2H), d
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24, 1348.