4β-methyl-5-(3-hydroxyphenyl)morphan opioid agonist and partial agonist derived from a 4β-methyl-5-(3-hydroxyphenyl)morphan pure antagonist

Article abstract of DOI:10.1021/jm401250s

In previous studies we reported that addition of 7α-acylamino groups to N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that additio

Full text of DOI:10.1021/jm401250s

Article
pubs.acs.org/jmc
4β-Methyl-5-(3-hydroxyphenyl)morphan Opioid Agonist and Partial
Agonist Derived from a 4β-Methyl-5-(3-hydroxyphenyl)morphan
Pure Antagonist
F. Ivy Carroll,*,† Moses G. Gichinga,† John D. Williams,† Eyal Vardy,‡ Bryan L. Roth,‡
S. Wayne Mascarella,† James B. Thomas,† and Hernan A. Navarro†
́
†Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina
27709, United States
‡National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical
Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building,
Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
ABSTRACT: In previous studies we reported that addition of 7α-acylamino
groups to N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to
compounds that were pure opioid receptor antagonists. In contrast to these
findings we report in this study that addition of a 7α-amino (5a), 7α-alkylamino
(5b−e), or 7α-dialkylamino (5f−h) group to 4 leads to opioid receptor ligands
with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-
methylamino analogues were full agonists at the μ and δ receptors and
antagonists at the κ receptor. The 7α-cyclopropylmethylamino analogue 5h was a full agonist at the μ receptor with weaker
agonist activity at the δ and κ receptors. Whereas the addition of a 7α-acylamino group to the pure nonselective opioid receptor
antagonist N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to κ selective pure opioid receptor antagonist, the
addition of a 7α-amino, 7α-alkylamino, or 7α-dialkylamino group to 4 leads to opioid ligands that are largely μ or δ agonist with
mixed agonist/antagonist properties.
-Substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)-
Npiperidines (1) are a structurally unique class of opioid
receptor antagonists.1 All N-substituted trans-3,4-dimethyl-4-
(3-hydroxyphenyl)piperidines (1) including the N-methyl
analogue 1a are opioid receptor pure antagonists at all three
opioid receptor subtypes.1−6 Numerous structure−activity
relationship (SAR) studies showed that the antagonist activity
of this class of antagonists resulted from the 3-methyl
substituent on the piperidine ring and its trans relative
relationship to the 4-methyl substituent and the equatorially
oriented 3-hydroxyphenyl group at the 4-position.2,4,7 A few of
the more interesting analogues include alvimopam (1b),8,9
which is a drug on the market for GI motility disorder, (3R,4R)-
1-[(S)-3-hydroxy-3-cyclohexylpropyl)-4-(3-hydroxyphenyl)-
3,4-dimethyl-1-piperidine (1c, LY255,582),2,10 which was
developed to treat obesity, and (3R)-7-hydroxy-N-{(1S)-1-
{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidine]-
methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinolinecar-
boxamide (1d, JDTic), which has shown activity in animal
models of cocaine relapse,11 nicotine withdrawal,12 depres-
sion,11 anxiety,13,14 and schizophrenia.15
In previous studies we showed that certain N-substituted
(1R,4S,5S,7R)-7-acylaminomorphans (2, see refs 16, 17, and 18
for specific structures) were potent and selective kappa opioid
receptor antagonists,17,18 whereas certain (1S,4R,5R,7S)-7-
acylaminomorphans (3, see refs 19, 20, and 21 for specific
structures) were potent and selective delta opioid receptor
antagonists.19−21 In the present study, we report, as expected,
that N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan
(4), which, like 2 and 3, can be viewed as a trans-3,4-
dimethyl-4-(3-hydroxyphenyl)piperidine with the 4-(3-hydrox-
yphenyl) group locked in an equatorial piperidine chair
Received: August 12, 2013
Published: October 21, 2013
© 2013 American Chemical Society
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conformation, was a nonselective opioid receptor pure
antagonist. In this study we report the surprising results that
(1R,4S,5S,7R)-7-aminomorphan (5a) and its enantiomer
(1S,4R,5R,7S)-7-aminomorphan (6) are opioid receptor partial
agonists and report the effects on the opioid receptor profile of
adding alkyl substituents to 5a to give 5b−h.
CHEMISTRY
■
7-Aminomorphans 5a and 6 were synthesized as previously
reported.20,21 Scheme 1 outlines the procedures used to
synthesize the 7-alkyl- and 7-dialkylaminomorphans 5b−e
and 5f−h, respectively. 7α-Aminomorphan (5a) was coupled
with formic acid using benzotriazol-1-yl-oxytripyrrolidinophos-
phonium hexafluorophosphate (PYBOP) in methylene chloride
containing diisopropylethylamine (DIPEA) to give the N-
formylaminomorphan 7. Reduction of the 7-formylaminomor-
phan 7 with lithium aluminum hydride (LAH) in tetrahy-
drofuran afforded 5b. Reductive amination of 5a with 1.1 equiv
of acetaldehyde, propionaldehyde, or cyclopropanecarboxalde-
hyde using sodium cyanoborohydride in 2,2,2-trifluoroethanol
yielded 7-alkylaminomorphans 5c, 5d, and 5e, respectively.
Reductive amination of 5a, 5d, and 5e with excess
paraformaldehyde using sodium cyanoborohydride provided
7-dialkylaminomorphans 5f, 5g, and 5h, respectively.
Compound 4 was synthesized starting with N-alkyl-4β-
methyl-5-phenylmorphan 8, which was prepared by a route
analogous to the one described previously (Scheme 2).18 The
ketone 8 was reduced under Clemenson reduction conditions
to provide 9. N-Demethylation of 9 was achieved in 86% yield
using 1-chloroethyl chloroformate (ACE-Cl) in refluxing
dichloroethane followed by treatment with refluxing methanol
to provide 10 (Scheme 2). Reductive amination of 10 with
phenylpropionaldehyde provided 11 in 60% yield. Treatment of
11 with boron tribromide in methylene chloride yielded 4.
BIOLOGY
■
Test compounds 4, 5a−h, and 6 were initially screened for
intrinsic and antagonist activity at 10 μM in the [35S]GTPγS
a
Scheme 1
a
Reagents: (a) Formic acid, PyBOP, DIPEA, CH2Cl2; (b) LAH, THF, (c) R1CHO, NaBH3(CN), CF3CH2OH; (d) paraformaldehyde,
NaBH3(CN), CF3CH2OH.
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a
Scheme 2
a
Reagents: (a) Zn,HCl; (b) ACE-Cl, DCE, reflux; (c) MeOH, reflux; (d) 3-phenylpropionaldehyde, NaBH3(CN), CF3CH2OH; (e) BBr3, CH2Cl2.
a
Table 1. [35S]GTPγS Binding Results for 5a−h in Cloned Human μ, δ, and κ Opioid Receptors
b
bc
,
agonist
antagonist
μ
δ
κ
μ, DAMGO
Ke (nM)
δ, DPDPE
κ, U50,488
Emax
DAMGO
%
Emax
DPDPE
%
Emax
U50,488
%
compd
R1
R2
EC50 (nM)
IA
EC50 (nM)
EC50 (nM)
Ke (nM)
Ke (nM)
4
IA
7.5
IA
IA
1.9 0.25
NT
32.7 8.9
NT
12.9 2.5
5a
6
H
H
H
19.5
20.6
15
9
2
74 12
2
101
4
IA
10.1
21.7
43.8
3
7
8
H
44
105
14
5
2
2
IA
NT
25.2
NT
8
5b
5c
5d
5e
5f
5g
5h
H
CH3
2
1
4
14.8 0.03
101 7.5
IA
NT
H
C2H5
33
IA
IA
IA
IA
NT
230 93
69.4 16
4.3 0.4
NT
60.8 19
NT
H
C3H7
18
57 11
293 129
20.7
4
3
NT
H
CH2C3H5
CH3
130 13
6.5 0.2
60 17
2.7 0.8
IA
52
104
94
2
7
5
9
IA
NT
31
4
CH3
CH3
CH3
38
6
55
24
2
2
IA
NT
176 50
93 29
NT
C2H5
IA
IA
NT
IA
CH2C3H5
109
10.3
IA
3
40 16
IA
38
NT
NT
d
13
52 22
10.3 3.7
62 20
0.09 0.04
13.2 2.6
e
14
IA
IA
IA
0.10 0.02
a
b
c
d
e
Data are from the mean SE from at least three experiments. IA > 5 μM. NT = not tested. Data taken from ref 17. Data taken from ref 21.
binding assay at the human μ, κ, and δ opioid receptors
overexpressed in CHO cells (Table 1).22 Compounds identified
as agonists were evaluated in receptor-appropriate assay using
eight different concentrations selected to provide clear
indication of the upper and lower asymptotes of the
concentration−response curve (Table 1). 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; and
U50,488, κ) 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 agonists
DAMGO (μ), DPDPE (δ), or U69,593 (κ).22 Agonist dose
response curves were run in the presence or absence of a single
concentration of test compound. 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.
Compounds 4, 5b−f, and 5h were also evaluated for
inhibition of binding to the human MOR, DOR, and KOR
using [3H]DAMGO, [3H]DADLE, and [3H]U69,593, respec-
tively, as the radioligands using previously reported meth-
ods.23,24 The results are listed in Table 2.
RESULTS AND DISCUSSION
■
In previous studies, we reported that N-methyl- and N-
phenylethyl-9β-methyl-5-(3-hydroxyphenyl)morphans (12a
and 12b, respectively), which like N-phenylpropyl-4β-methyl-
5-(3-hydroxyphenyl)morphan (4), can be viewed as a trans-3,4-
dimethyl-4-(3-hydroxyphenyl)piperidine with the 4-(3-hydrox-
yphenyl) group locked in an equatorial piperidine chair
conformation, were both nonselective opioid receptor pure
antagonists.6,16 Thus, it was not surprising that 4 was also a
nonselective opioid receptor pure antagonist with Ke values of
1.9, 32.7, and 12.9 nM at the μ, δ, and κ receptors, respectively.
The 7-aminomorphans (1R,4S,5S,7R) [5a] and its enan-
tiomer (6) were synthesized in previously reported studies as
intermediates for the synthesis of the 7-acylaminomorphans 2
and 3, respectively. Acylation of 5a with a number of acids
having an amino function in the acyl group led to several potent
and selective κ opioid receptor pure antagonists.17 For example,
compound 13 had Ke values of 0.09 nM at the κ receptor with
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epimeric 6 was a somewhat weaker agonist at μ with an IC50
=
Table 2. Binding Affinities (Ki) for 4 and 5b−f and 5h at
20.6 nM (Emax = 44%) and an antagonist at δ and κ with Ke
values of 25.2 and 21.7 nM, respectively. Since 5a was a
relatively potent agonist at the μ and δ receptors, we designed
and synthesized a series of mono- and dialkyl analogues of 5a to
see if it was possible to develop an even more potent μ/δ
agonist. The series of compounds was also designed to
determine what effect adding mono- and dialkyl groups to
the 7α-amino of 5a would have on the agonist/antagonist
activities and their subtype selectivities. The addition of a
methyl group to 5a to give the 7α-methylamino analogue 5b
resulted in an increase in μ efficacy (105% compared to 74% for
5a) with ED50 and Emax values at the δ receptor similar to those
of 5a, and an antagonist Ke value of 43.8 nM at the κ receptor
compared to 10.1 nM for 5a. Increasing the size of 5b by one
methylene group to give the N-ethylamino analogue 5c resulted
in a reduction of agonist activity at the μ receptor (EC50 = 33
nM and Emax = 14%) and complete loss of agonist activity at the
δ receptor. The compound was also a weak opioid antagonist
(Ke = 230 and 60.8 nM at δ and κ receptors, respectively).
MOR, KOR, and DOR
a
Ki (nM)
c
d
e
compound
MOR
DOR
KOR
b
Kd
1.13 0.028
1.61 0.216
0.371 0.046
3.35 0.47
1.66 0.12
7.55 1.18
0.28 0.018
0.43 0.034
1.24 0.14
160.5 14.2
36.2 5.66
264 15.7
73.8 4.18
43.2 4.31
18.4 3.12
9.04 0.80
3.26 0.34
7.79 0.69
20.92 2.60
8.22 1.78
1.40 0.20
13.67 1.74
9.9 1.80
4
5b
5c
5d
5e
5f
5h
0.92 0.096
a
The MOR, DOR, and KOR binding affinities for the synthesized
compounds were measured at the Psychoactive Drug Screening
Program (PDSP), University of North Carolina at Chapel Hill, using
competition radioligand binding assays as previously described (refs 23
b
and 24). The radioligand affinity (Kd) was determined by
homologous competition binding using receptor specific radioligands.
c
Radioligand used to determine MOR affinity is 3H-DAMGO.
d
Radioligand used to determine DOR affinity is 3H-DADLE.
e
Similar to 5c, 5d was an agonist at the μ receptor (EC50 =
3
Radioligand used to determine KOR affinity is H-U-69593.
18nM, Emax = 57%). The N-propylamino analogue had no
agonist activity at the δ receptor and was a weak antagonist at
the δ receptors (Ke = 69.4 nM). In contrast to 5c, 5d was a
weak agonist at κ receptor (EC50 = 293 nM, Emax = 20.7%).
Adding a cyclopropylmethyl group to 5a gave 5e, which was a
weak agonist at the μ receptor (EC50 = 130 nM, Emax = 52%),
potent antagonist at the δ receptor (Ke = 4.3 nM), and a
moderate antagonist at the κ receptor (Ke = 31 nM). The
addition of a methyl group to 5b to give the 7α-dimethylamino
analogue 5f resulted in a potent μ agonist (EC50 = 6.5 nM, Emax
= 104%) with weaker δ agonist potency and efficacy (EC50 = 38
nM, Emax = 55%) and a weak κ antagonist (Ke = 176 nM).
Addition of an ethyl substituent to 5b to give the 7α-
ethylmethylamino analogue 5g resulted in a weak μ agonist/κ
antagonist. Surprisingly, adding a methyl group to 5e to give
the 7α-methylcyclopropylmethyl analogue 5h resulted in the
most potent μ agonist in the series (EC50 = 2.7 nM, Emax
109%) with somewhat weaker agonist efficacy at the δ (EC50
=
=
10.3 nM, Emax = 24%) and κ (EC50 = 40 nM, Emax = 38%)
receptors.
The inhibition of radioligand binding Ki values for 4, 5b−f,
and 5h for the most part paralleled the EC50 and Ke values
obtained in the [35S]GTPγS binding assays. For example,
compound 4 had higher affinity for the MOR and KOR
receptor than the DOR receptor. In the case of the MOR
receptor, compounds 5b, 5f, and 5h had the highest affinities at
MOR, and 5e had the lowest affinity. Compounds 5c and 5d
had intermediate Ki values at MOR. It is interesting to note that
compounds 5b, 5f, and 5h all had higher affinity for MOR than
DAMGO. All of the compounds tested had weaker affinities for
the DOR than at the MOR. Compounds 5f and 5h had the
highest affinities for the DOR. Compounds 5b and 5e did not
parallel the [35S]GTPγS binding at DOR very well. Compound
5b had an EC50 = 14.8 at DOR and a Ki = 36.2 nM. Compound
5e had a Ke = 4.3 nM and a Ki = 43.2 nM at DOR. With the
exception of 5d all of the compounds tested had lower affinity
for the KOR than for the MOR. However, 5h has a Ki value of
0.43 and 0.92 nM at the MOR and KOR, respectively. This is
not too surprising since 5h had an EC50 = 40 nM at the KOR.
In an effort to visualize the structural basis for the unexpected
μ-opioid agonist activity of 5h, docking calculations were
performed using the recently reported X-ray crystallographic
578- and 689-fold selectivity relative to the μ and δ receptors
(Table 1).17 Acylation of 6 with 2-methyl-2-phenylpropionic
acid gave 14, which had Ke values of 10.3, 0.1, and 13.2 nM at
the μ, δ, and κ receptors, respectively, and, thus, was selective
for the δ opioid receptors (Table 1).20,21 Compound 14 was
also an inverse agonist with an IC50 = 0.4 nM (% of basal
binding = 64%).20,21
Since (S)-5a and 6 were intermediates used only for the
synthesis of the 7-acylaminomorphans selective pure kappa
opioid receptor antagonists (2)17 and the selective pure δ
opioid receptor antagonist (3),20,21 respectively, we only
determined their inhibition of radioligand binding at the μ, δ,
and κ receptors. The [35S]GTPγS binding properties for these
two compounds were not determined in our previous studies.
Surprisingly, in this study we found that 5a, which results from
adding a 7α-amino group to the pure opioid antagonist 4, was a
potent agonist at both the μ and δ opioid receptors and a
potent antagonist at the κ opioid receptor. The EC50 at μ was
19.5 nM (Emax = 74%), and the EC50 at δ was 7.5 nM (Emax
=
101%). The Ke value for 5a at the κ receptor was 10.1 nM. The
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structures of the MOR25 and KOR.26 However, although such
calculations27 examining the interaction of a variety of agonists
and antagonists docked to the KOR have provided reasonable
docking poses, thus far consistent results have not been
obtained for the MOR.
3-[(1R,4S,5S)-4-Methyl-2-(3-phenylpropyl)-2-azabicyclo-
[3.3.1]non-5-yl]phenol(4) Hydrochloride. To a solution of N-
phenylpropyl-4β-methyl-5-(3-(propan-2-yloxy)phenyl)morphan (11)
(100 mg, 0.26 mmol) in dichloromethane (10 mL) at −78 °C,
boron tribromide (0.51 mL, 0.51 mmol) (1 M solution in CH2Cl2)
was added dropwise. The reaction mixture was stirred at −78 °C for
30 min, treated with MeOH (10 mL), warmed to rt, and stirred for 10
min. The methanol was removed by evaporation, and the residue was
redissolved in MeOH (10 mL) and stirred for 10 min. The residue
resulting from evaporation of the methanol was treated with saturated
NaHCO3 aqueous solution (15 mL) and extracted with ethyl acetate
(3 × 15 mL). The combined organic layers were dried (Na2SO4),
filtered, and evaporated to obtain 11, which was subjected to column
chromatography on silica gel using CMA80−CH2Cl2 (1:1) as the
In summary, the nonselective opioid receptor pure
antagonist N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)-
morphan (4) is converted into agonists or mixed agonists/
antagonists by adding a 7α-amino (5a), 7α-alkylamino (5b−e),
or 7α-dialkylamino 5f−h group to 4. The 7α-amino and 7α-
methylamino analogues 5a and 5b, respectively, were full
agonists at the μ and δ receptors and antagonists at the κ
receptor. The 7α-ethylamino and 7α-propylamino analogues 5c
and 5d, respectively, were either inactive or very weak agonists
or antagonists at the δ and κ receptors. Somewhat surprising,
the 7α-cyclopropylamino analogue 5e was also a weak agonist
but a potent antagonist at the δ receptor and a somewhat
weaker antagonist at the κ receptor. Even more surprising was
the fact that the 7α-dimethylamino and 7α-cyclopropylmethy-
lamino analogues 5f and 5h were potent, full agonists at the μ
receptor. It is particularly interesting to note that acylation of
the partial agonist 5a leads to potent and selective κ opioid
receptor pure antagonists (see 13 in the table), whereas
alkylation of 5a leads to compounds with varying degrees of
agonist efficacy. Results from these studies provide unexpected
structure activity information on the N-substituted 4-(3-
hydroxyphenyl)morphan class of opioid receptor ligands.
Whereas the addition of a 7α-acylamino group to the pure
nonselective opioid receptor antagonist N-phenylpropyl-4β-
methyl-5-(3-hydroxyphenyl)morphan (4) led to κ selective
pure opioid receptor antagonist,17 the addition of a 7α-amino,
7α-alkylamino, or 7α-dialkylamino group to 4 led to opioid
ligands that are largely μ or δ agonist with mixed agonist/
antagonist properties. For the most part the [35S]GTPγS
binding data and inhibition of binding data paralleled each
other. Since 5h is a potent μ and δ agonist, this compound may
have potential for development as an analgesic. In addition,
since 5a has an opioid profile somewhat similar to
buprenorphine, this compound or further modification of this
lead structure could lead to a compound to treat opioid
addiction.
1
eluent to provide 60 mg (66%) of 4 as a colorless oil: H NMR
(CDCl3) δ 7.21−7.10 (m, 6H), 6.67 (m, 2H), 3.26 (d, 1H), 3.14 (b,
1H), 2.66 (m, 5H), 2.35 (d, 1H), 2.12 (m, 3H), 1.83 (m, 3H), 1.69−
1.55 (m, 3H), 1.37 (m, 1H), 0.72 (d, 3H); 13C NMR (CDCl3) δ
158.4, 153.6, 143.4, 130.1, 129.5, 129.4, 126.9, 117.5, 113.4, 113.2,
57.4, 55.8, 54.3, 41.1, 39.3, 34.6, 33.3, 29.8, 25.2, 23.9, 19.3; ESI MS
(M + H)+ 351.3.
The free base 4 was converted to 4·HCl salt by adding 1 M HCl in
ether to ethereal solution of product. MP 152−155 °C. [α]25 −15.7
D
(1.02, MeOH). Anal. (C24H32ClNO·0.25 H2O) C, H, N.
5-(3-Hydroxyphenyl)-4-methyl-7-methylamino-2-(3-phenyl-
prop-1-yl)-2-azabicyclo[3.3.1]nonane (5b) Dihydrochloride. To
a suspension of LAH (57 mg, 1.5 mmol) in THF (5 mL) in a 10-mL
microwave tube was added a solution of 7 (58 mg, 0.15 mmol) in
THF (1 mL) slowly. The reaction mixture was heated in the
microwave at 110 °C for 10 min. At this point TLC analysis showed
complete conversion of the starting material. The reaction mixture was
diluted with ethyl acetate (10 mL) and the solution was stirred for 10
min; then 20 mL 5% Na2CO3 solution was added slowly, and the
resulting solution was stirred for additional 10 min. The suspension
was filtered and the organic layer was separated. The aqueous layer
was extracted with ethyl acetate (3 × 10 mL), and the combined
organic layers were dried (Na2SO4), filtered, and evaporated to obtain
a yellow residue. The residue was subjected to column chromatog-
raphy on silica gel using CMA80−CH2Cl2 (1:1) as the eluent to
1
provide 32 mg (56%) of 5b as a colorless oil: H NMR (CDCl3) δ
7.29−7.10 (m, 6H), 6.63−6.71 (m, 3H), 3.30 (m, 1H), 3.17 (b, 1H),
2.85 (dd, 1H), 2.65 (m, 4H), 2.52−2.29 (m, 8H), 2.08 (m, 1H), 1.78
(quint, 2H), 1.56 (d, 1H), 1.20 (t, 1H), 1.01 (t, 1H), 0.72 (d, 3H); 13C
NMR (CDCl3) δ 157.21, 151.55, 142.59, 129.45, 128.70, 128.47,
125.88, 116.57, 113.20, 55.91, 54.68, 54.53, 53.54, 46.62, 40.19, 37.97,
33.61, 32.80, 31.25, 29.90, 29.35, 18.75; ESI MS (M + H)+ 379.5.
The free base 5b was converted to 5b·2HCl by adding 1 M HCl in
EXPERIMENTAL SECTION
■
ether to solution of product in dichloromethane. [α]25 −16.8 (0.88,
D
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
(water aspirator, 12 mmHg), 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−aq
NH4OH (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
MeOH). Anal. (C25H36Cl2N2O·2.5H2O) C, H, N.
7-Ethylamino-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenyl-
prop-1-yl)-2-azabicyclo[3.3.1]nonane (5c) Dihydrochloride. To
a solution of (−)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-
2-azabicyclo[3.3.1]nonan-7-amine [(S)-5a] hydrochloride (200 mg,
0.44 mmol) in trifluoroethanol (5 mL), triethylamine (140 mL, 1.0
mmol) was added, and the mixture was stirred for 30 min at room
temperature. Acetaldehyde (22 mg, 0.5 mmol) was added to the
reaction mixture, and stirring was continued for 10 min at which point
sodium cyanoborohydride (64 mg, 1.0 mmol) was added. TLC
analysis showed complete conversion of the starting material after 1 h.
The reaction mixture was evaporated, treated with saturated sodium
bicarbonate (5 mL), and extracted with ethyl acetate (3 × 10 mL).
The organic layer was dried (Na2SO4), filtered, and evaporated to
obtain a yellow residue. The residue was subjected to column
chromatography on silica gel using CMA80−CH2Cl2 (1:1) as the
1
were visualized under UV 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 determined relative to an internal
tetramethylsilane standard (0.00 ppm); chemical shift values for 13C
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
eluent to provide 5c (55%) as a colorless oil: H NMR (CDCl3) δ
7.31−7.10 (m, 6H), 6.62 (m, 3H), 3.33 (b, 1H), 3.18 (s, 1H), 2.87
(dd, 1H), 2.69−2.55 (m, 5H), 2.48 (t, 2H), 2.14 (m, 6H), 2.07 (m,
1H), 1.79 (quint, 2H), 1.49 (m, 2H), 1.25 (m, 2H),1.07 (t, 3H); 0.68
(d, 3H); 13C NMR (DMSO) δ 157.6, 148.3, 140.5, 129.6, 128.4, 128.2,
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126.1, 111.7, 54.1, 53.7, 53.4, 50.4, 45.5, 38.0, 35.1, 32.2, 28.5, 24.9,
24.8, 17.4, 11.3, 8.5; ESI MS (M + H)+ 393.8.
evaporated to obtain a brown residue. The residue was subjected to
column chromatography on silica gel using CMA80−CH2Cl2 (1:1) as
the eluent to provide 52 mg (60%) of a colorless oil: 1H NMR
(CDCl3) δ 7.32−7.05 (m, 6H), 6.63 (m, 3H), 3.20 (b, 1H), 3.12 (vb,
1H), 2.83 (dd, 1H), 2.65 (t, 3H), 2.49 (t, 2H), 2.34 (m, 9H), 2.05 (m,
The free base 5c was converted to 5c·2HCl by adding 1 M HCl in
ether to solution of 5c in dichloromethane. [α]25 −10.0 (0.56,
D
MeOH). Anal. (C26H38Cl2N2O·2.25H2O) C, H, N.
5-(3-Hydroxyphenyl)-4-methyl-2-(3-phenylprop-1-yl)-7-pro-
pylamino-2-azabicyclo[3.3.1]nonane (5d) Dihydrochloride. To
a solution of (−)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-
2-azabicyclo[3.3.1]nonan-7-amine [(S)-5a] hydrochloride (50 mg,
0.11 mmol) in trifluoroethanol (2 mL), triethylamine (35 mL, 0.25
mmol) was added, and the mixture was stirred for 30 min at room
temperature. Propionaldehyde (8 mg, 0.14 mmol) was added to the
reaction mixture and stirring was continued for 10 min. At this point
sodium cyanoborohydride (16 mg, 0.25 mmol) was added. TLC
analysis showed complete conversion of the starting material after 1 h.
The reaction mixture was evaporated, treated with saturated sodium
bicarbonate (5 mL), and extracted with ethyl acetate (3 × 10 mL).
The organic layer was dried (Na2SO4), filtered, and evaporated to
obtain a yellow residue. The residue was subjected to column
chromatography on silica gel using CMA80−CH2Cl2 (1:1) as the
1H), 1.79 (quint, 2H), 1.49 (m, 2H), 1.25 (m, 2H), 0.68 (d, 3H); 13
C
NMR (CDCl3) δ 156.5, 151.6, 142.4, 129.3, 128.5, 128.3, 125.7, 116.9,
113.3 (broad, 2C), 60.1, 55.6, 54.4, 53.6, 43.2, 41.4, 40.1, 38.0, 33.4,
32.1, 29.2, 27.2, 18.5; ESI MS (M + H)+ 393.7;
The free base 5f was converted to 5f·2HCl salt by adding 1 M HCl
in ether to ethereal solution of product. [α]25 −10.9 (0.51, MeOH).
D
Anal. (C26H38Cl2N2O·2.0H2O) C, H, N.
7-(N-Ethylmethylamino)-5-(3-hydroxyphenyl)-4-methyl-2-
(3-phenylprop-1-yl)-2 azabicyclo[3.3.1]nonane (5g) Dihydro-
chloride. A solution of 7-ethylamino-5-(3-hydroxyphenyl)-4-methyl-
2-(3-phenlylprop-1-yl)-2-azabicyclo[3.3.1]nonane (5c) (47 mg, 0.12
mmol) in trifluoroethanol (3 mL) was treated with paraformaldehyde,
and the reaction mixture was stirred for 10 min at room temperature.
At this point sodium cyanoborohydride (15 mg, 0.24 mmol) was
added, and the reaction mixture was stirred for 1 h. At this point TLC
analysis showed complete conversion of the starting material. The
reaction mixture was evaporated, treated with saturated sodium
bicarbonate (5 mL), and extracted with ethyl acetate (3 × 10 mL).
The organic layer was dried (Na2SO4), filtered, and evaporated to
obtain a brown residue. The residue was subjected to column
chromatography on silica gel using CMA80−CH2Cl2 (1:1) as the
1
eluent to provide 36 mg (68%) of 5d as a colorless oil: H NMR
(CDCl3) δ 7.31−7.07 (m, 6H), 6.60 (m, 3H), 3.39 (b, 2H), 3.15 (s,
1H), 2.84 (dd, 1H), 2.72−2.55 (m, 5H), 2.48 (t, 2H), 2.32 (m, 3H),
2.04 (b, 1H), 1.79 (quint, 2H), 1.51 (m, 3H), 1.25 (t, 1H), 1.08 (t,
1H); 0.90 (t, 3H), 0.67 (d, 2H); 13C NMR (CDCl3) δ 156.8, 151.8,
142.6, 129.4, 128.7, 128.4, 125.8, 117.2, 113.7, 113.1, 56.0, 54.4, 53.7,
53.1, 48.7, 47.2, 40.2, 37.9, 33.6, 32.8, 32.1, 29.3, 23.0, 18.6, 11.9; ESI
MS (M + H)+ 407.7
1
eluent to provide 27 mg (55%) of 5g as a white solid: H NMR
(CDCl3) δ 7.27−7.15 (m, 6H), 6.63 (m, 3H), 3.55 (b, 1H), 3.20 (s,
1H), 2.82 (dd, 1H), 2.64 (m, 5H), 2.51 (t, 2H), 2.30 (m, 6H), 1.79
(quint, 2H), 1.50 (m, 2H), 1.26 (t, 1H), 1.11 (t, 3H), 0.69 (d, 3H);
13C NMR (CDCl3) δ 156.8, 151.3, 142.3, 129.3, 128.5, 128.3, 125.7,
116.6, 113.9, 113.3, 57.7, 55.8, 54.5, 53.5, 50.7, 47.3, 42.4, 40.1, 37.9,
36.5, 33.4, 32.1, 29.1, 18.5, 10.9. ESI MS (M + H)+ 407.6.
The free base 5d was converted to 5d·2HCl by adding 1 M HCl in
ether to solution of product in ether. [α]25 −12.1 (0.98, MeOH).
D
Anal. (C27H40Cl2N2O·1.0H2O) C, H, N.
7-(N-Cyclopropylmethylamino)-5-(3-hydroxyphenyl)-4-
methyl-2-(3-phenylprop-1-yl)-2-azabicyclo[3.3.1]nonane (5e)
Dihydrochloride. To a solution of (−)-5-(3-hydroxyphenyl)-4-
methyl-2-(3-phenylpropyl)-2-azabicyclo-[3.3.1]nonan-7-amine [(S)-
5a] hydrochloride (100 mg, 0.22 mmol) in trifluoroethanol (5 mL),
triethylamine (70 mL, 0.5 mmol) was added, and the mixture stirred
for 30 min at room temperature. Cyclopropanecarboxaldehyde (18
mg, 0.25 mmol) was added to the reaction mixture, and stirring
continued for 10 min when sodium cyanoborohydride (32 mg, 1.0
mmol) was added. TLC analysis showed complete conversion of the
starting material after 1 h. The reaction mixture was evaporated,
treated with saturated sodium bicarbonate (5 mL) and extracted with
ethyl acetate (3 × 10 mL). The organic layer was dried (Na2SO4),
filtered, and evaporated to give a yellow residue. The residue was
subjected to column chromatography on silica gel using CMA80−
CH2Cl2 (1:1) as the eluent to provide 48 mg (52%) of 5e as a
The free base 5g was converted to 5g·2HCl salt by adding 1 M HCl
in ether to solution of product in ether. [α]25 −11.3 (0.73, MeOH).
D
Anal. (C27H40Cl2N2O·1.75H2O) C, H, N.
7-(N-Cyclopropylmethylmethylamino)-5-(3-hydroxyphen-
yl)-4-methyl-2-(3-phenylprop-1-yl)-2-azabicyclo[3.3.1]nonane
(5h) Dihydrochloride. A solution of 7-(N-cyclopropylmethylamino)-
5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylprop-1-yl)-2-azabicyclo-
[3.3.1]nonane (5e) (48 mg, 0.11 mmol) in trifluoroethanol (3 mL)
was treated with paraformaldehyde, and the reaction mixture was
stirred for 10 min at room temperature. At this point sodium
cyanoborohydride (15 mg, 0.22 mmol) was added. TLC analysis
showed complete conversion of the starting material after 1 h. The
reaction mixture was evaporated, treated with saturated sodium
bicarbonate (5 mL), and extracted with ethyl acetate (3 × 10 mL).
The organic layer was dried (Na2SO4), filtered, and evaporated to
obtain a brown residue. The residue was subjected to column
chromatography on silica gel using CMA80−CH2Cl2 (1:1) as the
eluent to provide 36 mg (73%) of a colorless oil: 1H NMR (CDCl3) δ
7.30−7.11 (m, 6H), 6.74 (m, 3H), 5.15 (b, 1H), 3.78 (m, 1H), 3.26 (s,
1H), 2.78 (dd, 1H), 2.64 (m, 5H), 2.49 (m, 5H), 2.36 (d, 2H), 2.24
(d, 1H), 1.81 (quint, 2H), 1.55 (m, 2H), 1.35 (t, 1H), 1.26 (s, 1H),
0.94 (m, 1H), 0.71−0.65 (m, 5H), 0.25 (d, 2H); 13C NMR (CDCl3) δ
156.6, 150.6, 142.1, 129.4, 128.5, 128.3, 125.8, 116.8, 113.7, 112.9,
58.8, 58.2, 55.6, 54.5, 53.5, 41.3, 40.2, 37.7, 36.7, 33.3, 31.9, 28.9, 26.4,
18.5, 7.2, 4.6, 4.4; ESI MS (M + H)+ 433.6.
1
colorless oil: H NMR (CDCl3) δ 7.20−7.00 (m, 6H), 6.60 (m, 3H),
4.37 (b, 2H), 3.45 (b, 1H), 3.16 (s, 1H), 2.83 (dd, 1H), 2.64(m, 3H),
2.49 (m, 4H), 2.33 (m, 3H), 2.06 (b, 1H), 1.79 (quint, 2H), 1.58 (d,
2H), 1.08 (t, 1H); 0.96 (m, 1H), 0.76 (d, 3H), 0.48 (d, 2H), 0.13 (d,
2H); 13C NMR (CDCl3) δ 156.7, 151.6, 142.5, 129.2, 128.5, 128.3,
125.7, 116.7, 113.1, 112.7, 55.8, 54.4, 53.3, 52.6, 51.7, 47.1, 40.1, 37.8,
33.4, 32.7, 31.8, 29.2, 18.6, 15.5, 10.8, 3.7, 3.6; ESI MS (M + H)+
419.7.
The free base 5e was converted to 5e·2HCl salt by adding 1 M HCl
in ether to solution of 5e in ether. [α]D −11.2 (0.57, MeOH). Anal.
(C28H40Cl2N2O·H2O) C, H, N.
7-Dimethylamino-5-(3-hydroxyphenyl)-4-methyl-2-(3-phe-
nylprop-1-yl)-2-azabicyclo[3.3.1]nonane (5f) Dihydrochloride.
To a solution of (−)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenyl-
propyl)-2-azabicyclo[3.3.1]nonan-7-amine [(S)-5a] hydrochloride
(100 mg, 0.22 mmol) in trifluoroethanol (5 mL), triethylamine (140
mL, 1.0 mmol) was added, and the reaction mixture was stirred for 30
min. Paraformaldehyde was added to the reaction mixture and stirred
for 10 min at room temperature. At this point sodium cyanoborohy-
dride (32 mg, 0.5 mmol) was added. The suspension was stirred
overnight then evaporated under reduce pressure, treated with
saturated sodium bicarbonate (5 mL), and extracted with ethyl acetate
(3 × 10 mL). The organic layer was dried (Na2SO4), filtered, and
The free base 5h was converted to 5h·2HCl salt by adding 1 M HCl
in ether to solution of product in ether. [α]25 −9.1 (0.66, MeOH).
D
Anal. (C29H42Cl2N2O·2.0 H2O) C, H, N.
7-Formylamino-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenyl-
prop-1-yl)-2-azabicyclo[3.3.1]nonane (7). To a cooled solution of
formic acid (14 mg, 0.3 mmol) in CH2Cl2 (5 mL), PyBOP (130 mg,
0.30 mmol) was added. To this solution was added a mixture of 7-
amino-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenprop-1-yl)-2-
azabicyclo[3.3.1]nonane [(S)-5a] (100 mg, 0.22 mmol) and
diisopropylethylamine (552 mL, 3 mmol) in CH2Cl2 (5 mL). The
combined solution was stirred at room temperature for 2 h and then
evaporated to yield a yellow residue. The residue was suspended in 5%
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aqueous Na2CO3 (15 mL), and the aqueous suspension was extracted
with EtOAc (2 × 15 mL). The combined extracts were dried
(Na2SO4), filtered and evaporated to yield a colorless oil. The oil was
subjected to flash chromatography on silica gel using CMA80−CH2Cl2
(1:1) as the eluent. Fractions containing product were pooled and
evaporated to yield 68 mg (78%) of 7 as a clear oil: 1H NMR (MeOD)
δ 7.96 (s, 1H), 7.23 (m, 6H), 6.69 (m, 3H), 4.66 (m, 1H), 3.42 (b,
1H), 3.20 (m, 1H), 2.94 (m, 1H), 2.69 (m, 5H), 2.38 (m, 4H), 1.89
(m, 3H), 1.35 (m, 3H), 0.75 (d, 3H); ESI MS (M + H)+ 393.7.
2,4-Dimethyl-5-[3-(propan-2-yloxy)phenyl]-2-azabicyclo-
[3.3.1]nonane (9). To a suspension of 2,4-dimethyl-5-[3-(propan-2-
yloxy)phenyl]-2-azabicyclo[3.3.1]nonan-7-one (8)18 (1.01 g, 3.35
mmol) in diethylether (100 mL) (2 M HCl) at 0 °C was added Zn
dust (14.2 g, 218 mmol) portion-wise over a 30-min period. HCl gas
was bubbled through the reaction solution until all the Zn0 had
reacted. The reaction mixture was poured into a mixture of water (500
mL) and chloroform (250 mL). The pH of the aqueous layer was
adjusted to 13 with 50% sodium hydroxide solution, and the insoluble
white material was removed by filtration through a Celite pad. The
filtrate was placed in a separatory funnel, and the chloroform layer was
separated, dried (Na2SO4), filtered, and evaporated to obtain 550 mg
(57%) of 9 after column chromatography using CH2Cl2−MeOH
(100% to 90%): 1H NMR (CDCl3) δ 7.12 (t, 1H), 6.80 (m, 2H), 6.74
(d, 1H), 4.56 (septet, 1H), 3.33 (dd, 1H), 3.07 (m, 1H), 2.63 (d, 1H),
2.45 (s, 3H), 2.40 (m, 1H), 2.19 (m, 2H), 1.95 (m, 1H), 1.70 (m, 3H),
1.35 (d, 6H), 0.77 (d, 3H); 13C NMR (CDCl3) δ 18.9, 22.1, 23.2, 23.8,
32.9, 37.9, 38.3, 39.8, 43.1, 54.3, 58.1, 69.8, 112.2, 113.8, 117.3, 128.9,
152.7, 157.9; ESI MS (M + H)+ 288.8.
4-Methyl-5-[3-(propan-2-yloxy)phenyl]-2-azabicyclo[3.3.1]-
nonane (10). To a solution of 2,4-dimethyl-5-[3-(propan-2-yloxy)-
phenyl]-2-azabicyclo[3.3.1]nonane (9) (260 mg, 0.9 mmol) in dry
dichloroethane was added 1-chloroethyl chloroformate (1.29 g, 9.0
mmol). The reaction mixture was refluxed overnight and cooled to
room temperature, and the solvent was evaporated in vacuo to provide
a yellow residue. The residue was dissolved in methanol (10 mL), and
the mixture was refluxed overnight. TLC analysis showed complete
conversion. The solvent was removed by evaporation, and the residue
was dissolved in water (10 mL) and basified using 50% sodium
hydroxide solution to pH 12. The product was extracted using ether (3
× 15 mL), and the combined ethereal layers were dried (Na2SO4),
filtered, and evaporated to give 210 mg (86%) of 10 as a colorless oil
after column chromatography using CHCl3−CMA80 (100% to 20%):
1H NMR (CDCl3) δ 7.12 (t, 1H), 6.66 (m, 3H), 4.46 (septet, 1H),
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.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Institute on Drug
Abuse (Grant DA09045).
ABBREVIATIONS USED
■
GPCRs, G-protein-coupled receptors; cDNAs, cDNA; SAR,
structure activity relationship; [35S]GTPγS, sulfur-35 guano-
sine-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; GDP, guanosine diphosphate; BOP, benzotriazole-1-
yloxy-tris(dimethylamino)phosphonium hexafluorophosphate;
DIPEA, diisopropylethylamine; PYBOP, benzotriazol-1-yl-oxy-
tripyrrolidinophosphonium hexafluorophosphate; ACE-Cl, 1-
chloroethylchloroformate
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1
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