Effect of the 3- and 4-methyl groups on the opioid receptor properties of N-substituted trans -3,4-dimethyl-4-(3-hydroxyphenyl)piperidines

Article abstract of DOI:10.1021/jm500184j

N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2a,b) are opioid receptor antagonists where the antagonist properties are not due to the type of N-substituent. In order to gain a better understanding of the contribution that the 3- and 4-methyl groups make to the pure antagonist properties of 2a,b, we synthesized analogues of 2a,b that lacked the 4-methyl (5a,b), 3-methyl (6a,b), and both the 3- and 4-methyl group (7a,b) and compared their opioid receptor properties. We found that (1) all N-methyl and N-phenylpropyl substituted compounds were nonselective opioid antagonists (2) all N-phenylpropyl analogues were more potent than their N-methyl counterparts, and (3) compounds 2a,b which have both a 3- and 4-methyl substituent, were more potent antagonists than analogues 5a,b, 6a,b, and 7a,b. We also found that the removal of 3-methyl substituent of N-methyl and N-phenylpropyl 3-methyl-4-(3-hydroxyphenyl)piperazines (8a,b) gives (4a,b), which are opioid antagonists.

Full text of DOI:10.1021/jm500184j

Article
pubs.acs.org/jmc
Effect of the 3- and 4‑Methyl Groups on the Opioid Receptor
Properties of N‑Substituted trans-3,4-Dimethyl-4-(3-
hydroxyphenyl)piperidines
Chad M. Kormos, Juan Pablo Cueva, Moses G. Gichinga, Scott P. Runyon, James B. Thomas,
Lawrence E. Brieaddy, S. Wayne Mascarella, Brian P. Gilmour, Hernan A. Navarro, and F. Ivy Carroll*
́
Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina
27709, United States
S
* Supporting Information
ABSTRACT: N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2a,b) are opioid
receptor antagonists where the antagonist properties are not due to the type of N-substituent. In
order to gain a better understanding of the contribution that the 3- and 4-methyl groups make to
the pure antagonist properties of 2a,b, we synthesized analogues of 2a,b that lacked the 4-methyl
(5a,b), 3-methyl (6a,b), and both the 3- and 4-methyl group (7a,b) and compared their opioid
receptor properties. We found that (1) all N-methyl and N-phenylpropyl substituted compounds
were nonselective opioid antagonists (2) all N-phenylpropyl analogues were more potent than their
N-methyl counterparts, and (3) compounds 2a,b which have both a 3- and 4-methyl substituent,
were more potent antagonists than analogues 5a,b, 6a,b, and 7a,b. We also found that the removal
of 3-methyl substituent of N-methyl and N-phenylpropyl 3-methyl-4-(3-hydroxyphenyl)piperazines (8a,b) gives (4a,b), which
are opioid antagonists.
hydroxyphenyl)piperidines lacking a 4-methyl and/or a 3-
methyl group on the piperidine ring have received little, if any,
study. We recently reported that the N-methyl- and N-
phenylpropyl-(S)-(3)-methyl-4-(3-hydroxyphenyl)piperazines
4a and 4b (Chart 1), respectively, which do not have a 4-
methyl substituent, were nonselective, potent, pure opioid
antagonists.15 These results suggested that N-methyl- and N-
phenylpropyl-3-methyl-4-(3-hydroxyphenyl)piperidines 5a and
5b could also be pure opioid receptor antagonists (Chart 1). In
order to gain a better understanding of the contributions that 3-
and 4-methyl groups make to the pure antagonist properties of
4-(3-hydroxyphenyl)piperidine and the 3-methyl group to the
antagonist properties of 4-(3-hydroxyphenyl)piperazine com-
pounds, we synthesized 2a,b, 4a,b, 5a,b, 6a,b, 7a,b, and 8a,b
(Chart 1) and compared their opioid receptor properties as
determined by the in vitro [35S]GTPγS functional assay. We
found that (1) with the exception of 6a, all compounds studied
were nonselective pure opioid antagonists at the μ, κ, and δ
receptors or inactive, and even compound 6a was only a very
weak agonist at the δ receptor and an antagonist at the μ and κ
receptors; (2) similar to 2b, all N-phenylpropyl analogues were
more potent antagonists than their N-methyl counterparts; and
(3) analogues 2a,b, which have both a 3- and a 4-methyl
substituent, were more potent antagonists than analogues that
lacked a 3-, 4-, or both methyl substituents.
INTRODUCTION
■
In many classes of opioid compounds, small changes in
structure modify the extent to which the opioid ligand exhibits
agonist and/or antagonist properties.1,2 In the morphine family
and in fused-ring opioids such as the 4,5-epoxymorphinon-3-
one,3 morphinan,4 benzomorphan,5 and isoquinoline6 series, N-
substituent variation modulates relative agonist/antagonist
potency. The N-methyl analogues are almost always pure
agonist, while the N-allyl and N-cyclopropylmethyl analogues
usually have antagonist properties. For example, naloxone (1a)
and naltrexone (1b) are pure opioid receptor antagonists
(Chart 1).1 In contrast to these polycyclic structures, pure
opioid receptor antagonist properties of N-substituted trans-
3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2) (Chart 1)
discovered by Zimmerman and co-workers7,8 were a con-
sequence of substitution at the 3-position on the piperidine ring
rather than substitution at the nitrogen. A number of
subsequent SAR studies have shown that all N-substituted
analogues of 2, including the N-methyl (2a) analogue, are pure
opioid receptor antagonists.7−9 The N-substituent on 2
apparently only affects the antagonist potency and opioid
receptor selectivity.9−14 In other SAR studies, Zimmerman
reported that replacing the 4-methyl group with a larger
substituent led to compounds with both opioid receptor
agonist and antagonist properties. For example, N-methyl-trans-
3-methyl-4-propyl-4-(3-hydroxylphenyl)piperidine (3) (Chart
1) showed both agonist and antagonist effects.8 In contrast to
numerous studies on the opioid antagonist properties of the N-
substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines
2,7−14 the opioid receptor properties of N-substituted 4-(3-
Received: February 3, 2014
Published: March 17, 2014
© 2014 American Chemical Society
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Chart 1. Structures of Compounds 1a,b, 2a,b, 3, 4a,b, 5a,b, 6a,b, 7a,b, 8a,b, and 22
a
Scheme 1
a
Reagents and conditions: (a) HCl/AcOH; (b) Pd/C, H2; (c) TsOH, tol; (d) ACE-Cl; (e) EtOH, reflux; (f) Ph(CH2)2CHO, NaBH(OAc)3; (g)
BCl3.
a
Scheme 2
a
Reagents and conditions: (a) n-BuLi, N-methyl-4-piperidinone; (b) TsOH, tol; (c) n-BuLi, Me2SO4; (d) NaBH4, MeOH; (e) ACE-Cl; (f) MeOH,
reflux; (g) Ph(CH2)2CHO, NaCNBH3; (h) BCl3.
afforded a solid that proved to be the pure cis-isomer as
determined by H NMR spectral analysis. In order to prepare
CHEMISTRY
■
1
Compounds 5a and 5b were prepared from a common
intermediate (9)16 (Scheme 1). Following deprotection and
dehydration with refluxing hydrochloric acid in glacial acetic
acid, the intermediate from 9 was reduced via catalytic
hydrogenation to afford 5a as a mixture of geometric isomers.
Careful chromatography and trituration of the resulting oil
the secondary amine 10, the dehydrated, hydrogenated
intermediate from 9 was treated with 1-chloroethyl chlor-
oformate (ACE-Cl) in refluxing chloroform and then refluxed
in ethanol to decompose the intermediate chloroethyl
carbamate. Reductive amination of 10 with 3-phenylpropanal
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afforded 11, which was deprotected with boron trichloride to
afford 5b as a mixture of isomers. The major, cis-isomer (as
determined by H NMR spectral analysis), selectively crystal-
lower asymptotes of the concentration−response curve. The
Emax and EC50 were calculated, and the Emax was reported as a
percentage of the Emax of the agonist standard (DAMGO, μ;
DPDPE, δ) run on the same assay plate. Measures of functional
antagonism and selectivity were obtained by measuring the
ability of test compounds to inhibit stimulated [35S]GTPγS
binding produced by the selective agonist DAMGO (μ),
DPDPE (δ), or U69,593 (κ). Agonist concentration−response
curves were run in the presence or absence of a single
concentration of test compound. At least two different
concentrations of test compound were used in these experi-
ments, and these had to cause a minimum 4-fold shift in the
agonist EC50 before a Ke was calculated. The Ke values were
calculated using the formula Ke = [L]/(DR − 1), where [L] is
the concentration of test compound and DR is the ratio of
agonist EC50 value in the presence or absence of test
compound.
1
lized as the tosylate salt from isopropanol and diethyl ether.
Compound 6b was prepared according to Scheme 2. The
aryllithium reagent prepared from 3-bromoisopropoxybenzene
(12)16 was added to N-methyl-4-piperidinone. The resulting
alcohol 13 was dehydrated with p-toluenesulfonic acid in
refluxing toluene to afford the tetrahydropyridine 14.
Deprotonation with n-butyllithium gave the blood-red anion
which was quenched with dimethylsulfate. The resulting
enamine was reduced with sodium borohydride to afford 15.
As with the preparation of 5b, reaction with ACE-Cl was
followed by refluxing 5b in methanol to afford the secondary
amine 16. Reductive amination of 16 with 3-phenylpropanal
afforded 17, which was treated with boron trichloride in
methylene chloride to yield 6b.
The preparation of 7b is shown in Scheme 3. Catalytic
hydrogenation of the readily available intermediate 1817
RESULTS AND DISCUSSION
■
The N-substituted 3,4-dimethyl-4-(3-hydroxyphenyl)-
piperidines (2) are a class of pure opioid antagonists discovered
by Zimmerman and co-workers.7−9 In 1978, Zimmerman
reported that the addition of a trans-3-methyl group to the
opioid agonist 1,4-dimethyl-4-(3-hydroxyphenyl)piperidine
(6a) gave trans-N-methyl-3,4-dimethyl-4-(3-hydroxyphenyl)-
piperidine (2a), which was a pure opioid antagonist. The
discovery of the structurally unique, pure antagonist 2a was
highly interesting, since prior to this discovery, all pure opioid
antagonists were N-allyl or N-cyclopropylmethyl analogues of
opioid agonists such as naloxone (1a) and naltrexone (1b).3
Resolution of the N-substituted trans-3,4-dimethyl-4-(3-
hydroxyphenyl)piperidines (2) showed that both the
(3R,4R)- and (3S,4S)-isomers were pure opioid antagonists
with the (3R,4R)-isomer being a more potent antagonist than
the (3S,4S)-isomer.9 However, even small alterations of the
trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine structure im-
parted opioid agonist activity to the molecule in animal
antinociceptive tests. For example, cis-N-methyl-3,4-dimethyl-4-
(3-hydroxyphenyl)piperidine (22) (Chart 1) has mixed
agonist−antagonist properties. In addition, when the 4-methyl
group of 2a was replaced with a 4-propyl group, the resulting
trans-N-methyl-3-methyl-4-propyl-4-(3-hydroxypiperidine) (3)
was a mixed agonist−antagonist.8 To our knowledge no
systematic study using the same assay has been conducted on
the N-substituted 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine
class of opioid ligands having the 3-methyl-, 4-methyl-, or both
methyl substituents removed to determine the effect that the
contribution of the 3- and 4-methyl substituents of the
piperidine ring has on antagonist properties at each of the
opioid receptors.
a
Scheme 3
a
Reagents: (a) H2, Pd(OH)2/C; (b) Ph(CH2)2CHO, NaBH3CN; (c)
BBr3, CH2Cl2.
reduced both the olefin and cleaved the N-benzyl group,
affording an intermediate of acceptable purity for reductive
amination with 3-phenylpropanal to give 19. Intermediate 19
was deprotected with boron tribromide in methylene chloride
to afford 7b.
As shown in Scheme 4, the N-arylation15 of N-methylpiper-
azine 20 with 3-bromoanisole afforded 21. Deprotection with
boron tribromide gave compound 8a.
a
Scheme 4
In this study, we compared the opioid receptor properties of
4a,b and 5a,b which have only a 3-methyl group, 6a,b which
have only a 4-methyl group, and 7a,b and 8a,b which have
neither methyl group to those of 2a,b which have both the 3-
and 4-methyl groups present. Each compound was tested for its
opioid receptor agonist and antagonist properties using the
[35S]GTPγS binding assay to gain information about the
contribution of the 3- and 4-methyl substituents on the
piperidine ring of 2a,b to the pure opioid antagonist properties
of these compounds. Zimmerman and co-workers reported that
2a had an AD50 of 0.74 mg/kg as an antagonist of morphine-
induced antinociception at the μ receptor and an AD50 of >5.0
mg/kg of κ agonist U50,488-induced antinociception in the
a
Reagents and conditions: (a) 3-bromoanisole, Pd(t-Bu3P)2, tol; (b)
BBr3, CH2Cl2.
BIOLOGY
■
All compounds were initially screened for intrinsic and
antagonist activity at 10 μM in the [35S]GTPγS binding assay
at the human μ, κ, and δ opioid receptors overexpressed in
CHO cells. Compounds identified as agonists were evaluated in
opioid receptor-appropriate assay using eight different concen-
trations selected to provide clear indication of the upper and
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a
Table 1. Inhibition of Agonist-Stimulated [35S]GTPγS Binding in Cloned Human μ, δ, and κ Opioid Receptors
Ke (nM)
compd
R
μ, DAMGO
δ, DPDPE
κ, U69,593
b
b
2a
2b
4a
4b
5a
5b
6a
6b
7a
7b
8a
8b
CH3
29.3 3.4
681 241
134 27.1
0.88 0.17
194 32
b
b
C6H5(CH2)3
CH3
0.1 0.02
0.9 0.32
d
508 26
IA
C6H5(CH2)3
CH3
0.88 0.03
1248 423
13.4 4.2
4.09 0.79
1307 447
d
IA
C6H5(CH2)3
CH3
11.9
2
46 18
16.5
5
c
974 230
5.5 0.59
agonist
477 150
21.3 9.0
2700 1300
5.8 2.0
C6H5(CH2)3
CH3
178 47
d
d
IA
IA
C6H5(CH2)3
CH3
75.6 21
418 120
d
4300 1700
8.47 1.42
1600 480
IA
C6H5(CH2)3
34.3 5.8
36.8 16.8
a
b
c
With the exception of 6a, all compounds had no agonist activity at 10 μM. Data taken from ref 15 Compound 6a had ED50 = 8300 2500 nM
d
with Emax = 64% 5% of DPDPE max. Compounds that at 10 μM caused less than a 4× shift in the agonist EC50 were considered inactive (IA).
The data represent the mean SE from at least three independent experiments.
mouse writhing test.9 Zimmerman and co-workers had
previously reported that 2a did not have any opioid receptor
agonist activity in the mouse writhing test and the rat tail heat
analgesic test.7,8 We found that 2a had Ke values of 29.3, 681,
and 134 nM at the μ, δ, and κ opioid receptors, respectively,
with no opioid agonist efficacy at 10 μM at all three opioid
receptors in a [35S]GTPγS assay. In a follow-up study to the
report by McElvain and Clemens18 that 6a was a morphine-like
opioid agonist, Zimmerman and co-workers reported that 6a
had ED50 = 3.4 mg/kg in the mouse writhing test.7 We found
nM (Table 1). Compound 7a is a weak antagonist at the κ
receptor and has no antagonist properties at the μ and δ
receptors. In contrast to the lack of antagonist properties of 7a
at the μ and δ receptors, 7b is a weak antagonist at the μ and δ
receptors with Ke values of 75.6 and 418 nM. Surprisingly, 7b,
with Ke = 5.8 nM at the κ receptor, showed 13- and 72-fold
selectivity for the κ relative to the μ and δ opioid receptors,
respectively.
In a previous study, we reported that both the N-methyl- and
N-phenylpropyl-3-methylpiperazine analogues 4a and 4b were
potent, pure opioid receptor antagonists.15 The N-methyl
compound 4a has Ke values of 508 and 194 at the μ and κ
receptors, respectively, and no antagonism at the δ receptor,
whereas the N-phenylpropyl 4b has Ke values of 0.88, 13.4, and
4.09 nM at the μ, δ, and κ receptors, respectively (Table 1). In
this study, we found that N-methyl- and N-phenylpropyl-4-(3-
hydroxyphenyl)piperidines (8a,b), which like 7a,b do not have
a 3- or 4-methyl substituent, were pure opioid antagonists.
Compound 8b, with Ke values of 8.47, 34.3, and 36.8 nM at the
μ, δ, and κ opioid receptors, was 507- and 47-fold more potent
at the μ and δ opioid receptors than 8a. Compounds 4a,b and
8a,b had no opioid agonist efficacy at 10 μM.
that 6a was a weak agonist at the δ opioid receptor with ED50
=
8300 nM and Emax = 64% and was an antagonist at the μ and κ
receptor with Ke values of 974 and 477 nM, respectively. In our
study, we even found that the N-methyl analogue 7a, which
does not have a 3- or 4-methyl, was still a pure but weak opioid
antagonist with Ke value of 2700 nM at the κ receptor, was
inactive at the μ and δ receptors, and had no agonist activity at
10 μM at all three receptors.
Zimmerman and co-workers reported that changing the N-
methyl group in 2a to the N-phenylpropyl group present in 2b
resulted in a much more potent antagonist. Compound 2b had
an AD50 value of 0.28 mg/kg for μ antagonism of morphine-
induced antinociception in the mouse writhing test compared
to 0.74 mg/kg for 2a in the test.9 Similar to 2a,b, we also found
that changing the N-methyl group in 5a, 6a, and 7a to give the
N-phenylpropyl analogues 5b, 6b, and 7b resulted in greatly
increased antagonist potency, particularly at the μ and κ
receptors with no agonist efficacy in the [35S]GTPγS binding
assay for all three compounds. Compound 5b had Ke values of
11.9 and 16.5 nM at the μ and κ receptors, respectively, and
was 105- and 79-fold more potent than 5a as an antagonist at
the μ and κ receptors (Table 1). Compound 6b with Ke values
of 5.5 and 21.3 nM at the μ and κ receptors, respectively, was
177 and 22 times more potent than 6a as an antagonist at the μ
and κ receptors. Unlike 6a, which is an agonist at the δ
receptor, 6b is an antagonist at the δ receptor with Ke = 178
1
Previous H NMR and single crystal X-ray structural studies
have suggested an equatorial orientation for the 4-(3-
hydroxyphenyl) group in the N-substituted trans-3,4-dimeth-
yl-4-(3-hydroxyphenyl)piperidine (2) class of opioid antago-
nists.19,20 The pure opioid receptor antagonists’ activity of this
class of compounds has been attributed to the compounds
having the 4-(3-hydroxyphenyl) group in the equatorial
orientation. The fact that compounds 5a,b, 6a,b, 7a,b, and
8a,b are all opioid receptor antagonists suggests that the 4-(3-
hydroxyphenyl) group in each of these compounds is in an
orientation similar to that found in the N-substituted 3,4-
dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antag-
onists.
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3-[(3R,4R)-1,3,4-Trimethylpiperidin-4-yl]phenol (2a) and 3-
[(3R,4R)-3,4-Dimethyl-1-(3-phenylpropyl)piperidin-4-yl]phenol
(2b). Compounds 2a and 2b were prepared according to a literature
method.9
In summary, a study of the in vitro functional opioid
agonist−antagonist properties of the N-substituted 4-(3-
hydroxyphenyl)piperidines 2a,b, 5a,b, 6a,b, and 7a,b revealed
that all these N-substituted 4-(3-hydroxyphenyl)piperidines
were opioid receptor antagonists at the μ and κ receptors. In
addition, all compounds with the exception of the 1,4-dimethyl-
4-(3-hydroxyphenyl)piperidine (6a) were also antagonists at
the δ opioid receptor. The very low δ opioid receptor efficacy
of ED50 = 8300 nM and antagonist properties at the μ and κ
receptors suggest that the analgesic activity seen in the animal
studies reported by McElvain and Clemens18 and Zimmerman
and co-workers7 for 6a might be due to the interaction with a
target other than the opioid receptors or metabolism to an
active metabolite. These studies show that neither the 3-methyl
nor 4-methyl substituents on the piperidine rings of 2a,b are
required to obtain potent μ and κ opioid receptor antagonists.
The study of the in vitro functional efficacy properties of the
N-methyl- and N-phenylpropyl-4-(3-hydroxyphenyl)-
piperazines (8a and 8b, respectively) revealed that both
compounds were opioid receptor antagonists at the μ, δ, and
κ receptors. Thus, the 3-methyl substituent present in 4a and
4b is not needed to obtain pure opioid antagonists in the N-
substituted 4-(3- hydroxyphenyl)piperazine class of com-
pounds.
Even though the 3- and 4-methyl substituents of 2a,b are not
required for obtaining pure opioid receptor antagonism, the
presence of these two methyl substituents does increase the
potency as an opioid receptor antagonist relative to the potency
of 5a,b, 6a,b, and 7a,b. However, compounds 5a,b, 6a,b, and
7a,b, particularly 6a,b and 7a,b which are not chiral, are much
simpler to synthesize than 2a,b. Compounds 4a,b, which have a
3-methyl substituent on the piperazine ring, are also more
potent than 8a,b which lack a 3-methyl substituent. Since
modification of the N-substituent in 2 led to alvimopam, a drug
on the market for the treatment of GI motility disorders; JDTic,
a potent and selective κ opioid receptor antagonist that is active
in several animal models of CNS disorder; and LY255582,
which was developed to treat obesity; it will be interesting to
see if additional structural modifications of 5a,b, 6a,b, and 7a,b
as well as 4a,b and 8a,b will lead to new opioid receptor
antagonists with potential for drug development.
3-[(2S)-2,4-Dimethylpiperazin-1-yl]phenol (4a) and 3-[(2S)-
2-Methyl-4-(3-phenylpropyl)piperazin-1-yl]phenol (4b). Com-
pounds 4a and 4b were synthesized as previously reported.15
3-(1,3-Dimethylpiperidin-4-yl)phenol (5a) Hydrobromide. A
solution of racemic 1,3-dimethyl-4-[3-(propan-2-yloxy)phenyl]-4-
piperidinol (9)16 (4.20 g, 15.9 mmol) was dissolved and refluxed in
12 N HCl (5 mL) and AcOH (10 mL) for 24 h. The solution was
concentrated to dryness and then dissolved in dilute NH4OH,
extracted with EtOAc, dried (Na2SO4), and concentrated to afford an
oil (3.23 g). A portion of the resulting oil (1.62 g) in EtOH (100 mL)
with 20% Pd(OH)2 on carbon (0.15 g) was shaken under 50 psi of H2
for 12 h. The solution was filtered through Celite, concentrated to a
residue, and subjected to chromatography on silica gel using a gradient
up to 50% CMA80 in CH2Cl2. The resulting oil was triturated to a
solid with CH2Cl2 and a trace of MeOH, filtered, and washed with
cold Et2O to afford 5a (1.24 g, 76% over two steps), which proved to
be the pure cis-isomer by NMR analysis. The solid was dissolved and
then concentrated from MeOH and 48% HBr to afford the
1
hydrobromide salt: mp 245−247 °C; H NMR (DMSO-d6) δ 9.32
(s, 1H), 8.99 (bs, 1H), 7.12 (t, 1H, J = 7.8 Hz), 6.67−6.55 (m, 3H),
3.54, 3.21 (m, 3H), 3.12−2.85 (m, 2H), 2.79 (d, 3H, J = 4.4 Hz),
2.37−2.31 (m, 2H), 1.94−1.76 (m, 1H), 0.76 (d, 3H, J = 7.4 Hz); 13C
NMR (DMSO-d6) δ 157.3, 143.6, 129.2, 117.6, 113.9, 113.3, 59.2,
54.2, 43.4, 40.3, 32.6, 21.5, 11.3; MS (ESI) m/z 206.2 (M + H)+. Anal.
(C13H20BrNO) C, H, N.
3-[3-Methyl-1-(3-phenylpropyl)piperidin-4-yl]phenol (5b)
Tosylate. A solution of 11 (246 mg, 0.70 mmol) in CH2Cl2 (7
mL) in a salt water−ice bath was treated with BCl3 (7 mL, 1 M in
CH2Cl2). After 30 min, the solution was washed with saturated
NaHCO3 (5 mL). The organic layer was dried (Na2SO4) and
concentrated. The residue was purified by chromatography on silica
gel using EtOAc and then 20% CH3OH in CHCl3 to obtain 174 mg
(80%) of 5b as a colorless oil that proved to be a mixture of the cis and
trans geometric isomers (4:1). The tosylate salt of the major, cis
isomer crystallized from i-PrOH/Et2O had mp 123−125 °C. 1H NMR
(CD3OD) δ 7.71 (d, 2H, J = 8.1 Hz), 7.33−7.16 (m, 7H), 7.13 (t, 1H,
J = 7.8 Hz), 6.69−6.59 (m, 3H), 3.62 (d, 1H, J = 12.0 Hz), 3.49 (d,
1H, J = 12.5 Hz), 3.32−3.21 (m, 1H), 3.18−2.97 (m, 4H), 2.70 (t, 2H,
J = 7.5 Hz), 2.44−1.96 (m, 4H), 2.35 (s, 3H), 1.89 (d, 1H, J = 14 Hz),
0.82 (d, 3H, J = 7.4 Hz); 13C NMR (CD3OD) δ 158.7, 144.6, 141.7,
141.5, 130.5, 129.9, 129.7, 129.5, 127.5, 127.0, 119.3, 115.1, 114.7,
98.2, 59.8, 58.4, 54.8, 42.7, 34.7, 33.6, 26.8, 23.2, 21.3, 11.7. Anal.
(C28H35NO4S) C, H, N.
3-(1,4-Dimethylpiperidin-4-yl)phenol (6a) Hydrochloride.
Compound 6a was synthesized as described by McElvain and
Clemens.18 1H NMR (CDCl3) δ 7.15 (t, 1H, J = 7.9 Hz), 6.81 (d,
1H, J = 8.0 Hz), 6.76 (t, 1H, J = 1.7 Hz), 6.62 (dd, 1H, J = 7.9, 1.9
Hz), 2.67−2.43 (m, 4H), 2.31 (s, 3H), 2.21−2.08 (m, 2H), 1.86−1.73
(m, 2H), 1.20 (s, 3H); 13C NMR (CDCl3) δ 157.1, 129.5, 117.1,
113.4, 113.2, 52.1, 45.7, 36.3, 35.5; MS (ESI) m/z 206.1 (M + H)+.
The free base was converted to 6a·HCl as white needles from
methanol/ether: mp 187−189 °C. Anal. (C13H20ClNO·0.25H2O) C,
H, N.
EXPERIMENTAL SECTION
■
General Procedures. All solvents were dried prior to use
according to known procedures; all reagents were obtained from
commercial sources or were synthesized from literature procedures
and were used without further purification unless otherwise noted. Air-
sensitive reactions were performed under slight positive pressure of
nitrogen. Room temperature is assumed to be between 20 and 25 °C.
Evaporation of solvents was accomplished under reduced pressure at
less than 40 °C, unless otherwise noted. Melting points were taken on
a Mel-Temp apparatus and are uncorrected. Chromatography solvent
systems are expressed in v:v ratios or as % v. CMA80 refers to a
solution of CHCl3−MeOH NH4OH−aq (80:18:2). Thin layer
chromatography was performed on aluminum oxide IB-F plated
from J. T. Baker (Phillipsburg, NJ) or silica gel 60 F254 plates from
EMD (Gibbstown, NJ). Chromatograms were visualized under UV
3-[4-Methyl-1-(3-phenylpropyl)piperidin-4-yl]phenol (6b)
Hydrochloride. A solution of 17 (98 mg, 0.45 mmol) in CH2Cl2
(5 mL) was treated with BCl3 (5 mL, 1 M in CH2Cl2) at −78 °C.
When the mixture was warmed to room temperature, the reaction was
quenched with aqueous piperazine and the mixture was refluxed for 30
min. The cooled solution was extracted with CH2Cl2. The combined
organic layers were washed with water, dried (Na2SO4), and
concentrated. The residue was subjected to chromatography on silica
1
light at 254 nm. H NMR spectra were obtained at 300 MHz on a
Bruker DPX300 spectrometer. 13C NMR spectra were obtained at 75
MHz on a Bruker DPX300 spectrometer. Chemical shift values for 1H
were determined relative to an internal tetramethylsilane standard
(0.00 ppm). Chemical shift values for 13C were determined relative to
solvent (CDCl3 = 77.23 ppm). Elemental analyses were performed by
Atlantic Microlabs, Norcross, GA. Purity of compounds (>95%) was
established by elemental analysis.
1
gel using a gradient of CMA80 in CH2Cl2 to afford 6b as an oil: H
NMR (CDCl3) δ 7.27−7.08 (m, 6H), 6.83 (d, 1H, J = 7.9 Hz), 6.76−
6.73 (m, 1H), 6.59 (dd, 1H, J = 7.9, 2.0 Hz), 5.87 (bs, 1H), 2.41−2.33
(m, 2H), 2.61−2.18 (m, 6H), 2.17−2.05 (m, 2H), 1.90−1.69 (m, 4H),
1.17 (s, 3H); 13C NMR (CDCl3) δ 156.5, 141.9, 129.4, 128.5, 128.3,
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125.8, 117.6, 113.5, 113.1, 58.4, 50.2, 36.6, 36.1, 33.9, 28.2; MS (ESI)
m/z 310.6 (M + H)+. The free base was converted to 32.5 mg (32%)
of 6b·HCl as a pale yellow powder from methanol/ether: mp 47−51
°C (fusion). Anal. (C21H28ClNO·1.25H2O) C, H, N.
3-(1-Methylpiperidin-4-yl)phenol (7a) Hydrochloride. Com-
pound 7a was synthesized as described by McElvain and Clemens.18
1H HMR (CDCl3) δ 7.12 (t, 1H, J = 7.8 Hz), 6.63−6.66 (m, 2H), 6.58
The organic layer was dried (Na2SO4) and concentrated. The residue
was purified by chromatography on silica gel with 0−40% EtOAc in
1
hexanes to yield 246 mg (55%) of 11 as a colorless oil. H NMR
(CDCl3) δ 7.34−7.13 (m, 6H), 6.80−6.67 (m, 3H), 4.54 (septet, 1H, J
= 6.0 Hz,), 3.07−2.93 (m, 1H), 2.90−2.57 (m, 4 H), 2.45−1.95 (m,
6H), 1.91−1.72 (m, 2H), 1.69−1.56 (m, 1H), 1.33 (d, 6H, J = 6.0
Hz), 0.83 (d, 3H, J = 7.0 Hz).
1-Methyl-4-[3-(propan-2-yloxy)phenyl]piperidin-4-ol (13). A
solution of n-BuLi (8.7 mL, 2.5 M in hexanes, 22 mmol) was added
dropwise to 1-bromo-3-(1-methylethoxy)benezene (12)16 (5.25 g,
24.4 mmol) in THF (14 mL) at −78 °C. After 1 h, N-methyl-4-
piperdinone (2.49 g, 22.0 mmol) was added dropwise at −78 °C. The
mixture was allowed to warm to room temperature overnight and then
was chilled to 0 °C and added to 6 M HCl (8 mL) and concentrated.
The aqueous emulsion was extracted with hexane. The organic layer
was discarded. The aqueous layer was adjusted to pH 13−14 with 2 M
NH4OH and extracted with hexane. The combined hexane layers were
(s, 1H), 3.02 (d, 2H, J = 11.7 Hz), 2.39−2.30 (m, 1H), 2.32 (s, 3H),
2.08 (t, 2H, J = 12.0 Hz), 1.73 (q, 2H, J = 13.1 Hz), 1.60 (d, 2H, J =
12.7 Hz); 13C NMR (CDCl3) δ 157.6, 147.7, 129.7, 119.1, 114.2,
113.2, 56.3, 46.2, 42.2, 32.9; MS (ESI) m/z 192.1 (M + H)+.
Concentration from HCl in CH3OH gave 7a·HCl: mp 203−206 °C.
Anal. (C12H18ClN2O) C, H, N.
3-[1-(3-Phenylpropyl)piperidin-4-yl]phenol (7b) Hydrochlor-
ide. A solution of 19 (1.0 g, 3.2 mmol) in CH2Cl2 (20 mL) at −78 °C
was treated with BBr3 (1 M in CH2Cl2, 6.78 mL). After warming to
room temperature and being stirred for 2 h, the mixture was again
cooled to −78 °C, treated with MeOH (20 mL), and then allowed to
warm to room temperature. The solution was evaporated, the residue
dissolved in MeOH (20 mL), then evaporated. The residue was
purified by chromatography on silica gel using CMA80/CH2Cl2 (1:1)
1
dried (Na2SO4) and concentrated to afford 2.29 g (42%) of 13. H
NMR (CDCl3) δ 7.25 (t, 1H, J = 7.9 Hz), 7.09−7.02 (m, 2H), 6.81−
6.76 (m, 1H), 4.56 (septet, 1H, J = 6.0 Hz), 2.79−2.70 (m, 2H), 2.51−
2.38 (m, 2H), 2.35 (s, 3H), 2.17 (td, 2H, J = 12.8, 4.2 Hz), 1.80−1.70
(m, 2H), 1.33 (d, 6H, J = 6.0 Hz).
1
to afford 0.51 g (54%) of 7b as a colorless oil. H NMR (CDCl3) δ
7.36−7.17 (m, 5H), 7.12 (t, 1H, J = 7.7 Hz), 6.77−6.60 (m, 3H), 3.66
(d, 2H, J = 12.1 Hz), 3.21−3.01 (m, 4H), 2.89−2.78 (m, 1H), 2.74 (t,
2H, J = 7.54 Hz), 2.18−1.87 (m, 6H); 13C NMR (DMSO-d6) δ 159.8,
146.4, 141.5, 130.8, 129.7, 129.5, 127.5, 118.7, 114.9, 114.6, 57.9, 54.4,
40.8, 33.6, 31.9, 26.9; ESI MS (M + H)+ 296.0. The hydrochloride salt
prepared by adding HCl (1 M in Et2O) to a solution of the free base in
Et2O gave 7b·HCl: mp 206−207 °C. Anal. (C20H26ClNO) C, H, N.
3-(4-Methylpiperazin-1-yl)phenol (8a) Dihydrochloride. A
solution of 21 in CH2Cl2 (10 mL) was treated with BBr3 (15 mL, 1 M
in CH2Cl2) at −78 °C. After warming to room temperature, the
mixture was concentrated to a residue, dissolved in aqueous piperazine
(10 mL), then refluxed for 1 h. The cooled solution was extracted with
EtOAc (3 × 25 mL). The combined organics were washed with water,
dried (Na2SO4), and concentrated. The residue was dissolved in
CH3OH, acidified with HCl (1 M in Et2O), and concentrated to yield
1-Methyl-4-[3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydro-
pyridine (14). A toluene (15 mL) solution of 13 (2.29 g, 9.2 mmol)
was refluxed with TsOH·H2O (3.50 g, 18.4 mmol) for 3 h. The cooled
solution was extracted with water, and the toluene layer was discarded.
The aqueous layer was adjusted to pH 13−14 with 2 M NaOH and
then extracted with hexane. The combined hexane layers were washed
with 2 M NaOH, dried (Na2SO4), and concentrated to afford 1.67 g
(79%) of 14. 1H NMR (CDCl3) δ 7.25−7.15 (m, 1H), 6.96 (d, 1H, J
= 8.0 Hz), 6.91 (s, 1H), 6.77 (dd, 1H, J = 8.1, 2.4 Hz), 6.05 (m, 1H),
4.55 (septet, 1H, J = 6.1 Hz), 3.13−3.08 (m, 2H), 2.69−2.63 (m, 2H),
2.61−2.53 (m, 2H), 2.40 (s, 3H), 1.33 (d, 6H, J = 6.0 Hz).
4-Dimethyl-4-[3-(propan-2-yloxy)phenyl]piperidine (15). A
solution of n-BuLi (4.5 mL, 2.5 M in hexanes, 11.3 mmol) was added
dropwise to a solution of 14 (1.67 g, 7.22 mmol) in THF (17.5 mL)
maintained between −10 and −20 °C. After 15 min, the solution was
cooled to −50 °C and dimethyl sulfate (0.77 mL, 8.1 mmol) was
slowly and cautiously added. The mixture was stirred an additional 30
min. Then 2 M NH4OH (10 mL) was added. The resulting mixture
was extracted with hexane. The hexane layer was washed with water,
dried (Na2SO4), and concentrated to a residue. The residue was
dissolved in CH3OH (20 mL), cooled in an ice bath, and treated with
NaBH4 (0.42 g, 11 mmol). The mixture was stirred for 3 h at room
temperature and then was quenched with the addition of acetone and
saturated NaHCO3. The concentrated residue was dissolved in water
and EtOAc. The aqueous layer was extracted again with EtOAc before
the combined organic layer was washed with water and then
concentrated to afford 1.45 g (81%) of 15. 1H NMR (CDCl3) δ
7.22 (t, 1H, J = 8.0 Hz), 6.91 (d, 1H, J = 7.8 Hz), 6.88 (s, 1H), 6.72
(dd, 1H, J = 8.0, 2.2 Hz), 4.54 (septet, 1H, J = 6.0 Hz), 2.54−2.33 (m,
4H), 2.56 (s, 3H), 2.20−2.08 (m, 2H), 1.81−1.70 (m, 2H), 1.34 (d,
6H, J = 6.1 Hz), 1.21 (s, 3H).
4-Methyl-4-[3-(propan-2-yloxy)phenyl]piperidine (16). A
sample of 15 (1.44 g, 5.8 mmol) was concentrated thrice from
toluene and then dissolved in 1,2-dichloroethane (8.7 mL). A freshly
distilled aliquot of 1-chloroethyl chloroformate (1.81 mL, 17.4 mmol)
was added under an inert atmosphere, and the resulting black solution
was refluxed overnight. The concentrated residue was then dissolved in
CH3OH and refluxed for 1 h. The concentrated residue was dissolved
in 2 M NaOH and extracted with CH2Cl2. The combined organic
layers were dried (Na2SO4), concentrated, and subjected to
chromatography on silica gel using a gradient of CMA80 in DCM
to afford 677 mg (50%) of 16. 1H NMR (CDCl3) δ 7.23 (t, 1H, J = 8.0
Hz), 6.94−6.86 (m, 2H), 6.72 (dd, 1H, J = 8.1, 2.3 Hz), 4.55 (septet,
1H, J = 6.0 Hz), 2.97−2.77 (m, 4H), 2.09−1.97(m, 2H), 1.74−1.59
(m, 2H), 1.34 (d, 6H, J = 6.1 Hz), 1.24 (s, 3H).
1
489 mg (54%) of 8a·HCl: H NMR (CDCl3) δ 11.4 (bs, 1H), 8.83
(bs, 2H), 7.04 (t, 1H, J = 8.1 Hz), 6.50−6.41 (m, 2H), 6.35 (d, 1H, J =
8.1 Hz), 3.72 (d, 2H, J = 8.8 Hz), 3.45 (d, 2H, J = 6.4 Hz), 3.14 (d,
4H, J = 8.6 Hz), 2.78 (s, 3H); 13C NMR (CDCl3) δ 158.3, 150.5,
129.8, 107.8, 107.1, 103.4, 51.8, 45.6, 41.8; MS (ESI) m/z 193.2 (M +
H)+. Mp 216−220 °C (fusion). Anal. (C11H18Cl2N2O·0.5H2O) C, H,
N.
3-[4-(3-Phenylpropyl)piperazin-1-yl]phenol (8b). Compound
8b was previously synthesized and reported.15
3-Methyl-4-[3-(propan-2-yloxy)phenyl]piperidine (10) Hy-
drochloride. A solution of racemic 9 was dehydrated according to
literature procedure.16 A sample of this material (5.01 g, 20.4 mmol) in
MeOH (60 mL) with 10% Pd on carbon (0.50 g) was shaken under 50
psi of H2 for 48 h. The suspension was filtered through Celite and
concentrated to provide a residue which was carried forward without
further purification. The residue was dissolved in CHCl3 (200 mL),
combined with 1-chloroethyl chloroformate (25.1 g, 0.176 mmol) and
NaHCO3 (14.0 g, 167 mmol), and refluxed 72 h, with additions of
ACE-Cl (7.8 g, 55 mmol after 12 h; 3.9 g, 27 mmol after 18 h). The
mixture was concentrated and then dissolved in a minimum of EtOH
at reflux. Upon cooling of the mixture, 0.92 g of 10·HCl (17% over
1
two steps) was collected by filtration. H NMR (CD3OD) δ 7.23 (t,
1H, J = 7.9 Hz), 6.83−6.70 (m, 3H), 4.59 (septet, 1H, J = 6.0 Hz),
3.56−3.25 (m, 3H), 3.25−3.02 (m, 2H), 2.44−2.29 (m, 1H), 2.26 (m,
1H), 1.96−1.84 (m, 1H), 1.30 (d, 6H, J = 6.0 Hz), 0.84 (d, 3H, J = 7.3
Hz); 13C NMR (CD3OD) δ 129.1, 119.0, 115.0, 113.43, 69.5, 49.7,
44.3, 41.6, 32.2, 21.0, 20.9, 10.1.
3-Methyl-1-(3-phenylpropyl)-4-[3-(propan-2-yloxy)phenyl]-
piperidine (11). A solution of 10·HCl (343 mg, 1.27 mmol) in 1,2-
dichloroethane (4.5 mL) was treated with NEt3 (362 μL, 2.6 mmol),
3-phenylpropanal (190 μL, 1.1 mmol), and NaBH(OAc)3 (393 mg,
1.85 mmol). After being stirred for 2 h, the mixture was poured into
saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 10 mL).
4-Methyl-1-(3-phenylpropyl)-4-[3-(propan-2-yloxy)phenyl]-
piperidine (17). A solution of 16 (105 mg, 0.45 mmol) and 3-
phenylpropanal (78 mg, 0.54 mmol) in trifluoroethanol (3 mL) was
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Journal of Medicinal Chemistry
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stirred for 15 min at room temperature before NaCNBH3 (60 mg, 0.9
mmol) was added. After 18 h, the solution was concentrated. The
residue was taken up in dilute NH4OH and extracted with CH2Cl2.
The concentrated organic layer was subjected to chromatography on
silica gel using a gradient of CMA80 in CH2Cl2 to afford 98 mg (62%)
Abraham, D. J., Rotella, D. P., Eds.; John Wiley & Sons, Inc.:
Hoboken, NJ, 2010; Vol. 8 (CNS Disorders), pp 569−735.
(2) Michne, W. F.; Lewis, T. R.; Michalec, S. J.; Pierson, A. K.; Gillan,
M. G. C.; Paterson, S. J.; Robson, L. E.; Kosterlitz, H. W. Novel
Developments of N-Methylbenzomorphan Narcotic Antagonists. In
Characteristics and Function of Opioids; Van Ree, J. M., Terenius, L.,
Eds.; Elsevier: Amsterdam, 1978; pp 197−206.
(3) Blumberg, H.; Dayton, H. B. Naloxone, Naltrexone and Related
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1
of 17. H NMR (CDCl3) δ 7.30−7.13 (m, 6H), 6.91 (s, 1H), 6.90−
6.86 (m, 1H), 6.71 (dd, 1H, J = 8.1, 2.0 Hz), 4.53 (septet, 1H, J = 6.1
Hz), 2.66−2.06 (m, 10H), 1.88−1.70 (m, 4H), 1.33 (d, 6H, J = 6.1
Hz), 1.20 (s, 3H).
4-(3-Methoxyphenyl)-1-(3-phenylpropyl)piperidine (19). A
solution of 1-benzyl-4-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine
(18)17 (1.14 g, 4.1 mmol) in EtOH (25 mL) with 20% Pd(OH)2 on
carbon (0.50 g) was shaken under 40 psi of H2 for 18 h. The
suspension was filtered through Celite, and the resulting solution was
treated with 3-phenylpropanal (550 mg, 4.1 mmol). After the mixture
was stirred for 30 min, NaBH3CN (0.75 g, 12 mmol) was added. After
18 h, the mixture was evaporated and the residue treated with
saturated NaHCO3 (20 mL) and extracted with EtOAc (3 × 25 mL).
The organic layer was dried over Na2SO4, filtered, and evaporated to
obtain a yellow residue. The residue was purified by chromatography
on silica gel with CMA80/CH2Cl2 (1:1) to afford 1.10 g (87%) of 19
(6) Zimmerman, D. M.; Cantrell, B. E.; Swartzendruber, J. K.; Jones,
N. D.; Mendelsohn, L. G.; Leander, J. D.; Nickander, R. C. Synthesis
and analgesic properties of N-substituted trans-4a-aryldecahydroiso-
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New structural concepts for narcotic antagonists defined in a 4-
phenylpiperidine series. Nature 1978, 275, 332−334.
1
as a colorless oil. H NMR (CDCl3) δ 7.28−7.14 (m, 6H), 6.79 (m,
3H), 3.79 (s, 3H), 3.07 (d, 2H, J = 15 Hz), 2.65 (t, 2H), 2.48 (m, 1H),
2.40 (t, 2H), 2.01 (m, 2H), 1.81 (m, 6H); 13C NMR (CDCl3) δ 159.8,
148.3, 142.4, 129.3, 128.4, 128.3, 125.8, 119.3, 112.7, 111.3, 58.6, 55.2,
54.4, 42.9, 33.9, 33.4, 28.9; ESI MS (M + H)+ 310.5.
1-(3-Methoxyphenyl)-4-methylpiperazine (21). A solution of
1-methylpiperazine (20) (500 mg, 5 mmol), 3-bromoanisole (0.94
mL, 7.5 mmol), and KO-t-Bu (842 mg, 7.5 mmol) in toluene (20 mL)
was degassed with nitrogen before Pd(t-Bu3P)2 (13 mg, 0.025 mmol)
was added. The mixture was refluxed overnight. Chromatography on
silica using a gradient of CMA80 in DCM afforded 687 mg (66%) of
21.
(8) Zimmerman, D. M.; Smits, S.; Nickander, R. Further
Investigation of Novel 3-Methyl-4-phenylpiperidine Narcotic Antago-
nists. In Proceedings of the 40th Annual Scientific Meeting of the
Committee on Problems of Drug Dependence; National Institute on Drug
Abuse: Rockville, MD, USA, 1978; pp 237−247.
(9) Zimmerman, D. M.; Leander, J. D.; Cantrell, B. E.; Reel, J. K.;
Snoddy, J.; Mendelsohn, L. G.; Johnson, B. G.; Mitch, C. H.
Structure−activity relationships of the trans-3,4-dimethyl-4-(3-
hydroxyphenyl)piperidine antagonists for μ and κ opioid receptors.
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(10) Thomas, J. B.; Mascarella, S. W.; Rothman, R. B.; Partilla, J. S.;
Xu, H.; McCullough, K. B.; Dersch, C. M.; Cantrell, B. E.;
Zimmerman, D. M.; Carroll, F. I. Investigation of the N-substituent
conformation governing potency and mu receptor subtype-selectivity
in (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antag-
onists. J. Med. Chem. 1998, 41, 1980−1990.
(11) Thomas, J. B.; Fall, M. J.; Cooper, J. B.; Rothman, R. B.;
Mascarella, S. W.; Xu, H.; Partilla, J. S.; Dersch, C. M.; McCullough, K.
B.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I. Identification of
an opioid κ receptor subtype-selective N-substituent for (+)-(3R,4R)-
dimethyl-4-(3-hydroxyphenyl)piperidine. J. Med. Chem. 1998, 41,
5188−5197.
(12) Thomas, J. B.; Atkinson, R. N.; Rothman, R. B.; Fix, S. E.;
Mascarella, S. W.; Vinson, N. A.; Xu, H.; Dersch, C. M.; Lu, Y.;
Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I. Identification of the
first trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine derivative
to possess highly potent and selective opioid kappa receptor antagonist
activity. J. Med. Chem. 2001, 44, 2687−2690.
(13) Thomas, J. B.; Atkinson, R. N.; Vinson, N. A.; Catanzaro, J. L.;
Perretta, C. L.; Fix, S. E.; Mascarella, S. W.; Rothman, R. B.; Xu, H.;
Dersch, C. M.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I.
Identification of (3R)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-
tetrahydro-3-isoquinolinecarboxamide as a novel potent and selective
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monoamine transporters and opioid receptors. Targets for addiction
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ASSOCIATED CONTENT
■
S
* Supporting Information
Elemental analysis data. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Phone: 919 541-6679. Fax: 919 541-8868. E-mail: fic@rti.org.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Institute on Drug
Abuse grant DA09045.
ABBREVIATIONS USED
■
[35S]GTPγS, sulfur-35 guanosine-5′-O-(3-thio)triphosphate;
DAMGO, [D-Ala2,MePhe4,Gly-ol5]enkephalin; DPDPE, [D-
Pen2,D-Pen5]enkephalin; U69,593, (5α,7α,8β)-(−)-N-methyl-
N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-
benzeneacetamide; CHO, Chinese hamster ovary; ACE-Cl, 1-
chloroethyl chloroformate
(15) Carroll, F. I.; Cueva, J. P.; Thomas, J. B.; Mascarella, S. W.;
Runyon, S. P.; Navarro, H. A. 1-Substituted 4-(3-hydroxyphenyl)-
piperazines are pure opioid receptor antagonists. ACS Med. Chem. Lett.
2010, 1, 365−369.
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