Elucidation of the bioactive conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of μ-opioid receptor antagonists

Article abstract of DOI:10.1021/jm060486f

The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)pipe

Full text of DOI:10.1021/jm060486f

7278
J. Med. Chem. 2006, 49, 7278-7289
Articles
Elucidation of the Bioactive Conformation of the N-Substituted
trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Class of µ-Opioid Receptor Antagonists
Bertrand Le Bourdonnec,*,† Allan J. Goodman,†,‡ Mathieu Michaut,†,§ Hai-Fen Ye,† Thomas M. Graczyk,| Serge Belanger,|
Torsten Herbertz,† Glenn P. A. Yap, Robert N. DeHaven,| and Roland E. Dolle†
Department of Chemistry and Pharmacology, Adolor Corporation, 700 PennsylVania DriVe, Exton, PennsylVania 19341, and Department of
Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
ReceiVed April 25, 2006
The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid
receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl
trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative 3, prototypical µ-opioid antagonist in this series.
In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of
an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl
moiety. The overall modification led to a novel series of fused bicyclic derivatives of the octahydroquinolizine
chemical class, conformationally restricted analogue of 3. The constrained analogues 6 and 9 showed high
affinity toward the µ-opioid receptor. Compound 6 was found to be a µ-opioid antagonist, whereas the
constrained analogue 9 displayed potent µ-agonist activity in vitro. This study provides additional information
about the molecular determinants for µ recognition, the structural features affecting ligand binding, and the
structure function relationships.
Introduction
It is now well-established that a family of G protein-coupled
seven transmembrane receptors, designated µ-, κ-, and δ-opioid
receptors, mediates the actions of endogenous opioid peptides.
In the central, peripheral, and enteric nervous systems, activation
of opioid receptors by endogenous opioid peptides plays an
important role in both behavioral and homeostatic functions,
including nociception, reward, respiration, food intake, and
gastrointestinal motility.1 Thus, opioid antagonists may find
therapeutic uses in a number of areas. In particular, these types
(phenyl or cyclohexyl rings) separated from the piperidine
of compounds could be effective in the treatment of obesity,
nitrogen by two or three atoms.9 A more thorough understanding
alcohol dependence, psychosis, depression, and irritable bowel
of the conformational requirements of the N-substituent was also
syndrome.2-7 In 1978, Zimmerman and co-workers described
investigated using semirigid derivatives.12 The (+)-N-phenethyl
the discovery of opioid antagonist activity in a series of trans-
trans-3(R),4(R)-dimethyl-4-(3-hydroxyphenyl)piperidine (3, Fig-
ure 1) has been previously reported to bind cloned human opioid
receptors with good affinity [Ki(µ) ) 1.8 nM; Ki(κ) ) 17 nM;
Ki(δ) ) 33 nM].13 As a result of the fact that the whole
phenethyl side chain of 3 can freely rotate relative to the
piperidine ring, it is not possible to pinpoint the exact location
of this binding site relative to the rest of the molecule. The
goal of the current studies was to investigate the bioactive
conformation of the prototypical trans-3,4-dimethyl-4-(3-hy-
droxyphenyl)piperidine µ-opioid receptor antagonist 3. In this
effort, the design of more structurally constrained molecules
was undertaken. Thus, we have carried out a further structural
rigidification on this template by linking the piperidine 2- or
6-position of 3 to the benzylic position of the N-phenethyl
moiety by an ethylene chain linker. This modification yielded
a novel series of fused bicyclic structures 4-11 (Figure 1). We
now wish to report the synthesis, the opioid receptor binding
properties, the in vitro functional activity, and the modeling
study of this novel series of octahydroquinolizine derivatives.
3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (1).8 These 4-phen-
yl piperidine antagonists were structurally unique, since prior
to their discovery, opioid antagonists were generally N-allyl or
N-cyclopropylmethyl analogues of oxymorphone (naloxone, 2a,
and naltrexone, 2b, respectively).
The opioid antagonist activity in the trans-3,4-dimethyl-4-
(3-hydroxyphenyl)piperidines was a consequence of substitution
at the 3-position of the piperidine ring. The structure-activity
relationship (SAR) in this trans-3,4-dimethyl-4-(3-hydroxyphen-
yl)piperidine series has focused largely on the substitution of
the piperidine nitrogen.9-12 Hence, it has been determined that
maximum potency and selectivity for the µ-opioid receptor was
achieved when the N-substituent incorporated a lipophilic entity
* To whom correspondence should be addressed. Tel.: 1-484-595-1061.
Fax: 1-484-595-1551. E-mail: blebourdonnec@adolor.com.
† Department of Chemistry, Adolor Corporation.
‡ Postdoctoral fellow, 2004-2005.
§ Postdoctoral fellow, 2001-2003.
| Department of Pharmacology, Adolor Corporation.
University of Delaware.
10.1021/jm060486f CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/10/2006

BioactiVe Conformation of µ-Opioid Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7279
Figure 1. Structures of compounds 4-11, constrained analogues of 3.
Scheme 1. Synthesis of Key Intermediates 18, 19, 20a,ba
a Reagents and conditions: (a) Na2WO4, H2O2, H2O/CH2Cl2/CH3OH, 0-25 °C, 68%; (b) CH2dCHCH2MgCl, THF, 0-25 °C, 56% (18), 8% (19), 11%
(20a,b).
Chemistry
phenylphosphorane, under standard reaction conditions to
provide the diolefin 25. Ring-closing metathesis (RCM) of
compound 25 using a catalytic amount of Grubbs’ second-
generation catalyst, in refluxing methylene chloride, gave the
cyclized compound 27. Hydrogenation of 27 using palladium
on activated carbon generated compounds 29 and 30, which
were separated by column chromatography. Reduction of
compound 29 with borane-dimethyl sulfide complex provided
the target compound 4. Similar treatment of compound 30
produced the octahydroquinolizine derivative 5. Compounds 6
and 7 were prepared from 19 according to synthetic procedures
similar to those described for the synthesis of 4 and 5. The
absolute regio- and stereochemistry of the lactam derivative 31
was determined by X-ray crystallography (Figure 2).15 This
crystal structure established by inference the absolute config-
uration of 32, the diastereomeric analogue of 31, the synthetic
precursors 19, 22, 24, 26, and 28, and the final compounds 6
and 7.
The structures and synthesis of the octahydroquinolizine
derivatives 4-11 and related analogues 12-15 prepared in this
investigation are shown in Schemes 1-5. The synthesis of
intermediates 18, 19, and 20a,b is outlined in Scheme 1. The
key step of the chemistry relied on the addition of allylmag-
nesium chloride to the nitrone derived from (+)-(3R,4R)-4-(3-
(benzyloxy)phenyl)-3,4-dimethylpiperidine (16).12 Oxidation of
16 using sodium tungstate and hydrogen peroxide provided a
1
mixture of nitrones 17a/17b (1:4 ratio, as determined by H
NMR) that could not be separated by column chromatography.14
Addition of allylmagnesium chloride to the mixture 17a/17b
provided the hydroxylamine derivatives 18, 19, and 20a,b that
were separated by column chromatography and isolated in 56,
8, and 11% yield, respectively.
Treatment of 18 with zinc powder in acetic acid under
sonication conditions afforded the 2R-allyl piperidine derivative
21 (Scheme 2). The absolute regio- and stereochemistry of
3-((2R,4R,5R)-4,5-dimethyl-2-propylpiperidin-4-yl)phenol, ob-
tained from 21 by hydrogenation, was determined by X-ray
crystallography,14 therefore establishing the absolute configu-
ration of 21. Coupling of 21 with benzoylformic acid in the
presence of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium
tetrafluoroborate (TBTU) gave the derivative 23. This material
reacted with the Wittig reagent, potassium methylenetri-
Compounds 8-11 were synthesized utilizing similar chem-
istry to that employed in the synthesis of compounds 4-7, with
the exception that the diolefins 34a,b, were prepared in a single-
step procedure by condensation of 33a,b with 2-phenylacrylic
acid in the presence of TBTU (Scheme 3). The mixture of
diastereoisomers 20a,b, 33a,b, or 34a,b could not be separated
by column chromatography. However, ring-closing metathesis

7280 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Scheme 2. Synthesis of 4-7a
Le Bourdonnec et al.
a Reagents and conditions: (a) Zn, CH3CO2H/H2O, sonication, 25 °C, 96% (21), 59% (22); (b) C6H5COCO2H, TBTU, i-Pr2EtN, CH3CN, 25 °C, 74%
(23), 26% (24); (c) (Ph)3PCH3Br, t-BuOK, THF, C6H6, reflux, 56% (25), 71% (26); (d) Grubbs’ catalyst (second-generation), CH2Cl2, 25 °C, 65% (27), 95%
(28); (e) H2, Pd/C, C2H5OH, 25 °C, 59% (29), 27% (30), 55% (31), 15% (32); (f) BH3S(CH3)2, THF, reflux, 73% (4), 66% (5), 83% (6), 78%d (7).
Scheme 3. Synthesis of 8-11a
a Reagents and conditions: (a) Zn, CH3CO2H/H2O, sonication, 25 °C, 92%; (b) C6H5(CdCH2)CO2H, TBTU, i-Pr2EtN, CH3CN, 25 °C, 76%; (c) Grubbs’
catalyst (second-generation), CH2Cl2, 25 °C, 45% (35), 31% (36); (d) H2, Pd/C, C2H5OH, 25 °C, 55% (37a,b), 79% (38a,b); (e) BH3S(CH3)2, THF, reflux,
46% (8), 26% (9), 13% (10), 8% (11).
of the diastereomeric mixture 34a,b gave the R,â-unsaturated
lactam derivatives 35 and 36, which were readily separated by
column chromatography. Hydrogenation of 35 and 36 provided
the diastereomeric mixtures 37a,b and 38a,b, respectively.
Borane reduction of 37a,b provided the target compounds 8
and 9, which were separated by column chromatography. Similar

BioactiVe Conformation of µ-Opioid Receptor Antagonists
Scheme 4. Synthesis of 12-13a
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7281
a Reagents and conditions: (a) CH2dCHCOCl, Et3N, CH2Cl2, 25 °C, 52% (39), 45% (40); (b) Grubbs’ catalyst (second-generation), CH2Cl2, 25 °C, 74%
(41), 95% (42); (c) H2, Pd/C, C2H5OH, 25 °C, 100% (43), 100% (44); (d) BH3S(CH3)2, THF, reflux, 41% (12), 26% (13).
Scheme 5. Synthesis of 14-15a
a Reagents and conditions: (a) CH2dCHCOCl, Et3N, CH2Cl2, 25 °C, 65%; (b) Grubbs’ catalyst (second-generation), CH2Cl2, 25 °C, 100%; (c) H2, Pd/C,
C2H5OH, 25 °C, 85%; (d) BH3S(CH3)2, THF, reflux, 6% (14), 15% (15).
Figure 2. X-ray structure of 31 showing labeling of the nonhydrogen
atoms. Displacement ellipsoids are at the 20% probability level.
Figure 3. X-ray structure of 8 showing labeling of the nonhydrogen
atoms. Displacement ellipsoids are at the 20% probability level.
treatment of the diastereomeric mixture 38a,b produced com-
pounds 10 and 11. The absolute regio- and stereochemistry of
the target compound 8 was also determined by X-ray crystal-
Results and Discussion
lography (Figure 3),16 thereby establishing by inference the
absolute configuration of its diastereomeric analogue 9.
The synthesis of compounds 12 and 13 is outlined in Scheme
4. Condensation of 18 or 19 with acryloyl chloride, followed
by ring-closing metathesis of the resulting acrylamide derivatives
39 and 40, provided the R,â-unsaturated lactam derivatives 41
and 42, respectively. Hydrogenation of 41 or 42, followed by
borane reduction of the resulting lactams 43 and 44, provided
the compounds 12 and 13, respectively. The target compounds
14 and 15 were prepared from 33a,b, according to synthetic
procedures similar to those described for the synthesis of 12
and 13 (Scheme 5).
The synthesis of conformationally restricted analogues of a
lead compound often results in improvement of the specific
binding affinity for the target molecule.17-19 A highly confor-
mationally constrained molecule shaped to the complementary
binding site of the protein is expected to exhibit high affinity
due to the less entropic penalty encountered (compared to the
flexible molecule). Restricting the conformation of a biologically
active compound is also effective in determining the bioactive
conformation.19 Because the three-dimensional structure of the
µ-opioid receptor is not known, one theoretical solution to
elucidate the bioactive conformation of a ligand bound to the
µ-opioid receptor is to develop sufficiently structurally con-

7282 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Le Bourdonnec et al.
Table 1. Opioid Receptor (Μ, κ, and δ) Binding Data and in Vitro
Antagonist Activity (µ) of Compounds 2-15
strained active molecules so as to “freeze” conformational
flexibility to a minimum degree. These constrained molecules
can then be used as a template for determination of the bioactive
conformation for the lesser-constrained version of molecules
belonging to the same subset of structures. In view of these
considerations, we pursued the approach of conformationally
constrained molecules as a mimic of the bioactive conformation
and as the basis for designing new µ-opioid receptor antagonists.
Compound 3 was an appropriate molecule on which one could
apply the concept of conformationally constrained structures
as mimics of the bioactive conformation. In this study, the
rotational degrees of freedom of the N-substituent of 3 were
limited by incorporation of an ethylene bridge between the
piperidine 2- or 6-position of 3 and the benzylic position of the
N-phenethyl moiety. The overall modification led to a novel
series that may represent a conformationally constrained ana-
logue of 3 and could be a mimic of its bioactive conformation.
The derivatives 2-15 were tested for their affinities toward the
cloned human µ-, δ-, and κ-opioid receptors as measured by
their abilities to displace [3H]-diprenorphine from its specific
binding sites (see also Experimental Section). The µ-antagonist
potencies of the compounds were assessed by their abilities to
inhibit agonist (loperamide)-stimulated guanosine 5′-O-(3-[35S]-
thio)triphosphate ([35S]GTPγS) binding to membranes contain-
ing µ-opioid receptors. The µ-agonist potencies of the target
compounds were assessed by their abilities to stimulate [35S]-
GTPγS binding to membranes containing µ-opioid receptors.
We reported recently SARs at the 2R-position of the
piperidine ring of the trans-4,5-dimethyl-4-(3-hydroxyphenyl)-
piperidine µ-opioid antagonist series.14 This study showed that
only small linear alkyl groups are tolerated at the 2R-position
of the piperidine ring of this series. In particular, introduction
of an ethyl group at the 2R position of the piperidine ring of 3
(compound 48) resulted in a 35-fold decrease in µ-binding [48:
Ki(µ) ) 75 nM].
Ki(µ)a (nM)
or % inh.b @
10 µM
Ki(κ)a (nM) Ki(δ)a (nM)
or % inh.b @ or % inh.b @
10 µM 10 µM
IC50(µ)c
(nM)
compd
2a
3.7
7.3
9.2
33
(3.1-4.5)
(5.0-10)
(6.9-13)
(27-41)
2b
3
1.0
4.1
4.4
14
(0.78-1.3)
1.8
(1.8-9.1)
1.1
(3.4-5.6)
17
(9.8-20)
33
(0.76-4.4)
110
(0.30-2.0)
210
(12-25)
430
(19-57)
900
4
(99-130)
430
(310-620)
0.62
(100-420)
ndd
(330-550)
1400
(990-2100)
9.0
(730-1100)
49% ( 2%
5
6
0.54
31
(0.41-0.81)
110
(32-410)
73
(0.32-0.89) (6.3-12)
(21-45)
7
110
440
51% ( 3%
(30-410)
(120-1500)
100
8
150
190
(43-130)
0.90
(44-480)
(77-130)
65
(130-290)
2.1
e
9
(0.51-1.6)
(41-100)
(1.5-3.0)
25
(7.9-79)
280
(95-840)
40% ( 3%
10
11
12
13
14
15
26
190
(65-560)
120
(42-360)
ndd
35
(6.5-100)
37
(16-88)
710
(430-1200)
940
(130-6900)
120
(6.6-180)
16
(9.1-29)
520
(220-1200)
44% ( 3%
ndd
37% ( 3%
1000
69
220
(38-1300)
47% ( 3%
(41-360)
43% ( 3%
(650-1600) (15-300)
ndd
520
(170-1500)
a The potencies of the compounds were determined by testing the ability
of a range of concentrations of each compound to inhibit the binding of
the nonselective opioid antagonist, [3H]diprenorphine, to cloned human µ,
κ and δ opioid receptors, expressed in separate cell lines. Ki values are
geometric means and 95% confidence intervals computed from at least three
separate determinations. b The % inhibition of [3H]diprenorphine binding
to the cloned human µ-, κ-, and δ-opioid receptors using a concentration
of the competitor of 10 µM. Mean ( S.E.M. c The potencies of the
antagonists were assessed by their abilities to inhibit agonist (loperamide)
stimulated [35S]GTPγS binding to membranes containing the cloned µ opioid
receptor. d nd ) not determined. e Compound 9 is an agonist: EC50(µ) )
53 nM, 95% C. I. ) 31-93.
and spatial orientation of the phenyl ring within the binding
site relative to the piperidine ring are of critical importance for
good binding affinity toward the µ-opioid receptor. In the
functional assay, compound 6 was a potent inhibitor of
loperamide-stimulated [35S]GTPγS binding with an IC50 value
of 0.54 nM, superior to the µ in vitro antagonist activity of 3
(IC50 ) 1.1 nM), naloxone (IC50 ) 7.3 nM), and naltrexone
(IC50 ) 4.1 nM). Furthermore, compound 6 was found to be a
pure µ-opioid antagonist, because no agonist activity was
detectable for this ligand at concentrations up to 10 µM.
Compound 6 also behaved as a potent κ- and δ-opioid antagonist
in the [35S]GTPγS assay [6: IC50(κ) ) 1.2 nM, 95% C. I. )
0.41-3.8; IC50(δ) ) 16 nM, 95% C. I. ) 9.3-26]. We then
investigated the opioid binding profile and functional activity
of the other set of constrained analogues 8-11. The octahyd-
roquinolizine derivative 8 binds with only weak affinity (Ki )
73 nM) at the µ-opioid receptor. However, inversion of the
configuration of the chiral center at the carbon atom bearing
the phenyl ring of 8 resulted in a 80-fold increase in µ-opioid
receptor binding affinity [9: Ki(µ) ) 0.90 nM]. Furthermore,
the binding data (Table 1) for compound 14 (Scheme 5), which
differs from 9 by the absence of the phenyl group, supported
the critical importance of this lipophilic substituent for high
affinity binding toward the µ-opioid receptor. The octahydro-
Similarly, the octahydroquinolizine derivatives 4 and 5,
constrained analogues of 48, bind weakly to the µ-opioid
receptor (Ki ) 110 and 430 nM, respectively). Inversion of the
configuration of the chiral center at the R position of the nitrogen
atom of 4 resulted in a dramatic increase in µ-opioid receptor
binding. The octahydroquinolizine derivative 6, the diastereo-
isomeric analogue of 4, exhibited greater µ binding affinity (Ki
) 0.62 nM) than the flexible ligand 3 (Ki ) 1.8 nM). As shown
in Table 1, replacement of the phenyl group of 6 with a
hydrogen atom (compound 13, Scheme 4) resulted in over a
1500-fold decrease in µ binding. This result supports the
existence of an important lipophilic binding region for the µ
receptor in the proximity of the piperidine nitrogen-binding
site.12 Comparison of the µ binding affinity of 6 with the binding
affinity of its diastereoisomeric analogue 7 also demonstrated
that the S-stereochemistry at the carbon atom bearing the phenyl
ring was highly preferred. These results showed that the presence

BioactiVe Conformation of µ-Opioid Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7283
moiety is positioned in the axial orientation relative to the
piperidine ring is 3.1 kcal/mol higher in energy than the lowest-
energy conformer of 3. The constrained µ-opioid antagonist 6
achieves its lowest-energy conformation with both phenyl rings
connected in an equatorial orientation relative to the octahyd-
roquinolizine template. As a result of the added constraints in
the bicyclic system, the lowest-energy conformer of 6 containing
an axial hydroxyphenyl group is 8.7 kcal/mol higher in energy
than the lowest-energy conformer. The availability of the
conformationally restricted ligand 6, in which the hydroxyphen-
yl, amine, and phenyl have a (relatively) fixed 3D orientation,
allowed probing of the binding site for acceptable positions of
these pharmacophoric groups. This study provides additional
support that the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperi-
dine opioid antagonists are interacting with the µ-opioid receptor
with the hydroxyphenyl group in the equatorial conformation.
Furthermore, the low-energy conformation of 3 could be
regarded as the bioactive conformation. The high affinity of
the rigid octahydroquinolizine derivative 6 strongly supports
this assertion. In contrast to the low-energy conformation of
the constrained µ-opioid antagonist 6, the constrained µ-opioid
agonist 9 achieves the lowest-energy conformation with the
hydroxyphenyl moiety positioned in an axial orientation (Figure
5). In this conformational search, the lowest-energy conformer
of 9 with an equatorial hydroxyphenyl group is 3.9 kcal/mol
higher in energy. As illustrated in Figure 5, the phenyl moieties
of compounds 6 and 9 as well as the central piperidine nitrogen
are located in different regions, while the hydroxyphenyl groups
overlap reasonably well. This may account for the differences
of functional activity between these two ligands.
Figure 4. Comparison of the structures of the axial and equatorial
conformers of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)-
piperidines.
Figure 5. Overlay of lowest energy conformations of 3 (grey), 6
(magenta), and 9 (teal). Compounds were aligned by superposition of
the C3-C4-C5 atoms of the piperidine ring (see numbering in Figure
1).
quinolizine derivative 9 exhibited comparable µ binding affinity
(Ki ) 0.90 nM) to that of the constrained analogue 6 (Ki )
0.62 nM). Surprisingly, in the functional assay, compound 9
did not exhibit any antagonism of loperamide-stimulated [35S]-
GTPγS binding. This constrained ligand behaved functionally
as a potent full µ-opioid agonist in the functional assay with an
EC50 ) 53 nM. Compound 9 also behaved as a potent δ-opioid
agonist and a partial κ-opioid agonist in the [35S]GTPγS assay
[9: EC50(δ) ) 55 nM, 95% C. I. ) 27-65; EC50(κ) ) 200
nM, 95% C. I. ) 170-630].
Seemingly minor changes in the structure of the ligand could
then lead to fundamental changes in the nature of the ligand-
receptor interaction not only with respect to affinity but also in
the expression of efficacy. This study provided compelling
evidence that the low-energy conformation of 9 could represent
the µ-agonist bioactive conformation and that the 3-hydroxy-
phenyl axial conformation might trigger the µ-agonist properties
of 9.
As illustrated in Figure 4, the 3-hydroxyphenyl moiety in the
N-substituted 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine ana-
logues can be in either axial or equatorial positions.
Studies showed that both opioid binding affinity and antago-
nist activity were dependent on a trans relative relationship
between the 3- and 4-methyl groups in the piperidine ring and
that the pure antagonist activity in this series was mediated
through a hydroxyphenyl equatorial mode at opioid receptors.8-10
1H and 13C NMR studies20,21 and X-ray crystallographic data10
confirmed these findings. To examine the conformational
behavior of the investigated ligands, a conformational analysis
was performed. All calculations were conducted using the MOE
software.22 Stochastic conformational searches using the default
MMFF94x force field without solvation were performed to
identify the global minimum energy conformers for the proto-
typical trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine µ-
opioid receptor antagonist 3 and the octahydroquinolizine
constrained analogues 6 and 9. All conformers that were within
20 kcal/mol of the lowest-energy conformers were included in
this conformational search. As shown in Figure 5, the flexible
ligand 3 assumes an extended conformation as its lowest-energy
conformer. In this low-energy conformation, the hydroxyphenyl
moiety of 3 is positioned in an equatorial orientation. This is in
agreement with the hypothesis that a 3-hydroxyphenyl equatorial
piperidine chair conformation and the presence of the piperidine
3-methyl axial substituent mediated the antagonist properties
of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class
of opioid antagonists. Extensive work from Ivy Carroll’s group
supported this hypothesis.23 In this conformational search, the
lowest-energy conformer of 3 in which the hydroxyphenyl
Conclusion
To better understand structural requirements for a µ ligand
of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class
to interact with the µ-opioid receptor, constrained analogues of
the N-phenethyl derivative 3 were prepared. Two of the eight
constrained analogues investigated showed high affinity toward
the µ-opioid receptor. One of the active constrained analogues,
compound 6, exhibited subnanomolar µ-opioid receptor affinity
and potent µ-opioid antagonist activity. The pure antagonist
activity of compound 6 provides further evidence that opioid
ligands of this class express potent opioid antagonist activity
with their 3-hydroxyphenyl in an equatorial position. It is
hypothesized that the analogous linear arrangement of the
pharmacophoric elements (hydroxyphenyl, piperidine nitrogen,
and phenyl moieties) reflects a most probable bioactive con-
formation of the flexible ligand 3. The other active rigid
analogue, compound 9, which achieves the lowest-energy
structure with the hydroxyphenyl moiety positioned in an axial
orientation, was found to be a potent µ-opioid agonist. Col-
lectively, these findings may create a basis for further receptor
modeling and docking studies with other flexible µ ligands of
the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine series.
The information provided herein should aid in the design of
novel potent, receptor-selective antagonists based upon similar
structural architecture.

7284 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Le Bourdonnec et al.
(s, 3H), 1.41 (m, 0.5H), 1.58 (m, 0.5H), 1.78 (d, J ) 14 Hz, 1H),
1.97 (t, J ) 13 Hz, 0.5H), 2.06-2.13 (br m, 1.5H), 2.24 (m, 0.5H),
2.78-2.82, (br m, 2H), 3.08 (d, J ) 10 Hz 0.5H), 3.18 (d, J ) 11
Hz, 0.5H), 3.65 (t, J, ) 6 Hz, 0.5H), 5.05 (s, 2H), 5.08-5.17 (m,
2H), 5.88 (m, 1H), 6.13 (br s, 1H), 6.79 (d, J ) 8 Hz, 1H), 6.84
(br d, J ) 7 Hz, 2H), 7.23 (t, J ) 8 Hz, 1H), 7.33-7.45 (m, 5H);
LCMS (ESI) m/z 352 [M + H]+.
(2R,3R,4R)-2-Allyl-4-(3-benzyloxy-phenyl)-3,4-dimethyl-pip-
eridin-1-ol (20a) and (2S,3R,4R)-2-Allyl-4-(3-benzyloxy-phenyl)-
3,4-dimethyl-piperidin-1-ol (20b). 1H NMR (CDCl3) δ 0.59 (d, J
) 7 Hz, 1.2H), 1.05 (d, J ) 7 Hz, 1.6H), 1.32 (s, 3H), 1.53 (m,
0.5H), 1.73-2.00 (br m, 2H), 2.06-2.14 (br m, 0.5H), 2.23-2.33
(br m, 1H), 2.63-2.97 (br m, 3H), 3.14 (dt, J ) 11 and 3 Hz,
0.5H), 3.23 (br m, 0.5H), 5.06 (s, 2H), 5.99 (m, 1H), 6.81 (m, 1H),
7.04 (m, 2H), 7.18-7.26 (m, 1H), 7.33-7.46 (m, 5H); LCMS (ESI)
m/z 352 [M + H]+.
(2R,4R,5R)-2-Allyl-4-(3-(benzyloxy)phenyl)-4,5-dimethylpip-
eridine (21). To a solution of 18 (3 g, 8.55 mmol) in acetic acid/
water (1:1; 30 mL) was added zinc dust (2.8 g, 42.75 mmol), and
the reaction mixture was sonicated for 3 h at room temperature.
The mixture was then filtered through Celite, and the Celite was
washed with warm methanol. The filtrate was concentrated under
reduced pressure, and the residue was basified with a saturated
sodium bicarbonate solution. The mixture was extracted with ethyl
acetate, and the combined organic extracts were washed with
saturated brine, dried (Na2SO4), filtered, and evaporated to give
the desired product as a yellow oil (2.74 g, 96%). 1H NMR (CDCl3)
δ 1.01 (d, J ) 7 Hz, 3H), 1.33 (s, 3H), 1.37 (m, 1H), 1.84 (m,
1H), 2.14 (m, 3H), 2.79 (m, 2H), 2.95 (m, 1H), 5.09 (m, 4H), 5.75
(m, 1H), 6.81 (d, J ) 8 Hz, 1H), 7.03 (m, 1H), 7.21 (t, J ) 9 Hz,
2H), 7.33 (m, 1H), 7.39 (t, J ) 7 Hz, 2H), 7.44 (d, J ) 7 Hz, 2H);
LCMS (ESI) m/z 336 [M + H]+.
Experimental Section
A. Chemistry. General. All chemicals were reagent grade and
used without further purification. Thin-layer chromatography (TLC)
was performed on silica gel 6F glass-backed plates (250 microns)
from Analtech and visualized by UV 254 irradiation and iodine.
Flash chromatography was conducted using the ISCO CombiFlash
with RediSep silica gel cartridges (4 g, 12 g, 40 g, and 120 g).
Chromatographic elution solvent systems are reported as volume/
volume ratios. All 1H NMR spectra were recorded at ambient
temperature on a Bruker 400 MHz spectrometer. They are reported
in ppm on the δ scale from TMS. LC-MS data were obtained using
a Thermo-Finnigan Surveyor HPLC and a Thermo-Finnigan AQA
MS using either positive or negative electrospray ionization.
Program (positive); solvent A, 10 mM ammonium acetate, pH 4.5,
1% acetonitrile; solvent B, acetonitrile; column, Michrom Biore-
sources Magic C18 Macro Bullet; detector, PDA λ ) 220-300
nm; gradient, 96% A-100% B in 3.2 min, hold 100% B for 0.4
min. Program (negative); solvent A, 1 mM ammonium acetate, pH
4.5, 1% acetonitrile; solvent B, acetonitrile; column, Michrom
Bioresources Magic C18 Macro Bullet; detector, PDA λ ) 220-
300 nm; gradient, 96% A-100% B in 3.2 min, hold 100% B for
0.4 min. Mass spectra were obtained on a Finnigan 4000 or
VG707EHF spectrometer by the mass spectrometry laboratories at
the Department of Chemistry, University of Minnesota. Elemental
analyses were performed by Atlantic Microlabs, Norcross, GA and
are within ( 0.4% of theoretical values.
(4R,5R)-4-(3-Benzyloxy-phenyl)-4,5-dimethyl-2,3,4,5-tetrahy-
dro-pyridine 1-oxide (17a) and (3R,4R)-4-(3-Benzyloxy-phenyl)-
3,4-dimethyl-2,3,4,5-tetrahydro-pyridine 1-oxide (17b). To a
stirred solution of 16 (29.35 g, 99.49 mmol) in methanol (200 mL)
and methylene chloride (200 mL) was added a solution of sodium
tungstate (1.50 g, 3.98 mmol) in water (50 mL). To this solution
was then added hydrogen peroxide (35 mL, 298.47 mmol), and
the reaction mixture was stirred at room temperature for 18 h. The
mixture was then poured into a saturated ammonium chloride
solution (500 mL) and extracted with methylene chloride. The
combined organic extracts were dried (Na2SO4), filtered, and
evaporated. The crude product was purified by column chroma-
tography on silica, eluting with 0-5% methanol in methylene
chloride to give the mixture of 17a and 17b as a yellow gum (20.76
(2S,4R,5R)-2-Allyl-4-(3-(benzyloxy)phenyl)-4,5-dimethylpip-
eridine (22). Compound 22 was synthesized in a manner similar
to compound 21, using compound 19 as starting material: yield
1
59% (colorless oil); H NMR (CDCl3) δ 0.67 (d, J ) 7 Hz, 3H),
1.36 (s, 3H), 1.58 (d, J ) 13 Hz, 1H), 1.74 (t, J ) 12 Hz, 2H),
1.89 (m, 1H), 2.22 (m, 2H), 2.76 (d, J ) 13 Hz, 1H), 2.94 (m,
1H), 3.29 (dd, J ) 13 and 3 Hz, 1H), 5.04 (s, 2H), 5.12 (m, 2H),
5.86 (m, 1H), 6.79 (d, J ) 7 Hz, 1H), 6.89 (m, 1H), 7.31 (t, J )
8 Hz, 1H), 7.35 (t, J ) 7 Hz, 2H), 7.44 (t, J ) 13 Hz, 1H); LCMS
(ESI) m/z 336 [M + H]+.
1
g, 68%). H NMR (CDCl3) δ 0.75 and 0.83 (d, J ) 7 Hz, 3H,
regioisomers), 1.39 and 1.43 (s, 3H, regioisomers), 2.33 (m, 1H),
2.58 (dd, J ) 2 and 20 Hz, 1H), 2.92 (d, J ) 20 Hz, 1H), 3.41 (dd,
J ) 3 and 15 Hz, 1H), 3.94 (d, J ) 15 Hz, 1H), 5.06 (s, 2H),
6.82-6.89, (m, 3H), 7.26-7.43 (m, 6H); LCMS (ESI) m/z 310 [M
+ H]+.
1-((2R,4R,5R)-2-Allyl-4-(3-(benzyloxy)phenyl)-4,5-dimethylpi-
peridin-1-yl)-2-phenylethane-1,2-dione (23). To a stirred solution
of 21 (1 g, 2.99 mmol) in acetonitrile (15 mL) under a nitrogen
atmosphere was added, sequentially, N,N-diisopropylethylamine (1.6
mL, 8.97 mmol), phenylglyoxalic acid (0.54 g, 3.58 mmol), and
TBTU (1.44 g, 4.49 mmol). The reaction mixture was stirred at
room temperature for 16 h, poured into a saturated ammonium
chloride solution, and extracted with ethyl acetate. The combined
organic extracts were washed with saturated brine, dried (Na2SO4),
filtered, and evaporated. The crude material was purified by flash
column chromatography on silica, eluting with 0-20% ethyl acetate
(2R,4R,5R)-2-Allyl-4-(3-benzyloxy-phenyl)-4,5-dimethyl-pip-
eridin-1-ol (18). An oven-dried flask was charged with a solution
of 17a and 17b (25 g, 80.91 mmol) in anhydrous THF (500 mL),
and the solution, under a nitrogen atmosphere, was cooled in an
ice bath. To this solution was then added, dropwise, a 2 M solution
of allylmagnesium chloride in THF (122 mL, 244 mmol). The ice
bath was removed after the addition, and the reaction mixture was
stirred at room temperature for 1.5 h. The reaction mixture was
then poured into a mixture of a saturated ammonium chloride
solution (250 mL) and a saturated sodium bicarbonate solution (250
mL). This mixture was extracted with ethyl acetate. The combined
organic extracts were washed with brine, dried (Na2SO4), filtered,
and evaporated. The crude material was purified by silica gel
chromatography, eluting with 0-50% ethyl acetate in hexanes to
give 18 (15.90 g, 56%) as a yellow oil, 19 (2.16 g, 8%) as an orange
solid, and an inseparable mixture of 20a and 20b (3.02 g, 11%) as
a yellow oil. 18: 1H NMR (CDCl3) δ 1.04 (d, J ) 7 Hz, 3H), 1.28
(s, 3H), 1.40 (m, 1H), 1.94 (br s, 1H), 2.12 (m, 1H), 2.24 (d, J )
14 Hz, 1H), 2.64 (br m, 2H), 2.85 (br s, 1H), 2.98, (d, J ) 9 Hz,
1H), 5.05 (s, 2H), 5.09 (m, 2H), 5.83 (m, 1H), 6.52 (br s, 1H),
6.81 (d, J ) 7 Hz, 1H), 7.00 (s, 2H), 7.18-7.22 (m, 1H), 7.32-
7.45 (m, 5H); LCMS (ESI) m/z 352 [M + H]+.
1
in hexanes to give 23 as a purple foam (1.03 g, 74%). H NMR
(CDCl3) δ 0.61 (d, J ) 7 Hz, 1.7H), 0.79 (d, J ) 7 Hz, 1.3H),
1.49 (s, 1.7H), 1.52 (s, 1.3H), 1.57 (s, 1H), 1.83 (d, J ) 14 Hz,
0.4H), 1.94 (d, J ) 14 Hz, 0.6H), 2.25 (m, 1H), 2.35 (dd, J ) 14
and 6 Hz, 0.6H), 2.62, (m, 1.4H), 2.75 (m, 0.6H), 3.23 (dd, J ) 14
Hz and 3 Hz, 0.6H), 3.42 (dd, J ) 14 Hz and 3 Hz, 0.4H), 3.77
(dd, J ) 14 Hz and 3 Hz, 0.6H), 3.85 (q, J ) 8 Hz, 0.4H), 4.49
(dd, J ) 14 Hz and 3 Hz, 0.4H), 5.03 (m, 3H), 5.20 (m, 1H), 5.56
(m, 0.5H), 5.96 (m, 0.5H), 6.82 (m, 3H), 7.24 (t, J ) 9 Hz 1H),
7.33 (m, 1H), 7.37 (t, J ) 7 Hz, 2H), 7.41 (m, 2H), 7.48 (m, 2H),
7.62 (m, 1H), 7.98 (m, 2H); LCMS (ESI) m/z 468 [M + H]+.
1-((2S,4R,5R)-2-Allyl-4-(3-(benzyloxy)phenyl)-4,5-dimethylpi-
peridin-1-yl)-2-phenylethane-1,2-dione (24). Compound 24 was
synthesized in a manner similar to compound 23, using compound
22 as starting material: yield 26% (orange oil); 1H NMR (CDCl3)
δ 0.40 (d, J ) 7 Hz, 3H), 1.39 (s, 1H), 1.44 (s, 3H), 1.93 (m, 1H),
2.08 (m, 1H), 2.46 (m, 2H), 2.92 (dd, J ) 11 and 3 Hz, 1H), 3.40
(dd, J ) 15 and 7 Hz, 1H), 4.58 (m, 1H), 5.06 (s, 2H), 5.17 (m,
(2S,4R,5R)-2-Allyl-4-(3-benzyloxy-phenyl)-4,5-dimethyl-pip-
eridin-1-ol (19). 1H NMR (CDCl3) δ 0.73 (d, J ) 7 Hz, 3H), 1.36

BioactiVe Conformation of µ-Opioid Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7285
2H), 5.92 (m, 1H), 6.81 (dd, J ) 8 and 3 Hz, 1H), 6.87 (m, 2H),
7.22 (t, J ) 8 Hz, 1H), 7.33 (t, J ) 7 Hz, 1H), 7.38 (t, J ) 7 Hz,
3H), 7.44 (d, J ) 7 Hz, 2H), 7.52 (t, J ) 8 Hz, 2H), 7.65 (t, J )
8 Hz, 1H), 7.99 (d, J ) 7 Hz, 2H); LCMS (ESI) m/z 468 [M +
H]+.
and the mixture was stirred at room temperature under a hydrogen
atmosphere for 16 h. The mixture was then filtered through Celite.
The Celite was washed with warm methanol. The filtrate was then
concentrated under reduced pressure. The crude product was
purified by silica gel flash column chromatography, eluting with
0-50% ethyl acetate in hexanes. Compound 29 was obtained as a
white solid (0.22 g, 59%). Compound 30 was obtained as a colorless
oil (0.1 g, 27%).
1-((2R,4R,5R)-2-Allyl-4-(3-(benzyloxy)phenyl)-4,5-dimethylpi-
peridin-1-yl)-2-phenylprop-2-en-1-one (25). To a suspension of
methyl triphenylphosphonium bromide (0.42 g, 1.2 mmol) in
anhydrous THF (10 mL) under a nitrogen atmosphere was added
potassium tert-butoxide (0.15 g, 1.3 mmol) in one portion. The
bright yellow mixture was stirred at room temperature for 30 min
before being transferred by syringe to a solution of 23 (0.5 g, 1.1
mmol) in anhydrous benzene (10 mL). The reaction mixture was
then heated to reflux for 1.5 h. The solvents were removed under
reduced pressure, and the crude product was purified by silica gel
column chromatography, eluting with 0-20% ethyl acetate in
hexanes to give the titled product as a colorless oil (0.28 g, 56%).
1H NMR (CDCl3) δ 0.61 (d, J ) 7 Hz, 1.8H), 0.79 (d, J ) 7 Hz,
1.2H), 1.49 (s, 1.6H), 1.52 (s, 1.4H), 1.83 (d, J ) 14 Hz, 0.5H),
1.94 (d, J ) 14 Hz, 0.5H), 2.04 (m, 0.5H), 2.25 (m, 1H), 2.35 (dd,
J ) 14 and 7 Hz, 0.5H), 2.61 (m, 1.5H), 2.74 (m, 0.5H), 3.23 (dd,
J ) 14 and 2 Hz, 0.5H), 3.42 (dd, J ) 14 and 3 Hz, 0.5H), 3.77
(dd, J ) 14 and 3 Hz, 0.5H), 4.48 (dd, J ) 14 and 2 Hz, 0.5H),
5.02 (m, 3.8H), 5.19 (m, 1.2H), 5.57 (m, 0.4H), 5.96 (m, 0.6H),
6.82 (m, 3H), 7.24 (t, J ) 8 Hz 1H), 7.33 (m, 1H), 7.38 (m, 3H),
7.42 (m, 3H), 7.49 (m, 2H), 7.63 (t, J ) 7 Hz, 1H), 7.97 (m, 2H);
LCMS (ESI) m/z 466 [M + H]+.
1-((2S,4R,5R)-2-Allyl-4-(3-(benzyloxy)phenyl)-4,5-dimethylpi-
peridin-1-yl)-2-phenylprop-2-en-1-one (26). Compound 26 was
synthesized in a manner similar to compound 25, using compound
24 as starting material: yield 71% (yellow oil); 1H NMR (CDCl3)
δ 0.34 (br s, 3H), 1.34 (s, 3H), 1.73-1.84 (m, 2H), 1.99 (d, J )
14 Hz, 1H), 2.38-2.43 (m, 2H), 2.78 (t, J ) 13 Hz, 1H), 3.65 (br
s, 1H), 4.55 (br s, 1H), 5.04 (s, 2H), 5.07 (m, 2H), 5.37 (s, 1H),
5.71 (s, 1H), 5.84 (br s, 1H), 6.79 (dd, J ) 8 and 2 Hz, 1H), 6.86
(s, 2H), 7.20 (t, J ) 8 Hz, 1H), 7.31-7.38 (m, 6H), 7.42 (d, J )
13 Hz, 2H), 7.48 (d, J ) 8 Hz, 2H); LCMS (ESI) m/z 466 [M +
H]+.
1
29: H NMR (CDCl3) δ 1.28 (d, J ) 7 Hz, 3H), 1.38 (s, 3H),
1.54 (m, 2H), 1.68 (m, 2H), 1.94 (m, 2H), 2.17 (d, J ) 14 Hz,
1H), 2.98 (d, J ) 14 Hz, 1H), 3.48 (m, 1H), 3.84 (m, 1H), 4.69
(dd, J ) 14 and 4 Hz, 1H), 6.67 (d, J ) 7 Hz, 1H), 7.10 (s, 1H),
7.16 (d, J ) 13 Hz, 1H), 7.22 (m, 3H), 7.33 (m, 3H); LCMS (ESI)
m/z 350 [M + H]+.
1
30: H NMR (CDCl3) δ 1.05 (d, J ) 7 Hz, 3H), 1.30 (s, 3H),
1.53 (t, J ) 14 Hz, 2H), 1.78 (m, 1H), 1.88 (m, 1H), 1.99 (m, 1H),
2.13 (m, 2H), 2.78 (t, J ) 13 Hz, 1H), 3.60 (q, J ) 5 Hz, 1H),
3.72 (m, 1H), 4.49 (dd, J ) 14 and 5 Hz, 1H), 6.53 (dd, J ) 8 and
2 Hz, 1H), 6.85 (d, J ) 8 Hz, 1H), 6.92 (s, 1H), 7.08 (t, J ) 8 Hz,
1H), 7.13 (d, J ) 7 Hz, 2H), 7.18 (d, J ) 7 Hz, 1H), 7.24 (t, J )
7 Hz, 2H), 7.53 (br s, 1H); LCMS (ESI) m/z 350 [M + H]+.
(3S,7R,8R,9RS)-8-(3-Hydroxyphenyl)-7,8-dimethyl-3-phenyl-
hexahydro-1H-quinolizin-4(6H)-one (31). Compound 31 was
synthesized in a manner similar to compound 29, using compound
1
28 as starting material: yield 55% (white solid); H NMR (CD3-
OD) δ 0.73 (d, J ) 7 Hz, 3H), 1.44 (s, 3H), 1.65 (m, 1H), 1.77 (d,
J ) 12 Hz, 1H), 1.93 (m, 1H), 2.03 (m, 2H), 2.20 (m, 2H), 3.24
(dd, J ) 13 and 3 Hz, 1H), 3.81 (m, 2H), 4.57 (dd, J ) 13 and 2
Hz, 1H), 6.61 (dd, J ) 8 and 2 Hz, 1H), 6.73 (s, 1H), 6.78 (d, J )
13 Hz, 1H), 7.13 (t, J ) 8 Hz, 1H), 7.21 (m, 3H), 7.31 (t, J ) 7
Hz, 1H); LCMS (ESI) m/z 350 [M + H]+.
(3R,7R,8R,9RS)-8-(3-Hydroxyphenyl)-7,8-dimethyl-3-phenyl-
hexahydro-1H-quinolizin-4(6H)-one (32). Compound 32 was
synthesized in a manner similar to compound 29, using compound
1
28 as starting material: yield 15% (white solid); H NMR (CD3-
OD) δ 0.64 (d, J ) 7 Hz, 3H), 1.47 (s, 3H), 1.80 (d, J ) 13 Hz,
2H), 2.18 (m, 3H), 3.28 (dd, J ) 13 and 3 Hz, 1H), 3.33 (s, 2H),
3.67 (dd, J ) 10 and 5 Hz, 1H), 3.92 (m, 1H), 4.54 (dd, J ) 13
and 3 Hz, 1H), 6.63 (dd, J ) 7 and 2 Hz, 1H), 6.77 (s, 1H), 6.81
(d, J ) 8 Hz, 1H), 7.16 (t, J ) 8 Hz, 1H), 7.23 (m, 3H), 7.32 (t,
J ) 8 Hz, 2H); LCMS (ESI) m/z 350 [M + H]+.
(7R,8R,9RR)-8-(3-(Benzyloxy)phenyl)-7,8-dimethyl-3-phenyl-
7,8,9,9R-tetrahydro-1H-quinolizin-4(6H)-one (27). A solution of
25 (0.77 g, 1.66 mmol) in anhydrous methylene chloride (40 mL)
was purged with nitrogen for 20 min. Grubbs’ second-generation
catalyst (0.07 g, 0.08 mmol) was then added to the reaction mixture,
which was heated to reflux for 1 h. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by silica gel column chromatography, eluting with 0-20% ethyl
3-((2R,3R,7S,9RR)-2,3-Dimethyl-7-phenyl-octahydro-1H-quin-
olizin-2-yl)phenol (4). To a solution of (29; 0.22 g, 0.63 mmol) in
anhydrous THF (10 mL) was added borane-dimethyl sulfide
complex (2 M anhydrous solution in THF, 0.63 mL, 1.26 mmol),
and the reaction mixture was heated to reflux under a nitrogen
atmosphere for 16 h. The mixture was then cooled to 0 °C and
methanol (10 mL) was added. The reaction mixture was stirred at
0 °C for 1 h. A 2 M anhydrous solution of HCl in diethyl ether
was then added to the reaction mixture, which was heated to reflux
for 1 h. The solvents were removed under reduced pressure, and
the residue was taken up in methanol and stripped of solvent under
reduced pressure (this process was repeated five times). The residue
was then basified with a 1 M aqueous solution of NaOH (5 mL)
and extracted with a 10% solution of methanol in methylene
chloride. The combined organic extracts were washed with saturated
brine, dried (Na2SO4), filtered, and evaporated. Purification of the
crude product by silica gel flash column chromatography, eluting
with 0-50% ethyl acetate in hexanes, afforded the desired product
as a white solid (0.155 g, 73%): 1H NMR (CD3OD) δ 0.89 (d, J
) 7 Hz, 3H), 1.15 (s, 3H), 1.27 (m, 2H), 1.45 (m, 1H), 1.52 (m,
1H), 1.66 (m, 2H), 1.75 (m, 2H), 1.91 (m, 1H), 2.32 (dd, J ) 12
and 4 Hz, 3H), 2.77 (t, J ) 4 Hz, 1H), 2.98 (dd, J ) 12 and 4 Hz,
1H), 3.43 (dt, J ) 10 and 3 Hz, 2H), 6.47 (dd, J ) 8 and 2 Hz,
1H), 6.78 (d, J ) 9 Hz, 1H), 6.83 (m, 1H), 6.94 (t, J ) 8 Hz, 1H),
6.99 (t, J ) 8 Hz, 1H), 7.11 (t, J ) 8 Hz, 2H), 7.37 (d, J ) 7 Hz,
1H); LCMS (ESI) m/z 336 [M + H]+. Anal. (C23H29NO‚0.66H2O)
C, H, N.
1
acetate in hexanes to give 27 as a colorless oil (0.47 g, 65%). H
NMR (CDCl3) δ 1.10 (d, J ) 7 Hz, 3H), 1.37 (s, 3H), 1.62 (d, J
) 14 Hz, 0.5H), 1.68 (d, J ) 14 Hz, 0.5H), 1.92 (m, 1H), 2.23
(dd, J ) 14 and 3 Hz, 1.2H), 2.33 (dd, J ) 14 and 3 Hz, 0.8H),
2.47 (t, J ) 6 Hz, 0.6H), 2.52 (t, J ) 6 Hz, 0.4H), 2.80 (t, J ) 14
Hz, 1H), 3.79 (m, 1H), 4.20 (dd, J ) 14 Hz and 5 Hz, 1H), 5.06
(s, 2H), 6.55 (q, J ) 3 Hz, 1H), 6.84 (dd, J ) 9 and 3 Hz, 1H),
7.01 (m, 2H), 7.24 (m, 2H), 7.32 (m, 3H), 7.38 (m, 3H), 7.43 (m
3H); LCMS (ESI) m/z 438 [M + H]+.
(7R,8R,9RS)-8-(3-(Benzyloxy)phenyl)-7,8-dimethyl-3-phenyl-
7,8,9,9R-tetrahydro-1H-quinolizin-4(6H)-one (28). Compound 28
was synthesized in a manner similar to compound 27, using
compound 26 as starting material: yield 95% (yellow oil); 1H NMR
(CDCl3) δ 0.72 (d, J ) 7 Hz, 3H), 1.41 (s, 3H), 1.56 (s, 1H), 1.83
(dd, J ) 13 and 3 Hz, 1H), 2.18 (m, 2H), 2.49 (m, 1H), 2.61 (t, J
) 6 Hz, 0.6H), 2.65 (t, J ) 6 Hz, 0.4H), 3.32 (dd, J ) 14 and 3
Hz, 1H), 3.89 (m, 1H), 4.30 (dd, J ) 14 and 2 Hz, 1H), 5.07 (s,
2H), 6.62 (dd, J ) 6 and 2 Hz, 1H), 6.83 (dd, J ) 8 and 2 Hz,
1H), 6.91 (m, 1H), 7.26-7.35 (m, 5H), 7.38-7.47 (m, 6H); LCMS
(ESI) m/z 438 [M + H]+.
(3S,7R,8R,9RR)-8-(3-Hydroxyphenyl)-7,8-dimethyl-3-phenyl-
hexahydro-1H-quinolizin-4(6H)-one (29) and (3R,7R,8R,9RR)-
8-(3-Hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-quin-
olizin-4(6H)-one (30). To a solution of 27 (0.47 g, 1.07 mmol) in
ethanol (30 mL) was added 10% palladium on charcoal (catalytic),
3-((2R,3R,7R,9RR)-2,3-Dimethyl-7-phenyl-octahydro-1H-quin-
olizin-2-yl)phenol (5). Compound 5 was synthesized in a manner
similar to compound 4, using compound 30 as starting material:

7286 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Le Bourdonnec et al.
1
yield 66% (white solid); H NMR (CD3OD) δ 1.07 (d, J ) 7 Hz,
2.54 (t, J ) 7 Hz, 0.5H), 3.65 (m, 1H), 3.75 (m, 2H), 5.03 (s, 1H),
5.06 (s, 2H), 6.59 (m, 1H), 6.84 (d, J ) 7 Hz, 1H), 7.00 (m, 2H),
7.24 (m, 1H), 7.28-7.39 (m, 4H), 7.45 (m, 4H); LCMS (ESI) m/z
438 [M + H]+.
3H), 1.33 (s, 3H), 1.40 (m, 1H), 1.50 (t, J ) 14 Hz, 1H), 1.59 (m,
1H), 1.75 (m, 1H), 1.88 (m, 1H), 2.03 (m, 1H), 2.11 (dd, J ) 14
and 3 Hz, 1H), 2.18 (d, J ) 9 Hz, 1H), 2.31 (m, 2H), 2.52 (dd, J
) 14 and 4 Hz, 1H), 2.87 (m, 1H), 6.60 (m, 1H), 6.93 (m, 2H),
7.09 (t, J ) 8 Hz, 1H), 7.17 (m, 3H), 7.25 (m, 2H); LCMS (ESI)
m/z 336 [M + H]+. Anal. (C23H29NO‚0.2H2O) C, H, N.
1
36: H NMR (CDCl3) δ 0.66 (d, J ) 7 Hz, 3H), 1.35 (s, 3H),
1.64 (m, 1H), 2.07 (m, 2H), 2.37 (m, 1H), 2.69 (t, J ) 6 Hz, 0.6H),
2.73 (t, J ) 6 Hz, 0.4H), 3.05 (dt, J ) 14 and 3 Hz, 1H), 3.54 (m,
1H), 4.44 (m, 1H), 5.07 (s, 2H), 6.61 (m, 1H), 6.84 (dd, J ) 9 and
2 Hz, 1H), 7.02 (m, 2H), 7.27-7.33 (m, 4H), 7.39 (t, J ) 7 Hz,
2H), 7.44 (t, J ) 7 Hz, 4H); LCMS (ESI) m/z 438 [M + H]+.
(3R,8R,9R,9RS)-8-(3-Hydroxyphenyl)-8,9-dimethyl-3-phenyl-
hexahydro-1H-quinolizin-4(6H)-one (37a) and (3S,8R,9R,9RS)-
8-(3-Hydroxyphenyl)-8,9-dimethyl-3-phenyl-hexahydro-1I-quin-
olizin-4(6H)-one (37b). Compounds 37a,b were synthesized in a
manner similar to compound 29, using compound 35 as starting
material: yield 55% (colorless oil); 1H NMR (CDCl3) δ 0.92 (d, J
) 7 Hz, 0.7H), 0.95 (d, J ) 7 Hz, 2.3H), 1.39 (s, 1.2H), 1.41 (s,
1.8H), 1.50 (m, 1H), 1.65 (m, 1H), 1.76 (m, 1H), 1.90 (m, 1H),
2.02 (m, 1H), 2.21 (m, 1H), 3.04 (m, 1H), 3.09 (m, 1H), 3.14 (m,
1H), 3.59 (m, 1H), 3.71 (m, 0.4H), 3.84 (m, 0.6H), 4.34 (m, 0.4H),
4.57 (t, J ) 5 Hz, 0.4H), 4.61 (t, J ) 5 Hz, 0.2H), 6.67 (m, 1H),
6.93 (m, 0.5H), 6.98 (m, 1.5H), 7.14-7.25 (m, 4H), 7.28-7.37
(m, 2H); LCMS (ESI) m/z 350 [M + H]+.
3-((2R,3R,7S,9RS)-2,3-Dimethyl-7-phenyl-octahydro-1H-quin-
olizin-2-yl)phenol (6). Compound 6 was synthesized in a manner
similar to compound 4, using compound 31 as starting material:
1
yield 83% (white solid); H NMR (CD3OD) δ 0.85 (d, J ) 7 Hz,
3H), 1.28 (s, 1H), 1.33 (s, 3H), 1.36 (s, 1H), 1.49 (dd, J ) 13 and
2 Hz, 1H), 1.90 (m, 3H), 2.04 (m, 1H), 2.22 (m, 1H), 2.52 (d, J )
13 Hz, 2H), 2.68 (dd, J ) 11 and 3 Hz, 1H), 3.05 (d, J ) 12 Hz,
2H), 6.56 (dd, J ) 8 and 2 Hz, 1H), 6.72 (m, 1H), 6.75 (d, J ) 8
Hz, 1H), 7.09 (m, 2H), 7.20 (t, J ) 8 Hz, 2H), 7.63 (d, J ) 7 Hz,
2H); LCMS (ESI) m/z 336 [M + H]+. Anal. (C23H29NO) C, H, N.
3-((2R,3R,7R,9RS)-2,3-Dimethyl-7-phenyl-octahydro-1H-quin-
olizin-2-yl)phenol (7). Compound 7 was synthesized in a manner
similar to compound 4, using compound 32 as starting material:
1
yield 78% (white solid); H NMR (CD3OD) δ 0.79 (d, J ) 7 Hz,
3H), 1.38 (s, 3H), 1.57 (m, 1H), 1.67 (m, 2H), 1.83 (m, 1H), 1.98
(m, 2H), 2.09 (m, 1H), 2.33 (m, 1H), 2.42 (m, 1H), 2.68 (d, J ) 7
Hz, 1H), 2.92 (m, 3H), 6.59 (dd, J ) 8 and 2 Hz, 1H), 6.73 (m,
1H), 6.77 (d, J ) 7 Hz, 1H), 7.11 (t, J ) 8 Hz, 1H), 7.19 (m, 1H),
7.27 (m, 4H); LCMS (ESI) m/z 336 [M + H]+. Anal. (C23H29NO‚
0.5H2O) C, H, N.
(3R,8R,9R,9RR)-8-(3-Hydroxyphenyl)-8,9-dimethyl-3-phenyl-
hexahydro-1H-quinolizin-4(6H)-one (38a) and (3S,8R,9R,9RR)-
8-(3-Hydroxyphenyl)-8,9-dimethyl-3-phenyl-hexahydro-1H-quin-
olizin-4(6H)-one (38b). Compounds 38a,b were synthesized in a
manner similar to compound 29, using compound 36 as starting
(2S,3R,4R)-2-Allyl-4-(3-(benzyloxy)phenyl)-3,4-dimethylpip-
eridine (33a) and (2R,3R,4R)-2-Allyl-4-(3-(benzyloxy)phenyl)-
3,4-dimethylpiperidine (33b). Compounds 33a and 33b were
synthesized in a manner similar to compound 21, using 20a,b as
starting material: yield 92% (yellow oil); 1H NMR (CDCl3) δ 0.59
(d, J ) 7 Hz, 1.6H), 1.01 (d, J ) 7 Hz, 1.4H), 1.32 (s, 1.6H), 1.37
(s, 1.4H), 1.48 (m, 0.7H), 1.62 (m, 0.3H), 1.79 (m, 0.5H), 1.88 (m,
0.5H), 2.05 (m, 2H), 2.50 (d, J ) 13 Hz, 1H), 2.69 (dt, J ) 13 and
3 Hz, 1H), 2.91 (m, 1H), 2.99 (m, 1H), 5.06 (s, 2H), 5.16 (m, 1H),
6.81 (m, 1H), 7.06 (m, 2H), 7.23 (m, 1H), 7.34 (m, 1H), 7.39 (t, J
) 7 Hz, 2H), 7.44 (m, 2H); LCMS (ESI) m/z 336 [M + H]+.
1-((2S,3R,4R)-2-Allyl-4-(3-(benzyloxy)phenyl)-3,4-dimethylpi-
peridin-1-yl)-2-phenylprop-2-en-1-one (34a) and 1-((2R,3R,4R)-
2-Allyl-4-(3-(benzyloxy)phenyl)-3,4-dimethylpiperidin-1-yl)-2-
phenylprop-2-en-1-one (34b). To a stirred solution of 33a,b (1.26
g, 3.76 mmol) in acetonitrile (20 mL) under a nitrogen atmosphere
was added, sequentially, N,N-diisopropylethylamine (2.0 mL, 11.28
mmol), R-methylene benzeneacetic acid (670 mg, 4.51 mmol), and
TBTU (1.81 g, 5.64 mmol). The reaction mixture was stirred at
room temperature for 16 h, poured into a saturated ammonium
chloride solution, and extracted with ethyl acetate. The combined
organic extracts were washed with saturated brine, dried (Na2SO4),
filtered, and evaporated. The crude material was purified by flash
chromatography on silica, eluting with 0-20 ethyl acetate in
hexanes to give 34a,b as a colorless oil (1.33 g, 76%): 1H NMR
(CDCl3) δ 0.22 (d, J ) 7 Hz, 0.8H), 0.67 (d, J ) 7 Hz, 2.2H),
1.42 (s, 2.4H), 1.44 (s, 0.6H), 1.62 (m, 0.3H), 1.71 (s, 0.7H), 2.03
(m, 1H), 2.17 (q, J ) 7 Hz, 1H), 2.59-2.75 (m, 2H), 2.99 (dt, J )
13 and 2 Hz, 3H), 3.31 (dt, J ) 13 and 2 Hz, 0.7H), 3.67 (m,
0.3H), 3.76 (d, J ) 14 Hz, 0.7H), 4.77 (t, J ) 14 Hz, 0.7H), 4.83
(d, J ) 15 Hz, 0.3H), 5.01 (s, 0.6H), 5.02 (s, 1.4H), 5.33 (s, 0.8H),
5.35 (s, 0.2H), 5.51 (m, 0.3H), 5.63 (s, 0.3H), 5.73 (s, 0.7H), 5.97
(m, 0.7H), 6.78 (m, 3H), 7.24 (t, J ) 13 Hz, 1H), 7.28-7.51 (m,
11H); LCMS (ESI) m/z 466 [M + H]+.
1
material: yield 79% (white solid); H NMR (CDCl3) δ 0.60 (d, J
) 7 Hz, 3H), 1.37 (s, 3H), 1.57 (m, 2H), 1.91 (br s, 2H), 2.02 (br
s, 2H), 2.15 (m, 1H), 2.87 (br s, 1H), 3.39 (br s, 0.7H), 3.46 (br s,
0.3H), 3.92 (br s, 1H), 4.78 (br s, 0.3H), 4.89 (br s, 0.7H), 6.67 (d,
J ) 8 Hz, 1H), 6.91 (m, 2H), 7.18 (t, J ) 8 Hz, 1H), 7.25 (m, 3H),
7.35 (m, 2H); LCMS (ESI) m/z 350 [M + H]+.
3-((1R,2R,7R,9RS)-1,2-Dimethyl-7-phenyl-octahydro-1H-quin-
olizin-2-yl)phenol (8) and 3-((1R,2R,7S,9RS)-1,2-Dimethyl-7-
phenyl-octahydro-1H-quinolizin-2-yl)phenol (9). Compounds 8
and 9 were synthesized in a manner similar to compound 4, using
compounds 37a,b as starting materials. Compound 8 was obtained
as a white solid in 46% yield. Compound 9 was obtained as a white
solid in 26% yield.
1
8: H NMR (CD3OD) δ 1.06 (d, J ) 7 Hz, 3H), 1.34 (s, 3H),
1.45 (br s, 1H), 1.77 (m, 3H), 1.93 (m, 3H), 2.58 (m, 4H), 2.92 (d,
J ) 4 Hz, 1H), 3.15 (dd, J ) 15 and 4 Hz, 1H), 6.58 (m, 1H), 6.97
(m, 2H), 7.08 (t, J ) 8 Hz, 1H), 7.14 (m, 1H), 7.26 (t, J ) 8 Hz,
2H), 7.49 (t, J ) 7 Hz, 2H); LCMS (ESI) m/z 336 [M + H]+.
Anal. (C23H29NO‚0.2H2O) C, H, N.
1
9: H NMR (CD3OD) δ 1.13 (d, J ) 7 Hz, 3H), 1.36 (s, 3H),
1.59 (dd, J ) 13 and 3 Hz, 1H), 1.67 (m, 1H), 1.90 (m, 1H), 1.97
(m, 1H), 2.05 (m, 1H), 2.14 (m, 1H), 2.23 (t, J ) 11 Hz, 1H), 2.40
(t, J ) 12 Hz, 1H), 2.63 (m, 1H), 2.85 (m, 2H), 6.58 (m, 1H), 6.96
(m, 2H), 7.09 (t, J ) 8 Hz, 1H), 7.16 (m, 1H), 7.24 (m, 4H); LCMS
(ESI) m/z 336 [M + H]+. Anal. (C23H29NO‚0.5H2O) C, H, N.
3-((1R,2R,7R,9RR)-1,2-Dimethyl-7-phenyl-octahydro-1H-quin-
olizin-2-yl)phenol (10) and 3-((1R,2R,7S,9RR)-1,2-Dimethyl-7-
phenyl-octahydro-1H-quinolizin-2-yl)phenol (11). Compounds 10
and 11 were synthesized in a manner similar to compound 4, using
compounds 38a,b as starting materials. Compound 10 was obtained
as a white solid in 13% yield. Compound 11 was obtained as a
white solid in 8% yield.
1
10: H NMR (CD3OD) δ 0.56 (d, J ) 7 Hz, 3H), 1.30 (s, 3H),
(8R,9R,9RS)-8-(3-(Benzyloxy)phenyl)-8,9-dimethyl-3-phenyl-
7,8,9,9R-tetrahydro-1H-quinolizin-4(6H)-one (35) and (8R,9R,
9RR)-8-(3-(Benzyloxy)phenyl)-8,9-dimethyl-3-phenyl-7,8,9,9R-
tetrahydro-1H-quinolizin-4(6H)-one (36). Compounds 35 and 36
were synthesized in a manner similar to compound 27, using
compounds 34a,b as starting material. Compound 35 was obtained
as a brown oil in 45% yield. Compound 36 was obtained as a brown
foam in 31% yield.
1.34 (s, 1H), 1.47 (br s, 1H), 1.72 (m, 1H), 1.81 (m, 1H), 1.97 (m,
1H), 2.08 (br s, 1H), 2.21 (m, 1H), 2.30 (br s, 1H), 2.66 (m, 3H),
2.97 (t, J ) 4 Hz, 1H), 3.25 (m, 1H), 6.58 (m, 1H), 6.88 (m, 2H),
7.10 (t, J ) 8 Hz, 1H), 7.16 (t, J ) 8 Hz, 1H), 7.29 (t, J ) 8 Hz,
2H), 7.51 (t, J ) 8 Hz, 2H); LCMS (ESI) m/z 336 [M + H]+;
HRMS for C23H29NO (M, 335.2249; [M + H]) calcd, 336.2322;
found, 336.2320.
11: H NMR (CD3OD) δ 0.63 (d, J ) 7 Hz, 3H), 1.32 (s, 3H),
1.37 (m, 1H), 1.48 (m, 1H), 1.62 (dq, J ) 8 and 4 Hz, 1H), 1.98
(m, 2H), 2.08 (m, 1H), 2.18 (dt, J ) 14 and 4 Hz, 2H), 2.37 (t, J
1
1
35: H NMR (CDCl3) δ 0.76 (d, J ) 7 Hz, 3H), 1.43 (s, 3H),
1.78 (m, 2H), 2.16 (m, 1H), 2.24 (m, 1H), 2.50 (t, J ) 7 Hz, 0.5H),

BioactiVe Conformation of µ-Opioid Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7287
) 8 Hz, 1H), 2.62 (dt, J ) 13 and 2 Hz, 1H), 2.74 (m, 1H), 2.92
(m, 2H), 6.61 (m, 1H), 6.89 (m, 1H), 6.92 (d, J ) 8 Hz, 1H), 7.13
(t, J ) 8 Hz, 1H), 7.19 (m, 1H), 7.28 (m, 4H); LCMS (ESI) m/z
336 [M + H]+; HRMS for C23H29NO (M, 335.2249; [M + H])
calcd, 336.2322; found, 336.2318.
1H), 6.71 (dd, J ) 8 and 1 Hz, 1H), 6.83 (dd, J ) 8 and 1 Hz,
1H), 7.17 (m, 2H), 8.95 (br s, 1H); LCMS (ESI) m/z 274 [M +
H]+.
(7R,8R,9RS)-8-(3-Hydroxyphenyl)-7,8-dimethyl-hexahydro-
1H-quinolizin-4(6H)-one (44). Compound 44 was synthesized in
a manner similar to compound 43, using compound 42 as starting
material: yield 100% (yellow foam).1H NMR (CDCl3) δ 0.61 (br
s, 3H), 1.41 (br s, 3H), 1.66 (m, 1H), 1.74 (m, 2H), 1.92 (m, 1H),
2.14 (m, 3H), 2.55 (m, 1H), 2.71 (m, 1H), 3.18 (m, 1H), 3.73 (m,
1H), 4.53 (m, 1H), 6.70 (d, J ) 8 Hz, 1H), 6.77 (d, J ) 6 Hz, 2H),
7.18 (t, J ) 8 Hz, 1H); LCMS (ESI) m/z 274 [M + H]+.
3-((2R,3R,9RR)-2,3-Dimethyl-octahydro-1H-quinolizin-2-yl)-
phenol (12). To a solution of 43 (0.15 g, 0.55 mmol) in anhydrous
THF (10 mL) was added borane-dimethyl sulfide complex (2 M
anhydrous solution in THF, 0.55 mL, 1.10 mmol), and the reaction
mixture was heated to reflux under a nitrogen atmosphere for 16
h. The mixture was then cooled to 0 °C. Methanol (10 mL) was
then added to the reaction, which was stirred at 0 °C for 1 h. A 2
M anhydrous solution of HCl in diethyl ether was then added to
the reaction mixture, which was heated to reflux for 1 h. Solvents
were removed under reduced pressure. The residue was taken up
in methanol and stripped of solvent under reduced pressure (this
process was repeated five times). The residue was then basified
with a 1 M aqueous solution of NaOH (5 mL), and the mixture
was extracted with a 10% solution of methanol in methylene
chloride. The organic extracts were washed with saturated brine,
dried (Na2SO4), filtered and evaporated. The crude product was
purified by silica gel flash column chromatography, eluting with
0-100% ethyl acetate in hexanes to give 12 as a white solid (0.058
1-((2R,4R,5R)-2-Allyl-4-(3-(benzyloxy)phenyl)-4,5-dimethylpi-
peridin-1-yl)prop-2-en-1-one (39). A solution of 18 (2.00 g, 5.97
mmol) and triethylamine (2.5 mL, 17.91 mmol) in dichloromethane
(20 mL) was cooled to 0 °C. To this solution was added, dropwise,
acryloyl chloride (0.75 mL, 8.96 mmol). The reaction mixture was
stirred at room temperature for 2 h, then poured into a saturated
ammonium chloride solution, and extracted with ethyl acetate. The
combined organic extracts were washed with saturated brine, dried
(Na2SO4), filtered, and evaporated. The crude material was purified
by silica gel flash column chromatography, eluting with 0-40%
ethyl acetate in hexanes to give 39 as a yellow oil (1.21 g, 52%).
1H NMR (CDCl3) δ 0.63 (d, J ) 7 Hz, 3H), 1.49 (s, 3H), 1.85 (d,
J ) 14 Hz, 1H), 2.15 (br s, 1H), 2.29 (br s, 1H), 2.59 (t, J ) 6 Hz,
1H), 3.68 (m, 1H), 5.09 (m, 3H), 5.66 (d, J ) 9 Hz, 1H), 6.26 (m,
1H), 6.60 (m, 1H), 6.81 (m, 3H), 7.22 (d, J ) 8 Hz, 1H), 7.33 (m,
1H), 7.39 (m, 2H), 7.44 (m, 2H); LCMS (ESI) m/z 390 [M + H]+.
1-((2S,4R,5R)-2-Allyl-4-(3-(benzyloxy)phenyl)-4,5-dimethylpi-
peridin-1-yl)prop-2-en-1-one (40). Compound 40 was synthesized
in a manner similar to compound 39, using compound 19 as starting
material: yield 45% (yellow oil).1H NMR (CDCl3) δ 0.40 (d, J )
7 Hz, 3H), 1.30 (s, 3H), 1.86 (m, 1H), 2.00 (m, 2H), 2.32 (m, 2H),
2.75 (br s, 1H), 4.29 (br s, 1H), 5.07 (m, 3H), 5.69 (dd, J ) 10 and
2 Hz, 1H), 5.81 (m, 1H), 6.35 (dd, J ) 16 and 2 Hz, 1H), 6.60
(dd, J ) 16 and 10 Hz, 1H), 6.80 (dd, J ) 8 and 2 Hz, 1H), 6.88
(m, 2H), 7.22 (t, J ) 8 Hz, 1H), 7.32 (m, 1H), 7.37 (m, 2H), 7.42
(m, 2H); LCMS (ESI) m/z 390 [M + H]+.
1
g, 41%). H NMR (CD3OD), δ 1.09 (d, J ) 7 Hz, 3H), 1.31 (m,
5H), 1.49 (dd, J ) 15 and 12 Hz, 1H), 1.67 (m, 3H), 1.75 (m, 1H),
2.04 (m, 2H), 2.22 (m, 1H), 2.37 (m, 2H), 2.61 (m, 1H), 2.90 (d,
J ) 12 Hz, 1H), 6.61 (dd, J ) 8 and 2 Hz, 1H), 6.91 (m, 2H), 7.10
(t, J ) 8 Hz, 1H); LCMS (ESI): m/z 260[M + H]+. Anal. (C17H25-
NO•0.25H2O) C, H, N.
(7R,8R,9RR)-8-(3-(Benzyloxy)phenyl)-7,8-dimethyl-7,8,9,9R-
tetrahydro-1H-quinolizin-4(6H)-one (41). A solution of 39 (1.21
g, 3.11 mmol) in anhydrous methylene chloride (40 mL) was purged
with nitrogen for 20 min. Grubbs’ second-generation catalyst (0.13
g, 0.16 mmol) was then added to the reaction mixture, which was
heated to reflux for 2 h. The solvents were removed under reduced
pressure, and the residue was purified by silica gel column
chromatography eluting with 0-40% ethyl acetate in hexanes: yield
3-((2R,3R,9RS)-2,3-Dimethyl-octahydro-1H-quinolizin-2-yl)-
phenol (13). Compound 13 was synthesized in a manner similar
to compound 12, using compound 44 as starting material: yield
26% (white solid).1H NMR (CD3OD) δ 0.75 (d, J ) 7 Hz, 3H),
1.33 (s, 4H), 1.37 (m, 2H), 1.52 (d, J ) 14 Hz, 1H), 1.66 (m, 3H),
1.78 (m, 1H), 1.92 (t, J ) 13 Hz, 1H), 2.03 (m, 1H), 2.10 (m,
0.5H), 2.19 (m, 0.5H), 2.56 (d, J ) 12 Hz, 1H), 2.75 (m, 2H), 6.57
(dd, J ) 8 and 3 Hz, 1H), 6.70 (t, J ) 2 Hz, 1H), 6.74 (d, J ) 8
Hz, 1H), 7.09 (t, J ) 8 Hz 1H); LCMS (ESI) m/z 260 [M + H]+.
Anal. (C17H25NO‚0.1H2O) C, H, N.
1
74% (beige solid). H NMR (CDCl3) δ 1.09 (d, J ) 7 Hz, 3H),
1.35 (s, 3H), 1.62 (dd, J ) 14 Hz and 12 Hz, 1H), 1.89 (m, 1H),
2.16 (m, 2H), 2.34 (t, J ) 6 Hz, 0.5H), 2.39 (t, J ) 6 Hz, 0.5H),
2.72 (dd, J ) 13 and 12 Hz, 1H), 3.70 (m, 1H), 4.12 (dd, J ) 14
and 5 Hz, 1H), 5.89 (dd, J ) 10 and 2 Hz, 1H), 6.47 (m, 1H), 6.83
(dd, J ) 7 and 2 Hz, 1H), 6.98 (m, 2H), 7.22 (t, J ) 8 Hz, 1H),
7.39 (m, 5H); LCMS (ESI) m/z 362 [M + H]+.
1-((2S,3R,4R)-2-Allyl-4-(3-(benzyloxy)phenyl)-3,4-dimethylpi-
peridin-1-yl)prop-2-en-1-one (45a) and 1-((2R,3R,4R)-2-Allyl-
4-(3-(benzyloxy)phenyl)-3,4-dimethylpiperidin-1-yl)prop-2-en-
1-one (45b). Compounds 45a and 45b were synthesized in a manner
similar to compound 39, using compound 33a,b as starting
(7R,8R,9rS)-8-(3-(Benzyloxy)phenyl)-7,8-dimethyl-7,8,9,9r-
tetrahydro-1H-quinolizin-4(6H)-one (42). Compound 42 was
synthesized in a manner similar to compound 41, using compound
40 as starting material: yield 95% (yellow oil).1H NMR (CDCl3)
δ 0.67 (d, J ) 7 Hz, 3H), 1.36 (s, 3H), 1.76 (m, 1H), 2.12 (m,
2H), 2.32 (m, 1H), 2.44 (t, J ) 6 Hz, 0.5H), 2.49 (t, J ) 6 Hz,
0.5H), 3.22 (dd, J ) 13 and 3 Hz, 1H), 3.76 (m, 1H), 4.21 (dd, J
) 14 and 3 Hz, 1H), 5.93 (dd, J ) 10 and 2 Hz, 1H), 6.52 (m,
1H), 6.82 (m, 1H), 6.89 (m, 1H), 7.25 (t, J ) 8 Hz, 1H), 7.32 (m,
1H), 7.37 (t, J ) 7 Hz, 2H), 7.43 (d, J ) 7 Hz, 2H); LCMS (ESI)
m/z 362 [M + H]+.
1
material: yield 65% (white solid). H NMR (CDCl3) δ 0.51 (d, J
) 7 Hz, 3H), 0.84 (m, 3H), 1.03 (br s, 3H), 1.37 (m, 3H), 1.52 (t,
J ) 12 Hz, 1H), 1.69 (m, 1H), 2.03 (m, 4H), 2.24 (br s, 1H), 2.50
(m, 2H), 2.94 (dt, J ) 16 and 3 Hz, 1H), 3.38 (dt, J ) 16 and 3
Hz, 1H), 3.73 (m, 1H), 3.86 (d, J ) 14 Hz, 1H), 4.57 (m, 0.5H),
4.74 (m, 1.5H), 4.86 (m, 1H), 4.96 (m, 3H), 5.03 (m, 2H), 5.55
(m, 2H), 5.70 (m, 1H), 6.20 (m, 2H), 6.46 (m, 2H), 6.73 (m, 3H),
6.87 (m, 2H), 7.15 (m, 2H), 7.30 (m, 3H), 7.34 (m, 3H); LCMS
(ESI) m/z 390 [M + H]+.
(7R,8R,9RR)-8-(3-Hydroxyphenyl)-7,8-dimethyl-hexahydro-
1H-quinolizin-4(6H)-one (43). To a solution of 41 (0.20 g, 0.55
mmol) in ethanol (30 mL) was added 10% palladium on charcoal
(catalytic), and the mixture was stirred at room temperature under
a hydrogen atmosphere for 3 h. The mixture was then filtered
through Celite. The Celite was washed with warm ethanol, and the
filtrate was evaporated under reduced pressure. The residue was
purified by flash chromatography on silica, eluting with 0-50%
ethyl acetate in hexanes to give 43 as a white solid (0.15 g, 100%).
1H NMR (CDCl3) δ 1.23 (d, J ) 7 Hz, 3H), 1.35 (s, 3H), 1.48 (m,
3H), 1.81 (m, 3H), 2.11 (dd, J ) 14 and 2 Hz, 1H), 2.38 (m, 2H),
3.01 (t, J ) 13 Hz, 1H), 3.35 (m, 1H), 4.55 (dd, J ) 14 and 5 Hz,
(8R,9R,9RS)-8-(3-(Benzyloxy)phenyl)-8,9-dimethyl-7,8,9,9R-
tetrahydro-1H-quinolizin-4(6H)-one (46a) and (8R,9R,9RR)-8-
(3-(Benzyloxy)phenyl)-8,9-dimethyl-7,8,9,9R-tetrahydro-1H-
quinolizin-4(6H)-one (46b). Compounds 46a,b were synthesized
in a manner similar to compound 41, using 45a,b as starting
1
material: yield 100% (brown oil). H NMR (CDCl3) δ 0.62 (d, J
) 6 Hz, 3H), 0.77 (d, J ) 6 Hz, 3H), 1.32 (s, 3H), 1.40 (s, 3H),
1.58 (t, J ) 3 Hz, 0.5H), 1.61 (t, J ) 3 Hz, 0.5H), 1.73 (m, 2H),
1.89 (br s, 1H), 2.05 (m, 3H), 2.19 (m, 2H), 2.39 (t, J ) 5 Hz,
0.5H), 2.43 (t, J ) 5 Hz, 0.5H), 2.55 (t, J ) 5 Hz, 0.5H), 2.59 (t,
J ) 5 Hz, 0.5H), 2.97 (dt, J ) 15 and 3 Hz, 1H), 3.45 (m, 2H),
3.67 (m, 0.5H), 3.76 (m, 0.5H), 4.36 (m, 1H), 5.95 (d, J ) 10 Hz,

7288 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Le Bourdonnec et al.
2H), 6.52 (m, 2H), 6.83 (d, J ) 9 Hz, 2H), 6.98 (m, 4H), 7.26 (m,
2H), 7.29-7.48 (m, 10H); LCMS (ESI) m/z 362 [M + H]+.
Radioactivity on the filters was determined by scintillation spec-
trometry in a Packard TopCount.
[3H]Diprenorphine with a specific activity of 50 Ci/mmol was
purchased from Perkin-Elmer Life Sciences, Inc. (Boston, MA).
The KD values for [3H]diprenorphine binding were 0.33 nM for
the κ and µ receptors and 0.26 nM for the δ receptor. Receptor
expression levels, determined as Bmax values from Scatchard
analyses, were 4400, 4700, and 2100 fmol/mg of protein for the κ,
µ, and δ receptors, respectively. Preliminary experiments were
performed to show that no specific binding was lost during the
wash of the filters, that binding achieved equilibrium within the
incubation time and remained at equilibrium for at least an
additional 60 min and that binding was linear with regard to protein
concentration. Nonspecific binding, determined in the presence of
10 µM unlabeled naloxone, was less than 10% of total binding.
Protein was quantified by the method of Bradford.25
(8R,9R,9RS)-8-(3-Hydroxyphenyl)-8,9-dimethyl-hexahydro-
1H-quinolizin-4(6H)-one (47a) and (8R,9R,9RR)-8-(3-Hydroxy-
phenyl)-8,9-dimethyl-hexahydro-1H-quinolizin-4(6H)-one (47b).
Compounds 47a and 47b were synthesized in a manner similar to
compound 43, using 46a,b as starting material: yield 85% (white
1
foam). H NMR (CDCl3) δ 0.62 (d, J ) 6 Hz, 3H), 0.93 (d, J )
7 Hz, 3H), 1.33 (s, 6H), 1.43 (m, 1H), 1.52 (m, 1H), 1.61 (m, 4H),
1.86 (m, 4H), 2.13 (m, 3H), 2.34 (m, 3H), 2.49 (m, 2H), 2.79 (t, J
) 14 Hz, 1H), 3.04 (t, J ) 14 Hz, 1H), 3.30 (m, 1H), 3.56 (m,
1H), 4.35 (m, 1H), 4.74 (m, 1H), 6.74 (d, J ) 8 Hz, 2H), 6.87 (t,
J ) 8 Hz, 2H), 6.92 (s, 1H), 7.01 (s, 1H), 7.14 (m, 2H), 8.30 (br
s, 1H), 8.61 (br s, 1H); LCMS (ESI) m/z 274 [M + H]+.
3-((1R,2R,9rS)-1,2-Dimethyl-octahydro-1H-quinolizin-2-yl)phe-
nol (14) and 3-((1R,2R,9rR)-1,2-Dimethyl-octahydro-1H-quino-
lizin-2-yl)phenol (15). To a solution of 47a,b (0.09 g, 0.33 mmol)
in anhydrous THF (10 mL) was added borane-dimethyl sulfide
complex (2 M anhydrous solution in THF, 0.33 mL, 0.66 mmol),
and the reaction mixture was heated to reflux under a nitrogen
atmosphere for 16 h. The mixture was then cooled to 0 °C. Methanol
(10 mL) was then added to the reaction, which was stirred at 0 °C
for 1 h. A 2 M anhydrous solution of HCl in diethyl ether was
then added to the reaction mixture, which was heated to reflux for
1 h. Solvents were removed under reduced pressure. The residue
was taken up in methanol and stripped of solvent under reduced
pressure (this process was repeated five times). The residue was
then basified with a 1 M aqueous solution of NaOH (5 mL), and
the mixture was extracted with a 10% solution of methanol in
methylene chloride. The organic extracts were washed with
saturated brine, dried (Na2SO4), filtered, and evaporated. The residue
was purified by silica gel flash column chromatography, eluting
with 0-100% ethyl acetate in hexanes to give a mixture of 14 and
15. LC separation of that mixture gave 14 as a white solid (0.005
g, 6%) and 15 as a white solid (0.012 g, 15%).
The data from competition experiments were fit by nonlinear
regression analysis with the program Prism (GraphPad Software,
Inc., San Diego, CA) using the four-parameter equation for one-
site competition, and Ki values were subsequently calculated from
EC50 values by the Cheng-Prusoff equation.
Receptor-Mediated [35S]GTPγS Binding. Receptor-mediated
[35S]GTPγS binding was performed by modifications of the
methods of Selley and collaborators26 and Traynor and Nahorski.27
Assays were carried out in 96-well FlashPlates (Perkin-Elmer Life
Sciences, Inc, Boston, MA). Membranes prepared from CHO cells
expressing the appropriate receptor (50-100 µg of protein) were
added to assay mixtures containing agonist with or without
antagonists, approximately 100 000 dpm (100 pM) [35S]GTPγS,
3.0 µM GDP, 75 mM NaCl, 15 mM MgCl2, 1.0 mM EGTA, 1.1
mM dithiothreitol, 10 mg/L leupeptin, 10 mg/L pepstatin A, 200
mg/L bacitracin, and 0.5 mg/L aprotinin in 50 mM Tris-HCl buffer,
pH 7.8. After incubation at room temperature for 1 h, the plates
were sealed and centrifuged at 800 g in a swinging bucket rotor
for 5 min, and bound radioactivity was determined with a TopCount
microplate scintillation counter (Packard Instrument Co., Meriden,
CT).
Agonist potency and efficacy were assessed by measuring
stimulation of [35S]GTPγS binding by a series of concentrations
of agonist. The concentration to give half-maximal stimulation
(EC50) was determined by nonlinear regression using Prism relative
to the maximal stimulation achieved by loperamide.
Antagonist activities were obtained by titration in the presence
of a concentration of loperamide (50 nM) that yielded 80% of its
maximal stimulation (EC80), and the data were analyzed by
nonlinear regression fit using Prism. Efficacy was expressed as the
maximum percent inhibition of the agonist-stimulated [35S]GTPγS
binding, and potency was expressed as the concentration of
antagonist that achieved 50% of the maximum inhibition of that
antagonist. Loperamide was used as µ agonist.
1
14: H NMR (CD3OD) δ 1.08 (d, J ) 7 Hz, 4H), 1.33 (s, 4H),
1.61 (m, 3H), 1.86 (m, 2H), 2.01 (m, 2H), 2.15 (m, 1H), 2.36 (m,
2H), 2.61 (m, 1H), 2.81 (m, 1H), 6.58 (m, 1H), 6.92 (m, 2H), 7.08
(t, J ) 8 Hz, 1H); LCMS (ESI) m/z 260 [M + H]+. HRMS for
C17H25NO (M, 259.1936; [M + H]) calcd, 260.2009; found,
260.2002.
15: 1H NMR (CD3OD) δ 0.57 (d, J ) 6 Hz, 3H), 1.15 (m, 1.5H),
1.29 (s, 3H), 1.45 (m, 1H), 1.65 (m, 2H), 1.80 (m, 1H), 1.92 (m,
2.5H), 2.05 (m, 1H), 2.15 (dt, J ) 13 and 9 Hz, 1H), 2.24 (dt, J )
11 and 4 Hz, 1H), 2.55 (dt, J ) 13 and 3 Hz, 1H), 2.70 (m, 1H),
2.88 (d, J ) 12 Hz, 1H), 6.59 (dd, J ) 8 and 2 Hz, 1H), 6.86 (d,
J ) 2 Hz, 1H), 6.89 (d, J ) 8 Hz, 1H), 7.11 (t, J ) 8 Hz, 1H);
LCMS (ESI) m/z 260 [M + H]+. Anal. (C17H25NO‚0.8H2O) C, H,
N.
B. Biological Methods. Radioligand Binding Assays. Mem-
brane preparations from Chinese hamster ovary (CHO) cells stably
expressing human κ-, µ-, or δ-opioid receptors were prepared as
described previously.24 The assay buffer used is composed of 50
mM tris(hydroxymethyl) aminomethane HCl, pH 7.8, 1.0 mM
ethylene glycol bis(â-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
(EGTA-free acid), 5.0 mM MgCl2, 10 mg/L leupeptin, 10 mg/L
pepstatin A, 200 mg/L bacitracin, and 0.5 mg/L aprotinin. After
dilution in assay buffer and homogenization in a Polytron homo-
genizer (Brinkmann, Westbury, NY) for 30 s at a setting of 1,
membrane proteins (10-80 µg) in 250 µL of assay buffer were
added to mixtures containing test compound and [3H]diprenorphine
(0.5-1.0 nM, 25 000-50 000 dpm) in 250 µL of assay buffer in
96-well deep-well polystyrene titer plates (Beckman) and incubated
at room temperature for 60 min. Reactions were terminated by
vacuum filtration with a Brandel MPXR-96T harvester through
GF/B filters that had been pretreated with a solution of 0.5%
polyethylenimine and 0.1% bovine serum albumin for at least 1 h.
The filters were washed four times with 1.0 mL each of ice-cold
50 mM Tris-HCl, pH 7.8, and 30 µL of Microscint-20 (Packard
Instrument Company, Meriden, CT) was added to each filter.
Supporting Information Available: Tables of crystallographic
data for compounds 31 and 8. Table of elemental analyses. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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JM060486F