Probes for narcotic receptor mediated phenomena. 41. Unusual inverse μ-agonists and potent μ-opioid antagonists by modification of the N-substituent in enantiomeric 5-(3-hydroxyphenyl)morphans

Article abstract of DOI:10.1021/jm1011676

Conformational restraint in the N-substituent of enantiomeric 5-(3-hydroxyphenyl)morphans was conferred by the addition of a cyclopropane ring or a double bond. All of the possible enantiomers and isomers of the N-substituted compounds were synthesized. Opioid receptor binding assays indicated that some of them had about 20-fold higher μ-affinity than the compound with an N-phenylpropyl substituent (K_i = 2-450 nM for the examined compounds with various N-substituents). Most of the compounds acted unusually as inverse agonists in the [³⁵S]GTP-γ-S functional binding assay using nondependent cells that stably express the cloned human μ-opioid receptor. Two of the N-substituted compounds with a cyclopropane ring were very potent μ-opioid antagonists ((+)-29, K_e = 0.17 and (-)-30, K_e =0.3) in the [³⁵S]GTP-γ-S functional binding assay. By comparison of the geometry-optimized structures of the newly synthesized compounds, an attempt was made to rationalize their μ-opioid receptor affinity in terms of the spatial position of N-substituents. This article not subject to U.S. Copyright. Published 2011 by the American Chemical Society.

Full text of DOI:10.1021/jm1011676

J. Med. Chem. 2011, 54, 957–969 957
DOI: 10.1021/jm1011676
Probes for Narcotic Receptor Mediated Phenomena. 41. Unusual Inverse μ-Agonists and
Potent μ-Opioid Antagonists by Modification of the N-Substituent in Enantiomeric
5-(3-Hydroxyphenyl)morphans
Kejun Cheng,† Yong Sok Lee,‡ Richard B. Rothman,§ Christina M. Dersch,§ Ross W. Bittman,§ Arthur E. Jacobson,† and
Kenner C. Rice*,†
†Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and the National Institute on Alcohol
Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 4N03, Bethesda,
Maryland 20892-9415, United States, ‡Center for Molecular Modeling, Division of Computational Bioscience, CIT, National Institutes of Health,
Department of Health and Human Services, Bethesda, Maryland 20892, United States, and §Clinical Psychopharmacology Section, Chemical
Biology Research Branch, National Institute on Drug Abuse, Addiction Research Center, National Institutes of Health, Department of Health and
Human Services, Baltimore, Maryland 21224, United States
Received September 8, 2010
Conformational restraint in the N-substituent of enantiomeric 5-(3-hydroxyphenyl)morphans was
conferred by the addition of a cyclopropane ring or a double bond. All of the possible enantiomers and
isomers of the N-substituted compounds were synthesized. Opioid receptor binding assays indicated
that some of them had about 20-fold higher μ-affinity than the compound with an N-phenylpropyl
substituent (Ki = 2-450 nM for the examined compounds with various N-substituents). Most of the
compounds acted unusually as inverse agonists in the [35S]GTP-γ-S functional binding assay using
nondependent cells that stably express the cloned human μ-opioid receptor. Two of the N-substituted
compounds with a cyclopropane ring were very potent μ-opioid antagonists ((þ)-29, Ke = 0.17 and
(-)-30, Ke=0.3) in the [35S]GTP-γ-S functional binding assay. By comparison of the geometry-
optimized structures of the newly synthesized compounds, an attempt was made to rationalize their
μ-opioid receptor affinity in terms of the spatial position of N-substituents.
Introduction
side chain (Ki = 14 nM vs 42 nM, respectively, Figure 1A) in
the 1R,5S enantiomeric series. However the N-phenylpropyl-
substitutedcompoundwas more potentasa pureμ-antagonist
(Ke = 3.2 nM vs 7.5 nM for the N-phenethyl compound in
the [35S]GTP-γ-S binding assay).2 The N-phenylpropyl sub-
stituents in the compounds of Hashimoto et al.2 have unrest-
ricted rotation. We were interested in determining whether
conformational restraint of the N-phenylpropyl substituent
conferred by the addition of a cyclopropane ring or a double-
bond effected the receptor affinity and efficacy of enantio-
meric 5-(3-hydroxyphenyl)morphans. We now report the
synthesis of a series of enantiomeric N-arylcyclopropyl and
N-arylalkenyl substituted 5-(3-hydroxyphenyl)morphans. We
Opioid enantiomers are known to have pharmacological
properties dissimilar in affinity and efficacy to those of the
parent racemic mixture, and the N-substituents in these
opioids also play a major role in affinity and efficacy. The
1R,5S-N-phenylpropyl- and the 1S,5R-N-phenylpropyl-5-(3-
hydroxyphenyl)morphans (Figure 1A and Figure 1B, re-
spectively) were previously found1,2 to have moderate affinity
for the μ-opioid receptor (14 and 27 nM, respectively) and
were found to be moderately potent antagonists in the [35S]-
GTP-γ-S assay (Ke = 7.5 and 5.5 nM, respectively). A trans-
oriented (racemic) N-phenylcyclopropylmethyl (NPCMa)
substituent in the phenylpiperidine series (a rotationally re-
stricted N-substituent of LY272922, Figure 1C) has been
found to have good affinity (Ki =1.75 nM) for the μ-opioid
receptor, as did a trans (E)-oriented N-phenylpropenyl moiety
(Figure 1D).3 The latter was found to be a potent and selective
μ-antagonist with good δ- and κ-antagonist activity as well.
Hashimoto et al.2 found that an N-phenethyl substituted 5-(3-
hydroxyphenyl)morphan (Figure 1E) had higher μ-affinity
than a comparable phenylmorphan with an N-phenylpropyl
*To whom correspondence should be addressed. Phone: 301-496-
1856. Fax: 301-402-0589. E-mail: kr21f@nih.gov.
a Abbreviations: NPCM, N-phenylcyclopropylmethyl; 1H NMR,
proton nuclear magnetic resonance; 13C NMR, carbon nuclear magnetic
resonance; TLC, thin-layer chromatography; ESI, electrospray ioniza-
tion; HRMS (TOF MS ESþ), high resolution mass spectrometry (time-
of-flight mass spectra from electrospray positive ionization).
Figure 1. Structures of N-substituted 5-(3-hydroxyphenyl)mor-
phans (A, B, E) and 3-(3R,4R-dimethylpiperidin-4-yl)phenols
(C, D).
This article not subject to U.S. Copyright. Published 2011 by the American Chemical Society
Published on Web 01/19/2011
pubs.acs.org/jmc

958 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4
Cheng et al.
Scheme 1. Synthesis of the 2-(E)-Cinnamyl and 2-(Z)-3-Phenylallyl) Isomers of the Enantiomers of 3-(2-Azabicyclo[3.3.1]nonan-
5-yl)phenol ((þ)-6, (-)-6, (þ)-9, and (-)-9)a
a Reagents and conditions: (a) compound 2 or 3 (Scheme 2), EDCI/CH2Cl2, room temp, 75-81%; (b) 48% HBr/HOAc, reflux, 0.5-1 h, 65-72%; (c)
Red-Al, THF, room temp, 1.5 h, 58-68%.
Scheme 2. Synthesis of (Z)-3-Phenylacrylic Acid (3)a
Scheme 3. Synthesis of Racemic cis-2-Phenylcyclopropanecar-
boxylic Acid (14)a
a Reagents and conditions: (a) Pd/CaCO3, H2 (1 equiv at 1 atm),
pyridine, room temp; (b) diisopropylamine/Et2O, recrystallization;
(c) HCl/Et2O; 36% yield in three steps.
have examined the affinity all of the possible enantiomers
and isomers in opioid receptor binding assays and their
efficacy in the [35S]GTP-γ-S assay and compared the geome-
try-optimized structures of the newly synthesized compounds.
a Reagents and conditions: (a) CHBr3, benzyltriethylammonium
chloride (TEBA), 50% NaOH aqueous, room temp, 20 h, 78%; (b)
synthesis gas (CO/H2 3:1), toluene, 5 N KOH, CoCl2 6H2O, KCN,
Results and Discussion
3
Ni(CN)2 4H2O, PEG-400, 90 °C, 3 days, 43%; (c) EtOH, TsOH H2O,
3
3
Chemistry. The enantiomeric starting materials, 1S,5R-
(-)-5-(3-methoxyphenyl)-2-azabicyclo[3.3.1]nonane ((-)-1)
and 1R,5S-(þ)-5-(3-methoxyphenyl)-2-azabicyclo-[3.3.1]-
nonane ((þ)-1) were prepared as previously descri-
bed.4 Reaction of (-)- and (þ)-1 with commercially available
cinnamic acid (2) and the synthesized (Z)-3-phenylacrylic acid
(3),5-7 using EDCI in CH2Cl2 at room temperature, gave
pairs of enantiomeric methoxyphenylamides (þ)-4 (1S,5R)
and (-)-4 (1R,5S), and (þ)-7 (1S,5R) and (-)-7 (1R,5S),
respectively, in 75-81% yield (Scheme 1). The (Z)-3-pheny-
lacrylic acid (4) was obtained through Pd/CaCO3 reduction of
commercially available 3-phenylpropiolic acid (10, Scheme 2).8
The reduction gave a mixture of both the desired 3 (Z isomer)
and cinnamic acid 2 (the E isomer). Recrystallization of the
diisopropylamine salt (11) of the isomers gave pure 3 in 36%
overall yield.
toluene, 115 °C, 8 h, 68%; (d) NaOH, EtOH, H2O, reflux, 50% based on
cis isomer; (e) NaOH, EtOH, H2O, reflux, 70%.
in 48% HBr and acetic acid (Scheme 1). Reduction of the
four phenolic amide isomers to the desired enantiomeric
amines (þ)-6, (-)-6, (þ)-9, and (-)-9, in 58-68% yield,
was carried out using Red/Al in THF (Scheme 1).
Introduction of the N-substituent bearing a cyclopropyl
moiety required the preparation of the phenylcyclopropane-
carboxylic acid enantiomers (-)-13, and (þ)-13 and their
diastereomeric relatives (-)-14 and (þ)-14. Although both of
the racemic starting materials (()-13 and (()-14 could be
obtained as shown in Scheme 3, 2-phenylcyclopropanecar-
boxylic acid (()-13 was commercially available. The racemic
cis isomer ((()-14, (1S*,2R*)-2-phenylcyclopropanecar-
boxylic acid) was synthesized from styrene in five steps
(Scheme 3) and resolved. (2,2-Dibromocyclopropyl)benzene
(12, Scheme 3) was obtained in 78% yield using the proce-
dure of Shim et al.9 Catalytic reductive carbonylation of 12,
Conversion of the enantiomeric amides (þ)-4, (-)-4,
(þ)-7, and (-)-7 to their phenolic relatives (þ)-5, (-)-5,
(þ)-8, and (-)-8 was achieved in 65-72% yield by refluxing

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4 959
using the procedure of Grushin and Alper,10 gave a 6:4
mixture of the racemic cis and trans isomers of 2-phenylcy-
clopropane carboxylic acid ((()-13 and (()-14). Conversion
of (()-13 and (()-14 to the racemic mixture of trans and cis
esters ((()-15) was carried out using the procedure of Kaiser
et al.7 Separation of the racemic cis isomer (()-16 from
(()-15 was achieved under reflux conditions using 1 equiv of
NaOH in EtOH-H2O. The cis esters were more stable to the
alkaline conditions and required 2 equiv of NaOH for
hydrolysis to the racemic acid (()-14, with concentrated
HCl used for neutralization.
The commercially available racemic trans isomer (()-13
was resolved6,11 as shown in Scheme 4. The 10R,20R and
10S,20S mixture of enantiomers (()-13 was separated using
(þ)-dehydroabietylamine. The 10R,20R salt (17) that formed
was purified by recrystallization from aqueous methanol.
Base hydrolysis of the salt 17 gave the desired (-)-13 (trans-
10R,20R, 98% ee via chiral HPLC). The residual material
from the 1R,2R salt formation with (þ)-dehydroabietyl-
amine was recovered, and the base was reacted with 1 equiv
of quinine in EtOAc. The 10S,20S salt (18) that formed was
recrystallized from EtOAc; base hydrolysis provided (þ)-13
(trans-10S,20S, 98% ee via chiral HPLC).
Optical resolution of (()-14 (cis racemate) was carried out
similarly (Scheme 5)6,11 to give (-)-14 (cis-10R,20S) from the
(þ)-dehydroabietylamine salt 19 and to give (þ)-14 (cis-
10S,20R) from the salt with quinine (20). Both enantiomers
were obtained in 98% ee via chiral HPLC.
With the pure (-)-13, (þ)-13, (-)-14, and (þ)-14 enantio-
meric acids in hand, the corresponding amides ((-)- and (þ)-
21 through 24) could be prepared as shown in Scheme 6 from
the known4 enantiomeric amines (1S,5R)- and ((1R,5S)-
5-(3-methoxyphenyl)-2-azabicyclo[3.3.1] nonane ((-)-1 and
(þ)-1). Reduction of the various amides ((-)- and (þ)-21
through 24) to the tertiary amines ((-)- and (þ)-25 through
28) followed by cleavage of the aromatic ether to the
corresponding phenol resulted in the formation of four
enantiomers in the 1S,5R series (Scheme 6 top, (-)- and
(þ)-29 through 32) and another set of four amines in the
1R,5S series (Scheme 6 bottom, (-)- and (þ)-29 through 32).
Opioid Receptor Binding and Efficacy Studies. In the series
of the cis- and trans-NPCM substituted compounds ((-)-
and (þ)-29 through 32, Scheme 6), both of the trans
compounds (þ)-29 and (-)-30 had high affinity for the
μ-receptor (Ki = 3 and 4 nM, respectively, Table 1). All of
the compounds in Table 1 had, at most, moderate affinity for
δ or κ receptors, and their selectivity for the μ-receptor
ranged from 4- to 70-fold. The NPCM substituted com-
pounds were also found to be the most potent μ-antagonists
in the [35S]GTP-γ-S binding assays (Ke = 0.17 and 0.31 nM,
respectively, Table 2). Figure 2 is an overlay of four NPCM
derivatives in the 1R,5S-phenylmorphan series ((þ)-29,
(-)-30, (þ)-31, and (-)-32) obtained by superposing the
carbon and nitrogen atoms of the phenylmorphans to those
of the geometry optimized naltrexone starting from its X-ray
structure.12 This overlay depicts a spatial position of the
NPCM moiety among the four compounds while fixing their
essentially invariant phenylmorphan backbone in space with
respect to that of naltrexone. Specifically, the extended trans
isomer (þ)-29 (Figure 2, Ki = 3 nM) is epimeric with respect
to the C2 atom of the NCPM of the compact cis form (þ)-31
(Ki = 459 nM). The cyclopropyl group of both compounds
(þ)-29 and (þ)-31 coincides well with that of naltrexone,
suggesting that the ∼135-fold lower Ki of (þ)-31 arises from a
Scheme 4. Optical Resolution of of trans-2-Phenylcyclopro-
panecarboxylic Acid ((-)-13 (1R,2R) and (þ)-13 (1S,2S))a
a Reagents and conditions: (a) 1.0 equiv of dehydroabietylamine,
MeOH, H2O, recryst 5ꢀ from 90% aqueous MeOH, 25%; (b) 1.0 equiv
of quinine, EtOAc, recryst 5ꢀ from EtOAc, 34%; (c) (i) saturated
NaHCO3/Et2O; (ii) conc HCl/Et2O, 98%, >98% ee via chiral HPLC;
(d) 2 N HCl/Et2O, 98%, >98% ee via chiral HPLC.
Scheme 5. Optical Resolution of cis-2-Phenylcyclopropanecarboxylic Acid ((-)-14 (1R,2S) and (þ)-14 (1S,2R))a
a Reagents and conditions: (a) 1.0 equiv of dehydroabietylamine, MeOH, H2O, recryst 4ꢀ from 90% aqueous MeOH, 16%; (b) 1.0 equiv of quinine,
EtOAc, recryst 6ꢀ from EtOAc, 9%; (c) (i) saturated NaHCO3/Et2O; (ii) conc HCl/Et2O, 98%, >98% ee via chiral HPLC; (d) 2 N HCl/Et2O, 98%,
>98% ee via chiral HPLC.

960 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4
Cheng et al.
Scheme 6. Synthesis of the N-(2-Phenylcyclopropyl)methyl Enantiomers of (þ)- and (-)-2-Azabicyclo[3.3.1]nonan-5-yl)phenol ((þ)-
and (-)-29 through 32)a
a Reagents and conditions: (a) EDCI, CH2Cl2, 1.1 equiv of (-)-13 or (þ)-13 or (-)-14 or (þ)-14, room temp, 94-98%; (b) Red-Al, THF, room temp,
1.5 h, 92-96%; (c) 48% HBr/HOAc, reflux, 0.5-1 h, 55-65%.
steric clash between its phenyl group and amino acid residues
at the μ-receptor site. Similarly, (-)-30 (Ki = 4 nM) and (-)-
32 (Ki = 11 nM) are epimeric with respect to the C2 atom of
the cyclopropane, while their NPCM groups are enantio-
meric to (þ)-29 and (þ)-31, respectively (Figure 2). The
cyclopropyl groups of both (-)-30 and (-)-32 do not overlap
with that of naltrexone. These comparisons of the spatial
NCPM moieties with their binding affinity suggest that the
NCPM’s 1S,2R stereochemistry in (þ)-31 needs to be
avoided in the design of a higher afffinity ligand. Between
the two trans stereoisomers ((þ)-29 and (-)-30) in the 1R,5S-
phenylmorphan series, little stereospecificity was observed in
terms of Ki whereas about a 42-fold difference is seen
between the cis stereoisomers ((þ)-31, and (-)-32). Also, it
was observed that when the stereochemistry of the NPCM
side chain is invariant, the (1R,5S) series tends to have higher
affinity at the μ-receptor site, as seen in (-)-30 (Ki = 4 nM) vs
(-)-29 (Ki = 47 nM) and (-)-32 (Ki =11 nM) vs (-)-31
(Ki = 265 nM) as well as in (þ)-29 (Ki = 3 nM) vs (þ)-30
(Ki = 16 nM). This favorable topology of (1R,5S) is,
however, lost in ((þ)-31 (Ki = 459 nM) vs ((þ)-32 (1S,5R)
(Ki = 76 nM) likely because of the steric repulsion experi-
enced by the phenyl group of (þ)-31. One of the compounds
with moderate affinity for the μ-opioid receptor (þ)-30 (Ki =
16 nM) was found to be equipotent with naloxone as a
μ-antagonist, and its enantiomer (-)-30 had 4-fold higher
μ-affinity and was about equipotent with naltrexone as an
antagonist in the [35S]GTP-γ-S assay. The most potent
NCPM antagonist (þ)-29 was more than 13 times more
potent than naloxone. None of the NPCM-substituted com-
pounds had good affinity for either the δ- or κ-opioid
receptors (Ki > 70 nM at δ and κ). As shown in Figure 5,
all of the NPCM substituted compounds except (-)-32 were
found to have unusual inverse agonist activity in that they
showed considerably more inverse agonist activity in non-
dependent cells than has been previously found.13
In the N-phenylpropenyl series (Scheme 3), we have found
that the E (trans) enantiomers of the N-phenylpropenyl
compounds (þ)-6 and (-)-6 had higher affinity for the
μ-receptor (Ki = 2 and 6 nM, respectively) than the compa-
rableZ (cis) enantiomers(þ)-9and (-)-9(Ki =14and26nM,
respectively) and that all of them had equivalent or better
affinity for μ-receptors than a comparable N-phenylpropyl
compound. The higher affinity of the E (trans) enantiomers
over the corresponding Z-isomers may arise from an im-
proved overlap of the extended N-phenylpropenyl group in
the E-enantiomer with amino acid residues at the active site.
Figure 3, obtained by overlaying (-)-6 and (-)-9 onto
the geometry optimized naloxone,14 illustrates such an ex-
tended and compact N-phenylpropenyl group, which spans
well beyond the space circumscribed by an allyl moiety of
naloxone.
The two N-phenylpropenyl compounds in Figure 3 along
with the naloxone were further superimposed onto the
naltrexone in Figure 2, and this superposition (Figure 4)
depicts the spatial position of both the allyl and cyclopropyl
moieties as well as phenyl substituents. It illustrates that the
double bond in the allyl moiety of naloxone, (-)-6, and (-)-9
literally bisects the cyclopropane ring in naltrexone and in
(þ)-29 and (þ)-31, suggesting that both the double bond and
the cyclopropane moiety have a similar effect in binding
affinity at the μ receptor via hydrophobic interactions.

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4 961
Table 1. 125I-IOXY Opioid Receptor Binding Dataa (Ki, nM)
a Assays were conducted using125I-IOXY to label the μ-, δ-, or κ-opioid receptors stably expressed in CHO cells.17 All results are for n = 3 ((SD). For
comparison, the Ki of morphine at μ is 2.55 ( 0.01 nM; the Ki of naloxone at μ is 0.98 ( 0.05 nM, at δ is 51 ( 3 nM, and at κ is 3 ( 0.19 nM. Supporting
Information (http://pubs.acs.org) contains a complete table of standards for these assays.
In addition, Figure 4 shows the extensive space spanned by
the phenyl groups of the NCPM and the N-phenylpropenyl
compounds. Despite the wide spatial distribution of the
conformationally restrained phenyl groups, the Ki of (-)-6
and (-)-9 as well as (þ)-29, (-)-30, and (-)-32 are all in the
range of 3-14 nM. This, in turn, suggests that a rather wide
binding pocket exists in the μ-receptor binding site that can
encompass these phenyl substituents.
All four of the N-phenylpropenyl compounds were
μ-opioid antagonists, and (þ)-6 was the most potent (Ke =
0.58). Thus, the N-phenylpropenyl compounds, like the
N-phenylpropyl compound of Hashimoto at al.,2 were
opioid antagonists. However, unlike the compound of Ha-
shimoto at al.,2 three of the four N-phenylpropenyl com-
pounds acted as inverse μ-agonists, as determined by the
[35S]-GTP-γ-S binding assay (Figure 5). Of the four, only the
N-phenylpropenyl analogue (-)-6 had little or no activity as
an inverse agonist. We previously reported the full inverse
agonist curve for one of the initial compounds that was
prepared, (þ)-9.15 Although it had low efficacy, it was found
to be an inverse agonist at nondependent μ-opioid receptors.
This was a rare example of a compound that could act as an
inverse agonist at nondependent μ-opioid receptors.15 Given
the low degree of inverse agonist efficacy (∼20%) of the
other compounds, generating inverse agonist dose-response
curves under such a low signal-to-noise condition was pro-
blematic and would have required a larger number of
replications than is customary. Under these constraints, we
opted to generate a bar graph showing the effect of a single
concentration (10 μM) on [35S]-GTP-γ-S binding (Figure 5).
The results show that most of the compounds are inverse
agonists in nondependent cells. Since the compounds are
also μ-antagonists, we have also generated antagonist Ke
values for each compound in Table 2. It would be of interest
in future studies to examine why (-)-32 and the N-phenyl-
propenyl substituted compound, (-)-6, did not act as inverse
agonists. Both of them ((-)-32 and (-)-6) showed moderate
to good affinity (Table 1) for the μ-receptor (Ki = 11 and

962 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4
Cheng et al.
6 nM, respectively), and both were 4-fold less active as opioid
antagonists (Table 2) than naloxone, showing moderate Ke
values (8.2 and 6.6 nM). The relationship, if any, between the
spatial characteristics of these compounds that enables them
to bind with high affinity to the μ-opioid receptor and the
inverse agonist activity that results from that binding is not
readily apparent.
unsaturated side chains, and/or those with cyclopropyl
groups, were found to have this unusual inverse agonist
activity in nondependent cells, for reasons that are
not apparent. Two of the NCPM compounds, (þ)-29 and
(-)-30, and one of the N-propenyl compounds, (þ)-6, were
found to be potent antagonists more potent than naloxone in
the [35S]GTP-γ-S functional binding assay (13-, 7-, and 4-fold
more potent, respectively, Ke = 0.17, 0.31, and 0.58nM). Two
others, an N-propenyl compound (þ)-9 and an NPCM
compound (þ)-30, were about as potent as naloxone as
μ-opioid antagonists (Ke = 3.1 and 2.2 nM, respectively).
The overlay of both N-phenylpropenyl and N-phenylpropyl
Conclusion
It is extremely unusual to find compounds that act as
μ-inverse agonists in nondependent cells. The ∼20% inverse
agonist efficacy observed with many of the compounds
reported here far exceeds that of previous reports. For exam-
ple, to our knowledge there is only one report in the literature
where a few compounds were found to have extremely mini-
mal inverse agonist activity (3-5%) in nondependent cells.13
Yet many of the phenylmorphans that we have examined with
Table 2. Functional Data ([35S]GTP-γ-S)a for Selected Compounds
[test agent]
Ke (nM)
þ2 nM (þ)-6 ((1S,5R)-(E))
0.58 ( 0.07
6.6 ( 0.7
3.1 ( 0.7
7.7 ( 1.6
9.4 ( 1.5
0.17 ( 0.02
2.2 ( 0.4
0.31 ( 0.06
8.6 ( 1.9
33 ( 7
þ6 nM (-)-6 ((1R,5S)-(E))
þ10 nM (þ)-9 ((1S,5R)-(Z))
þ10 nM (-)-9 ((1R,5S)-(Z))
þ50 nM (-)-29 ((1S,5R)-2-(10R,20R)-(trans))
þ2 nM (þ)-29 ((1R,5S)-2-(10S,20S)- (trans))
þ16 nM (þ)-30 ((1S,5R)-2-(10S,20S)-(trans))
þ2 nM (-)-30 ((1R,5S)-2-(10R,20R)- (trans))
þ50 nM (-)-31 ((1S,5R)-2-(10R,20S)-(cis))
þ50 nM (þ)-31 ((1R,5S)-2-(10S,20R)-(cis))
þ6 nM (þ)-32 ((1S,5R)-2-(10S,20R)-(cis))
þ11 nM (-)-32 ((1R,5S)-2-(10R,20S)-(cis))
naloxoneb
18 ( 6
8.2 ( 1.8
2.3 ( 0.3
0.34 ( 0.03
naltrexone
a
[
35S]GTP-γ-S binding was conducted as described in Experimental
Section. DAMGO dose-response curves (10 points/curve) were gener-
ated in the absence and presence of the indicated concentrations of test
agents. The data for each experimental condition were pooled and the
best-fit estimates of the EC50 and EMAX values determined using
MLAB-PC. The Ke values were calculated according to the equation
[test agent]/(EC50-2/EC50-1 - 1), where EC50-2 is the EC50 value in the
presence of the test drug and EC50-1 is the value in the absence of the test
drug. Each parameter value is (SD. b From Kurimura et al.19
Figure 3. Overlay obtained by fitting the nine heavy
(phenethylamine) atoms of two phenylalkenyl-substituted phenyl-
morphans (-)-6 (1R,5S-(E)) and (-)-9 (1R,5S-(Z)) to that of the
geometry optimized naloxone. The carbon atoms of naloxone are
in yellow. Atoms represented by colors are as follows: green/yellow,
carbon; blue, nitrogen; red, oxygen. Hydrogen atoms are not
shown.
Figure 2. Overlay obtained by fitting the nine heavy (phenethylamine) atoms of each of the four N-phenylcyclopropylmethyl-substituted
1R,5S-phenylmorphans to that of the geometry optimized naltrexone; the carbon atoms of naltrexone are in yellow. Atoms represented by
colors are as follows: green/yellow, carbon; blue, nitrogen; red, oxygen. Hydrogen atoms are not shown.

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4 963
compounds suggests a wide binding or a flexible hydrophobic
pocket at the μ-receptor to accommodate the different spatial
positions and sizes of the N-phenyl substituents. However, the
relationship between the topology of these compounds and
their inverse agonist activity is not apparent and will be the
subject of future studies.
with a Shimadzu SPD-6AV UM detector (at 254 nm) using
Daicel’s Chiralcel OD and OJ column (250 mm ꢀ 4.6 mm)).
Elemental analyses were performed by Atlantic Microlabs Inc.,
Norcross, GA, and were within (0.4% for C, H, and N. The
elemental analysis, 1HNMR, and13C NMRwereusedtoconfirm
g95% purity.
General Procedure for Syntheses of (Z)-3-Phenylacrylic Acid
or (E)-Cinnamoylamides of the Enantiomers of 5-(3-Methoxy-
phenyl)-2-azabicyclo[3.3.1]nonane ((-)-1 and (þ)-1). The enantio-
meric amine4 (-)-1 (or (þ)-1) (2 -3 mmol), (Z)-3-phenylacrylic
acid (3) or cinnamic acid ((E) 2) (1.2 equiv), and EDCI (1.3 equiv)
in CH2Cl2 (6 mL) were stirred at room temperature overnight. The
mixture was diluted with 5% propan-2-ol in CH2Cl2, washed with
aqueous Na2CO3 solution (to ∼pH 10) and brine, dried over
Na2SO4, and passed through a pad of silica gel. After evaporation,
the residue was purified by silica gel column chromatography with
hexanes/EtOAc/EtOH (60/30/1.5) to give the amide products.
(Z)-3-Phenylacrylic Acid (3).8 To a solution of 3-phenylpro-
piolic acid (10, 5.85 g, 40 mmol) in anhydrous pyridine (90 mL)
was added 5% Pd on calcium carbonate (0.80 g). The mixture
was stirred under 1 atm of hydrogen and consumed about 900
mL of hydrogen. The catalyst was removed by filtration and the
pyridine distilled from the filtrate under reduced pressure. The
residue was acidified with 10% hydrochloric acid (20 mL) and
then extracted with Et2O (3 ꢀ 30 mL). The combined organic
layers were washed with brine, dried over MgSO4, and concen-
trated to give crude product. Column chromatography of this
crude product with CH2Cl2-MeOH-acetic acid (75:5:0.4) gave
(Z)-3-phenylacrylic acid (3) with about 10% of cinnamic acid
(2, 3.5 g, 59% yield). The crude 3 (3.3 g, 22 mmol) was dissolved
in anhydrous Et2O (30 mL), and diisopropylamine (3.4 mL,
24 mmol) was then added to this solution. The resulting mixture
was keep at room temperature overnight and gave colorless
crystals of diisopropylammonium (Z)-3-phenylacrylate (11,
3.2 g, 64%). Mp 108.0-109.0 °C; 1H NMR (CDCl3, free base)
δ 7.53-7.58 (m, 2H), 7.16-7.26 (m, 3H), 6.38 (d, 1H, J = 12.6
Hz), 6.08 (d, 1H, J = 12.6 Hz), 3.11 (m, 2H), 1.19 (d, 12H, J =
6.6 Hz); 13C NMR (CDCl3) δ 173.45, 137.26, 130.05, 129.55,
129.04, 127.94, 127.29, 46.19, 19.20. The diisopropylammonium
(Z)-3-phenylacrylate (11, 3.2 g) was acidified with 10% hydro-
chloric acid (10 mL) and then extracted with Et2O (3 ꢀ 20 mL).
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated to give pure (Z)-3-phenylacrylic acid
(3) as a colorless solid (1.80 g, 95%). Mp 66.0-68.0 °C (lit.8 mp
65-68 °C); 1H NMR (CDCl3) δ 7.61 (d, 1H, J = 4.5 Hz), 7.58
(d, 1H, J = 1.8 Hz), 7.33-7.38 (m, 3H), 7.07 (d, 1H, J =
12.6 Hz), 5.97 (d, 1H, J = 12.6 Hz); 13C NMR (CDCl3) δ 171.16,
164.00, 134.60, 130.15, 129.60, 128.32, 118.85.
Experimental Section
All melting points were determined on a Thomas-Hoover
melting point apparatus and are uncorrected. Proton nuclear
magnetic resonance (1H NMR, 300 MHz) and carbon nuclear
magnetic resonance (13C NMR, 75 MHz) spectra were recorded
on a Varian Gemini-300 instrument in CDCl3 (unless otherwise
noted) with the values given in ppm (TMS as internal standard)
and J (Hz) assignments of 1H resonance coupling. The high
resolution electrospray ionization (ESI) mass spectra were ob-
tained on a Waters LCT Premier time-of-flight (TOF) mass
spectrometer. Thin-layer chromatography (TLC) was performed
on 0.25 mm Analtech GHLF silica gel. Flash column chroma-
tography was performed with Bodman silica gel LC 60 A.
Enantiomeric purity was assessed by HPLC (Shimadzu LC-6A
Figure 4. Two views of the obtained by fitting the nine heavy
(phenethylamine) atoms of each of the six phenylmorphans ((-)-6
(1R,5S)-(E), (-)-9 (1R,5S)-(Z), (þ)-29 (1R,5S)-2-(10S,20S)-(trans),
(-)-30 (1R,5S)-2-(10R,20R)-(trans), (þ)-31 (1R,5S)-2-(10R,20S)-
(cis), and (-)-32 (1R,5S)-2-(10R,20S)-(cis)) and naloxone to that of
the geometry optimized naltrexone. The carbon atoms of naltrexone
are in yellow. Atoms represented by colors as follows: green/yellow,
carbon; blue, nitrogen; red, oxygen. Hydrogen atoms are not
shown.
Figure 5. As described in the Experimental Section, the effect of each test compound (10 μM) on [35S]GTP-γ-S binding to μ-opioid receptors
was determined. Each value is the mean ( SD (N = 3). A negative stimulation indicates inverse agonist activity. All changes were significant (p
< 0.05) except for no. 12 ((-)-32) (Student’s t test).

964 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4
Cheng et al.
1
(E)-1-((1S,5R)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)-3-phenylprop-2-en-1-one ((þ)-4). Yield, 76.5% as a syrup;
[R]2D0 þ16.5° (c 1.0, MeOH); 1H NMR (CDCl3) δ 7.71 (m, 1H),
7.51-7.57 (m, 2H), 7.33-7.42 (m, 3H), 7.24-7.30 (m, 1H),
6.86-6.96 (m, 3H), 6.76 (dd, 1H, J = 8.4, 2.4 Hz), 4.70 (br-d,
1H, J = 124 Hz), 3.90-4.05 (m, 2H), 3.81 (s, 3H), 1.90-2.30 (m,
7H), 1.50-1.80 (m, 3H); 13C NMR (CDCl3) δ 166.69, 166.27,
159.60, 153.23, 153.00, 142.22, 142.05, 135.51, 129.42, 129.34,
128.73, 127.71, 118.45, 117.93, 117.17, 117.08, 111.52, 111.44,
110.41, 55.16, 49.26, 46.78, 42.44, 39.89, 38.86, 38.53, 36.95,
36.43, 36.20, 35.55, 34.95, 34.71, 31.84, 29.17, 20.45, 20.32;
HRMS (TOF MS ESþ) calcd for C24H28NO2 (M þ H)þ
362.2120, found 362.2117.
(E)-1-((1R,5S)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)-3-phenylprop-2-en-1-one ((-)-4). Yield, 80.5% as syrup;
[R]2D0 -16.5° (c 1.0, MeOH); 1H NMR (CDCl3) δ 7.71 (dd, 1H,
J = 15.3, 12 Hz), 7.51-7.57 (m, 2H), 7.33-7.42 (m, 3H),
7.24-7.30 (m, 1H), 6.86-6.96 (m, 3H), 6.75 (dd, 1H, J = 8.1,
2.4 Hz), 4.70 (br-d, 1H, J = 124 Hz), 3.90-4.05 (m, 2H), 3.81
(s, 3H), 1.90-2.30 (m, 7H), 1.50-1.80 (m, 3H); 13C NMR
(CDCl3) δ 166.65, 166.23, 159.58, 153.19, 152.97, 142.17,
142.00, 135.48, 129.39, 129.31, 128.70, 127.68, 118.43, 117.91,
117.14, 117.05, 111.49, 111.41, 110.39, 55.13, 49.22, 46.75, 42.40,
39.86, 38.84, 38.50, 36.93, 36.41, 36.17, 35.54, 34.92, 34.69,
31.82, 29.14, 20.44, 20.29; HRMS (TOF MS ESþ) calcd for
C24H28NO2 (M þ H)þ 362.2120, found 362.2117.
þ11.9° (c 0.47, MeOH); H NMR (CDCl3, free base) δ 8.71
(br, 1H), 7.05-7.40 (m, 6H), 6.54-6.82 (m, 4H), 6.30-6.43 (m,
1H), 3.46 (d, 2H, J = 6.6 Hz), 3.34 (br, 1H), 2.95-3.15 (m, 2H),
2.10-2.28 (m, 2H), 1.76-2.06 (m, 5H), 1.20-1.70 (m, 3H); 13
C
NMR (CDCl3, free base): δ 156.70, 152.40, 136.22, 134.51,
129.21, 128.46, 127.76, 126.46, 124.05, 116.00, 113.56, 112.54,
57.49, 52.29, 49.36, 37.78, 37.20, 35.93, 34.34, 23.71, 22.27; 1H
NMR (CD3OD, free base) δ 7.24-7.32 (m, 2H), 7.06-7.23
(m, 3H), 6.70 (t, 1H, J = 7.8 Hz), 6.65-6.75 (m, 2H), 6.45-6.57
(m, 2H), 6.12-6.25 (m, 1H), 3.17-3.22 (m, 1H), 3.09 (br, 1H),
2.98 (d-t, 1H, J = 4.8, 12.6 Hz), 2.80 (dd, 1H, J = 12.0, 4.8 Hz),
2.10 (br-d, 2H, J = 13.8 Hz), 1.70-2.06 (m, 5H), 1.40-1.66 (m,
2H), 1.14-1.40 (m, 2H); 13C NMR (CD3OD, free base) δ
158.46, 154.67, 138.36, 134.94, 130.35, 129.78, 128.84, 127.55,
127.02, 117.09, 113.77, 112.96, 58.89, 53.67, 50.83, 39.65, 39.48,
38.15, 35.96, 25.14, 24.02; HRMS (TOF MS ESþ) calcd for
C23H28NO (M þ H)þ 334.2171, found 334.2180. Anal. (C23H27-
NO HCl) C, H, N.
3
3-((1R,5S)-2-Cinnamyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol
((-)-6). Yield, 58%; HCl salt, mp 201-203 °C (dec);
[R]2D0 -12.0° (c 0.36, MeOH); H NMR (CDCl3, free base) δ
1
7.05-7.40 (m, 5H), 6.82 (d, 1H, J = 7.8 Hz), 6.77 (br-t, 1H,
J = 2 Hz), 6.64 (dd, 1H, J = 8 and 2 Hz), 6.52-6.62 (m, 2H),
6.26-6.38 (m, 1H), 3.41 (m, 2H), 3.25 (br, 1H), 2.90-3.10 (m,
2H), 2.10-2.14 (m, 2H), 1.82-2.07 (m, 5H), 1.50-1.75 (m, 2H),
1.30-1.44 (m, 1H); 13C NMR (CDCl3, free base) δ 156.57,
153.64, 137.03, 133.18, 129.46, 128.74, 127.71, 126.87, 126.59,
116.81, 113.38, 112.64, 58.14, 52.12, 49.83, 38.54, 38.46, 37.10,
34.99, 24.39, 23.09; HRMS (TOF MS ESþ) calcd for C23H28NO
(M þ H)þ 334.2171, found 334.2180. Anal. (C23H27NO
General Procedure for Syntheses of Phenolic Amides ((1S,5R)-
(þ)-5, (1R,5S)-(-)-5 and (1S,5R)-(þ)-8, (1R,5S)-(-)-8) from the
Corresponding Methyl Ethers ((1S,5R)-(þ)-4, (1R,5S )-(-)-4,
and (1S,5R)-(þ)-7, (1R,5S)-(-)-7). A mixture of enantiomeric
amide (1-2 mmol), 48% hydrogen bromide (2 mL), and HOAc
(3 mL) was refluxed for 30 min to 1 h under argon. The HOAc
was removed in vacuo, and the mixture was neutralized with
saturated NaHCO3 to pH 10. The mixture was extracted with
5% propan-2-ol in CH2Cl2 (3 ꢀ 30 mL). The combined extracts
were washed with H2O and brine and then dried over Na2SO4.
After evaporation, the residue was purified by silica gel column
chromatography with hexanes/EtOAc/EtOH (40/28/2) to give
the amide products.
(E)-1-((1S,5R)-5-(3-Hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)-3-phenylprop-2-en-1-one ((þ)-5). Yield, 71% as syrup; [R]D20
þ22.0° (c 0.42, MeOH); 1H NMR (CDCl3) δ 7.72 (m, 1H),
7.48-7.55 (m, 2H), 7.28-7.44 (m, 4H), 7.15-7.22 (m, 1H),
6.81-6.97 (m, 3H), 6.75 (dd, 1H, J = 8.4, 2.4 Hz), 4.70 (br-d,
1H, J = 124 Hz), 3.75-4.05 (m, 2H), 1.40-2.25 (m, 10H);
HRMS (TOF MS ESþ) calcd for C23H26NO2 (M þ H)þ
348.1964, found 348.1968.
(E)-1-((1R,5S)-5-(3-Hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)-3-phenylprop-2-en-1-one ((-)-5). Yield, 75% as syrup;
[R]2D0 -22.3° (c 0.68, MeOH); 1H NMR (CDCl3) δ 7.71 (m,
1H), 7.48-7.54 (m, 2H), 7.32-7.40 (m, 3H), 7.14-7.22 (m, 1H),
6.80-6.96 (m, 3H), 6.75 (dd, 1H, J = 8.1, 2.4 Hz), 4.70 (br-d,
1H, J = 152 Hz), 3.75-4.05 (m, 2H), 1.75-2.25 (m, 7H), 1.50-
1.75 (m, 3H); HRMS (TOF MS ESþ) calcd for C23H26NO2
(M þ H)þ 348.1964, found 348.1961.
HCl 0.25H2O) C, H, N.
3
3
(Z)-1-((1S,5R)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)-3-phenylprop-2-en-1-one ((þ)-7). Yield, 74.7% as syrup;
[R]2D0 þ45.4° (c 0.95, MeOH); H NMR (CDCl3) δ 7.37-7.45
1
(m, 2H), 7.19-7.35 (m, 4H), 6.70-6.83 (m, 3H), 6.63 (d, 1H, J =
12.6 Hz), 6.86-6.96 (m, 3H), 6.09 (dd, 1H, J = 12.6, 8.4 Hz),
4.62 (d-m, 1H, J = 180 Hz), 3.79 (d, 3H, J = 2.7 Hz), 3.42-3.78
(m, 2H), 1.80-2.20 (m, 5H), 1.48-1.80 (m, 5H); 13C NMR
(CDCl3) δ 168.80, 168.65, 159.78, 153.27, 152.77, 136.07,
135.74, 133.02, 132.61, 129.48, 128.73, 128.63, 128.58, 128.36,
124.68, 123.95, 117.31, 117.19, 111.66, 111.53, 110.68, 110.57,
55.38, 50.46, 45.93, 43.02, 39.89, 38.60, 38.04, 37.47, 36.46,
35.93, 35.28, 31.21, 28.76, 21.52, 20.77; HRMS (TOF MS ESþ)
calcd for C24H28NO2 (M þ H)þ 362.2120, found 362.2108.
(Z)-1-((1R,5S)-(-)-5-(3-methoxyphenyl)-2-azabicyclo[3.3.1]-
nonan-2-yl)-3-phenylprop-2-en-1-one ((-)-7). Yield, 78.0% as
syrup; [R]2D0 -45.3° (c 1.0, MeOH); 1H NMR (CDCl3) δ
7.37-7.43 (m, 2H), 7.19-7.35 (m, 4H), 6.70-6.83 (m, 3H),
6.63 (d, 1H, J = 12.6 Hz), 6.86-6.96 (m, 3H), 6.09 (dd, 1H, J =
12.6, 8.4 Hz), 4.62 (d-m, 1H, J = 180 Hz), 3.79 (d, 3H, J = 2.7
Hz), 3.42-3.72 (m, 2H), 1.80-2.20 (m, 5H), 1.46-1.80 (m, 5H);
13C NMR (CDCl3) δ 168.80, 168.65, 159.78, 153.27, 152.77,
136.07, 135.74, 133.02, 132.61, 129.48, 128.73, 128.63, 128.58,
128.36, 124.68, 123.95, 117.31, 117.19, 111.66, 111.53, 110.68,
110.57, 55.38, 50.46, 45.93, 43.02, 39.89, 38.60, 38.04, 37.47,
36.46, 35.93, 35.28, 31.21, 28.76, 21.52, 20.77; HRMS (TOF
MS ESþ) calcd for C24H28NO2 (M þ H)þ 362.212, found
362.2117.
General Procedure for Syntheses of Amines ((1S,5R)-(þ)-6,
(1R,5S)-(-)-6 and ((1S,5R)-(þ)-9 and (1R,5S)-(-)-9) from the
Phenolic Amides ((1S,5R)-(þ)-5, (1R,5S)-(-)-5 and (1S,5R)-
(þ)-8, (1R,5S)-(-)-8).3 Red-Al (65%, 2.5 equiv) was added to
the solution of amide (1-2 mmol) in anhydrous THF (60 mL)
dropwise under argon at room temperature, and the mixture
was stirred for 2 h at room temperature. The reaction was
quenched with saturated NaHCO3 (20 mL), and the organic
layer was separated. The aqueous layer was extracted with Et2O
(3 ꢀ 20 mL). The combined organic layers were washed with
brine and dried over Na2SO4. After removal of solvent in vacuo,
the residue was purified by silica gel column chromatography with
hexanes/EtOAc/EtOH (40/40/2) to give the phenolic amides.
3-((1S,5R)-2-Cinnamyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol
((þ)-6). Yield, 61%; HCl salt, mp 202-204 °C (dec); [R]D20
(Z)-1-((1S,5R)-5-(3-Hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)-3-phenylprop-2-en-1-one ((þ)-8). Yield, 72% as syrup; [R]D20
þ46.3° (c 0.95, MeOH); 1H NMR (CDCl3) δ 7.08-7.42 (m, 6H),
6.60-6.88 (m, 4H), 6.07 (dd, 1H, J = 12.6, 7.2 Hz), 4.62 (d-m,
1H, J = 198 Hz), 3.36-3.70 (m, 2H), 1.40-2.20 (m, 10H);
HRMS (TOF MS ESþ) calcd for C23H26NO2 (M þ H)þ
348.1964, found 348.1962.
(Z)-1-((1R,5S)-(-)-5-(3-Hydroxyphenyl)-2-azabicyclo[3.3.1]-
nonan-2-yl)-3-phenylprop-2-en-1-one ((-)-8). Yield, 65.0% as
1
syrup; [R]2D0 -46.4° (c 1.0, MeOH); H NMR (CDCl3) δ 7.64
(s, 1H), 7.20-7.40 (m, 5H), 7.05-7.14 (m, 1H), 6.60-6.78 (m,
4H), 6.07 (dd, 1H, J = 12.6, 7.2 Hz), 4.55 (d-m, 1H, J = 198 Hz),

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4 965
3.35-3.70 (m, 2H), 1.40-2.20 (m, 10H); HRMS (TOF MS ESþ)
calcd for C23H26NO2 (M þ H)þ 348.1964, found 348.1948.
3-((1S,5R)-2-((Z)-3-phenylallyl)-2-azabicyclo[3.3.1]nonan-5-yl)-
phenol ((þ)-9). Yield, 68%; HCl salt, mp 201-203 °C (dec); [R]D20
EtOH). The free acid was liberated from the salt by treatment with 2
N HCl. Extraction with Et2O and removal of solvent in vacuo gave
3.2 g of (þ)-13 as an oil, which solidified on standing. Mp 45-
46 °C; [R]2D0 þ406.0° (c 1.0, CHCl3); >98% ee in chiral HPLC
[Chiralcel OD column; hexane/propan-2-ol/TFA 91:9:0.2; flow
rate 1 mL/min; detection 254 nm; retention time 8.18 min].
1
þ27.3° (c 0.42, MeOH); H NMR (CDCl3, free base) δ 7.20-
7.40 (m, 5H), 7.11 (t, 1H, J = 7.8 Hz), 6.79 (d, 1H, J = 7.8 Hz),
6.76 (br, 1H), 6.64 (dd, 1H, J = 7.8, 2.1 Hz), 6.57 (d, 1H,
J = 11.7 Hz), 5.86 (d-t, 1H, J = 12.6, 6.3 Hz), 3.55 (m, 2H), 3.23
(br, 1H), 2.96 (m, 2H), 2.14 (d-br, 1H, J = 12.6 Hz), 1.76-2.06
(m, 6H), 1.20-1.70 (m, 3H); 13C NMR (CDCl3, free base) δ
156.64, 153.61, 137.25, 131.53, 129.55, 129.41, 129.07, 128.36,
127.09, 116.67, 113.34, 112.67, 53.21, 52.26, 49.75, 38.46, 37.03,
34.86, 24.45, 22.99; HRMS (TOF MS ESþ) calcd for C23H28NO
(1R,2R)-2-Phenylcyclopropanecarboxylic Acid (trans-(-)-
13).11 A warm solution of commercially available trans-2-phe-
nylcyclopropane-1-carboxylic acid ((()-13, 24 g, 147 mmol) in
MeOH (150 mL) was added to a solution of dehydroabietyla-
mine (41.7 g, 147 mmol) in warm MeOH (120 mL). The mixture
was cooled to room temperature and the precipitate was col-
lected and dried to afford a white solid, which was recrystallized
from 90% aqueous MeOH five times to give 8.2 g (25%)
of ((1R,4aS)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-oc-
tahydrophenanthren-1-yl)methanaminium (1R,2R)-2-phenyl-
cyclopropanecarboxylate ((-)-17) as colorless crystals. Mp
167.5-168 °C, [R]2D0 -80.8° (c 0.61, MeOH). The free acid was
liberated from the salt by treatment with a saturated NaHCO3
solution and extraction with Et2O. Acidification of the aqueous
fraction with cold, 37% hydrochloric acid, extraction with
Et2O, and removal of solvent in vacuo gave 2.9 g of crude (-)-
13. One recrystallization from acetone gave 2.8 g of (-)-13, mp
47-48 °C (lit.6 mp 49.5-50 °C; [R]D20 -401.0° (c 0.88, CHCl3)
(lit.6 [R]2D5 -309° (c 1, 95% EtOH); >98% ee in chiral HPLC
[Chiralcel OD column; hexane/propan-2-ol/TFA 91:9:0.2; flow
rate 1 mL/min; detection 254 nm; retention time 5.56 min].
(1S*,2R*)-2-Phenylcyclopropanecarboxylic Acid (cis-((()-
14).7 A 500 mL flask equipped with a 30 cm Vigreux column,
to which was attached a partial takeoff distilling head with a
reflux condenser, was charged with (1S*,2R*)-(()-16 (20.0 g,
0.105 mol), H2O (75 mL), NaOH (8.4 g, 0.21 mol), and EtOH
(100 mL). The mixture was refluxed for 5 h, during which
time 120 mL of distillate was obtained. After cooling
to room temperature, the mixture was washed with benzene
(30 mL), and then benzene (40 mL) and concentrated hydro-
chloric acid (20 mL) were added. The organic layer was sepa-
rated, and the aqueous layer was extracted with benzene (2 ꢀ
30 mL). The combined organic layer was dried over MgSO4.
Removal of solvent afforded (()-14 as colorless crystals (12 g,
70% yield). Mp 86-87 °C (lit.7 mp 106-109 °C); 1H NMR
(CDCl3) δ 7.35 - 7.55 (m, 5H), 3.86 (q, 2H, J = 7.2 Hz), 2.57
(dd, 1H, J = 16.5, 9.0 Hz), 2.03-2.12 (m, 1H), 1.67-1.74 (m,
1H), 1.28-1.36 (m, 1H), 0.965 (t, 3H, J = 7.2 Hz); 13C NMR
(CDCl3): δ 171.52, 136.75, 129.49, 128.06, 126.82, 60.35, 25.64,
21.99, 14.20, 11.29.
(1R,2S)-2-Phenylcyclopropanecarboxylic Acid ((-)-14). Op-
tical Resolution of ((1S*,2R*)-2-phenylcyclopropanecarboxylic
Acid (()-14). The (()-14 (14.8 g, 91.6 mmol)7 was added to a
boiling solution of (þ)-dehydroabietylamine (26.2 g, 91.6 mmol)
in MeOH (1300 mL) and H2O (330 mL). The mixture was cooled
to room temperature, and the precipitate was collected and
dried to afford the light yellow solid, which was recrystallized
from 90% aqueous methanol four times to give 3.3 g (16%)
of ((1R,4aS)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-oc-
tahydrophenanthren-1-yl)methanaminium (1R,2S)-2-phenyl-
cyclopropanecarboxylate ((þ)-19) as colorless crystals. Mp 189-
190 °C; [R]2D0 þ37.1° (c 1.0, EtOH). The free acid was liberated
from the salt by treatment with a saturated NaHCO3 solution
and extracted with Et2O. The aqueous fraction was acidified
with cold, concentrated hydrochloric acid and extracted with
Et2O. The ethereal solutions were combined and the solvent was
removed to give 1.1 g of (-)-14 as colorless crystals. Mp
82.5-83.5 °C (lit.6 mp 83-84 °C); [R]D20 -28.4° (c 1.0, CHCl3)
(lit.6 [R]D20 -28° (c 1.023, CHCl3)); >98% ee in chiral HPLC
(Chiralcel OJ column; hexane/propan-2-ol/TFA 95:5:0.1; flow
rate 1 mL/min; detection 254 nm; retention time 12.87 min).
(1S,2R)-2-Phenylcyclopropane-1-carboxylic Acid ((þ)-14). A
solution of (þ)-(1S,2R) enriched cis-2-phenylcyclopropanecar-
boxylic acid (13.2 g, 81.4 mmol) and quinine (27.9 g, 86.2 mmol)
(M þ H)þ 334.2171, found 334.2176. Anal. (C23H27NO HCl
3
0.25H2O) C, H, N.
3
3-((1R,5S)-2-((Z)-3-phenylallyl)-2-azabicyclo[3.3.1]nonan-5-
yl)phenol ((-)-9). Yield, 60%; HCl salt, mp 200-202 °C (dec);
[R]2D0 -27.0° (c 0.42, MeOH); 1H NMR (CDCl3, free base) δ 7.70
(br, 1H), 7.18-7.40 (m, 5H), 7.10 (t, 1H, J = 7.8 Hz), 6.78 (d,
1H, J = 7.8 Hz), 6.72 (br, 1H), 6.60 (dd, 1H, J = 7.8, 1.8 Hz),
5.56 (d, 1H, J = 12.6 Hz), 5.86 (d-t, 1H, J = 12.6, 6.3 Hz), 3.54
(m, 2H), 3.22 (br, 1H), 2.96 (m, 2H), 2.14 (d-br, 1H, J = 12.6
Hz), 1.700-2.04 (m, 6H), 1.44-1.62 (m, 2H), 1.20-1.36 (m,
1H); 13C NMR (CDCl3, free base) δ 156.70, 153.52, 137.22,
131.55, 129.45, 129.40, 129.06, 128.35, 127.07, 116.58, 113.53,
112.80, 53.16, 52.24, 49.73, 38.35, 37.00, 34.81, 24.40, 22.96;
HRMS (TOF MS ESþ) calcd for C23H28NO (M þ H)þ
334.2171, found 334.2182. Anal. (C23H27NO HCl 0.5H2O) C,
3
3
H, N.
(2,2-Dibromocyclopropyl)benzene (12).9 A 3 L round-bot-
tomed flask equipped with a mechanical stirrer was charged
with styrene (99.9 g, 0.96 mmol) and bromoform (485 g, 1.92 mol).
Benzyltriethylammonium chloride (TEBA, 46 g, 0.2 mol) and
50% aqueous NaOH (500 mL) were added to the solution, and
the resulting mixture was stirred vigorously at room tempera-
ture for 20 h. The reaction mixture was then treated with H2O
(1 L) and extracted with Et2O (3 ꢀ 500 mL). The combined
organic layers were dried over MgSO4, and the solvent was
removed in vacuo. Distillation of the residue gave 12 as a yellow
1
oil (86-88 °C/∼2 mmHg, 206 g, 78%). H NMR (CDCl3) δ
7.20-2.40 (m, 5H), 2.95 (dd, 1H, J = 10.5, 8.1 Hz), 2.13 (dd, 1H,
J = 10.5, 8.1 Hz), 2.01 (t, 1H, J = 8.1 Hz); 13C NMR (CDCl3) δ
135.95, 128.88, 128.27, 127.59, 35.89, 28.41, 27.19.
2-Phenylcyclopropanecarboxylic Acid ((()-13 (trans-1R*,2R*)
and (()-14 (cis-1S*,2R*)).10 Synthesis gas (CO/H2, 3:1) was
bubbled through a vigorously stirred mixture of 5 N KOH
(1100 mL), toluene (600 mL), cobalt(II) chloride hexahydrate
(14.28 g, 60 mmol), potassium cyanide (7.81 g, 120 mmol),
nickel(II) cyanide tetrahydrate (10.97 g, 60 mmol), and PEG-
400 (5 mL, 15 mmol) at 95 °C for 2 h. A solution of 12 (82.8 g,
300 mmol) in toluene (200 mL) was added, and the resulting
mixture was stirred vigorously, continuously bubbling in addi-
tional synthesis gas for 2 days at 95 °C. After cooling to room
temperature, the mixture was filtered through Celite. The aqu-
eous layer was separated, washed with Et2O (2 ꢀ 200 mL),
acidified with 6 N hydrochloric acid to pH 1, and extracted with
Et2O (3 ꢀ 120 mL). The combined extracts were washed with
brine and dried over MgSO4. Removal of solvent gave a
6:4 mixture of isomers (()-13 and (()-14 as a light yellow solid
(21 g, 43%).
(1S,2S)-2-Phenylcyclopropane-1-carboxylic acid (trans-(þ)-
13). A solution of (þ)-(1S,2S)-enriched (()-13 (19 g, 117 mmol)
and quinine (40.1 g, 124 mmol) in EtOAc (760 mL) was refluxed
until most of the solid was dissolved. The solution was filtered,
and the filtrate was allowed to stand at room temperature for
5 days. The precipitate was collected and recrystallized from
EtOAc five times to yield 10.2 g (34%) of (1S,4S)-2-((R)-
hydroxy(6-methoxyquinolin-4-yl)methyl)-8-vinyl-1-azoniabi-
cyclo[2.2.2]octane (1S,2S)-2-phenylcyclopropanecarboxylate ((-)-
18) as colorless crystals. Mp 152.0-152.5 °C; [R]2D0 -10.2° (c 1.0,

966 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4
Cheng et al.
in EtOAc (530 mL) was refluxed until most of solid was
dissolved. The solution was filtered, and the filtrate was allowed
to stand at room temperature overnight. The precipitate
was collected and recrystallized from EtOAc six times to
yield 3.8 g (9%) of (1S,4S)-2-((R)-hydroxy(6-methoxyquinolin-
4-yl)methyl)-8-vinyl-1-azoniabicyclo[2.2.2]octane (1S,2R)-2-
phenylcyclopropanecarboxylate ((-)-20) as colorless crystals.
Mp 142-144 °C; [R]2D0 -116.5° (c 1.0, EtOH). The free acid was
liberated from the salt by treatment with 2 N HCl and extracted
with Et2O. Removal of solvent gave 1.2 g of (þ)-14 as colorless
crystals. Mp 83-84 °C; [R]2D0 þ28.4° (c 1.0, CHCl3); >98% ee in
chiral HPLC (Chiralcel OJ column; hexane/propan-2-ol/TFA
95:5:0.1; flow rate 1 mL/min; detection 254 nm; retention time
13.95 min).
1.42-1.78 (m, 4H), 1.22-1.34 (m, 1H); HRMS (TOF MS ESþ)
calcd for C25H30NO2 (M þ H)þ 376.2277, found 376.2256.
(1S,5R)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)((10R,20R)-2-phenylcyclopropyl)methanone ((-)-21). Yield,
90% as colorless resin; [R]2D0 -546.5° (c 1.0, MeOH); 1H NMR
(CDCl3) δ 7.16-7.32 (m, 4H), 7.10-7.16 (m, 2H), 6.84-6.92 (m,
2H), 6.72-6.76 (m, 1H), 4.62 (d-m, 1H, J = 100 Hz), 3.81-3.94
(m, 2H), 3.79 (m, 3H), 2.54 (m, 1H), 1.82-2.24 (m, 8H),
1.42-1.80 (m, 4H), 1.20-1.34 (m, 1H); HRMS (ESI) calcd for
C25H30NO2 (M þ H)þ 376.2277, found 376.2260.
((1S,5R)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)((10S,20S)-2-phenylcyclopropyl)methanone ((þ)-22). Yield,
90% as colorless resin; [R]2D0 þ565.5° (c 1.0, MeOH); 1H NMR
(CDCl3) δ 7.16-7.32 (m, 4H), 7.08-7.16 (m, 2H), 6.84-6.94 (m,
2H), 6.72-6.78 (m, 1H), 4.64 (d-m, 1H, J = 100 Hz), 3.74-3.96
(m, 5H), 2.42-2.54 (m, 1H), 1.80-2.24 (m, 8H), 1.42-1.76 (m,
4H), 1.23-1.31 (m, 1H); HRMS (TOF MS ESþ) calcd for
C25H30NO2 (M þ H)þ 376.2277, found 376.2261.
Ethyl 2-Phenylcyclopropanecarboxylate (trans/cis (()-15).7 A
1 L round-bottomed flask equipped with a short fractionating
column connected to a downward condenser was charged with
the trans/cis mixture ((()-13 and (()-14, 89 g, 0.55 mol),
p-toluenesulfonic acid (3.0 g), absolute EtOH (165 mL), and
toluene (100 mL). The mixture was heated in an oil bath at
115 °C, and an azeotropic mixture of EtOH, toluene, and H2O
was collected in a flask containing anhydrous K2CO3 (70 g) until
the temperature at the top of the column rose to 78 °C. The
distillate was shaken thoroughly with K2CO3, filtered, and then
returned to the reaction flask. The mixture was heated until the
temperature at the top of the column rose to 78-80 °C. The
residue was distilled at 84-91 °C/0.5 mmHg to give a 6:4
trans-(1R*,2R*)/cis-(1S*,2R*) mixture of the isomers of (()-
15 (71 g, 68%) as a colorless oil.
(1S*,2R*)-Ethyl 2-phenylcyclopropanecaboxylate ((()-16). A
500 mL three-neck round-bottomed flask equipped with a
dropping funnel, stirrer, and a 30 cm Vigreux column, to which
was attached a partial takeoff distilling head with reflux
condenser, was charged with (()-15 (83.3 g, 0.438 mol), EtOH
(107 mL), H2O (35 mL), and NaOH (13.1 g, 0.328 mol). The
mixture was refluxed for 5 h during which time 107 mL of EtOH
was slowly distilled from the mixture and replaced by an equal
volume of H2O, added through a dropping funnel. After cooling
to room temperature, H2O (120 mL) and benzene (80 mL) were
added. The organic layer was separated, and the aqueous layer
was extracted with benzene (2 ꢀ 30 mL). The combined organic
layers were dried over MgSO4. Removal of solvent gave a crude
trans/cis-mixture (1:9) of ethyl 2-phenylcyclopropanecarboxy-
late as a light yellow solid (23 g). Purification of the crude
material by column chromatography with 2% EtOAc in hex-
anes afforded (()-16 as a light yellow oil (20 g, 50% yield, based
on the (1S*,2R*)-cis-isomer (()-16). 1H NMR (CDCl3)
δ 7.35-7.55 (m, 5H), 3.86 (q, 2H, J = 7.2 Hz), 2.57 (dd, 1H,
J = 16.5, 9.0 Hz), 2.03-2.12 (m, 1H), 1.67-1.74 (m, 1H),
1.28-1.36 (m, 1H), 0.965 (t, 3H, J = 7.2 Hz); 13C NMR
(CDCl3) δ 171.52, 136.75, 129.49, 128.06, 126.82, 60.35, 25.64,
21.99, 14.20, 11.29.
General Procedure for Syntheses of the Enantiomers of 5-(3-
Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-2- yl((cis or trans)-2-
phenylcyclopropyl)methanone ((þ)- and (-)-21 through 24). A
mixture of the enantiomeric amine (-)-1 or (þ)-1 (2 -3 mmol),
chiral 2-phenylcyclopropane-1-carboxylic acid (1.2 equiv), and
EDCI (1.3 equiv) in CH2Cl2 (6 mL) was stirred at room
temperature overnight. The mixture was diluted with 5% pro-
pan-2-ol in CH2Cl2, washed with aqueous Na2CO3 solution (to
∼pH 10) and brine, dried over Na2SO4, and passed through a
pad of silica gel. After removal of solvent in vacuo, the residue
was purified by silica gel column chromatography with hexanes/
EtOAc/EtOH (60/30/1.5) to give the amide products.
((1R,5S)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-2-yl)-
((10S,20S)-2-phenylcyclopropyl)methanone ((þ)-21). Yield, 90%
as a colorless resin; [R]2D0 þ547.0° (c 1.0, MeOH); 1H NMR
(CDCl3) δ 7.16-7.32 (m, 4H), 7.10-7.16 (m, 2H), 6.83-6.93
(m, 2H), 6.71-6.76 (m, 1H), 4.43-4.83 (m, 1H), 3.80-3.94 (m,
2H), 3.77-3.80 (m, 3H), 2.54 (m, 1H), 1.80-2.24 (m, 8H),
((1R,5S)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)((10R,20R)-2-phenylcyclopropyl)methanone ((-)-22). Yield,
88% as a colorless resin; [R]2D0 -564.5° (c 1.0, MeOH); 1H NMR
(CDCl3) δ 7.15-7.32 (m, 4H), 7.08-7.15 (m, 2H), 6.83-6.92 (m,
2H), 6.71-6.76 (m, 1H), 4.64 (d-m, 1H, J =100 Hz), 3.71-3.95
(m, 5H), 2.40-2.55 (m, 1H), 1.80-2.25 (m, 8H), 1.42-1.76 (m,
4H), 1.21-1.30 (m, 1H); HRMS (TOF MS ESþ) calcd for
C25H30NO2 (M þ H)þ 376.2277, found 376.2261.
((1R,5S)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)((10S,20R)-2-phenylcyclopropyl)methanone ((þ)-23). Yield,
79% as a colorless resin; [R]2D0 þ103.0° (c 0.76, EtOH);
1H NMR (CDCl3) δ 7.14-7.28 (m, 4H), 7.07-7.14 (m, 2H),
6.68-6.88 (m, 3H), 4.50-4.60 (m, 1H), 3.45-3.92 (m, 5H),
2.38-2.50 (m, 1H), 1.75-2.30 (m, 6H), 1.24-1.75 (m, 7H);
HRMS (TOF MS ESþ) calcd for C25H30NO2 (M þ H)þ
376.2277, found 376.2287.
((1S,5R)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)((10R,20S)-2-phenylcyclopropyl)methanone ((-)-23). Yield,
71% as a colorless resin; [R]2D0 -102° (c 0.50, EtOH); 1H NMR
(CDCl3) δ 7.14-7.28 (m, 4H), 7.07-7.14 (m, 2H), 6.68-6.88 (m,
3H), 4.50-4.60 (m, 1H), 3.45-3.92 (m, 5H), 2.38-2.50 (m, 1H),
1.75-2.30 (m, 6H), 1.24-1.75 (m, 7H); HRMS (TOF MS ESþ)
calcd for C25H30NO2 (M þ H)þ 376.2277, found 376.2281.
((1S,5R)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)((10S,20R)-2-phenylcyclopropyl)methanone ((þ)-24). Yield,
72% as a colorless resin; [R]2D0 þ139.0° (c 0.59, EtOH); 1H NMR
(CDCl3) δ 7.10-7.28 (m, 6H), 6.67-6.86 (m, 3H), 4.42-
4.54 (m, 1H), 3.36-4.02 (m, 2H), 3.79 (s, 3H), 2.40-2.50 (m,
1H), 2.10-2.24 (m, 1H), 1.62-2.05 (m, 7H), 1.02-1.44 (m, 4H),
0.60-0.78 (m, 1H); HRMS (TOF MS ESþ) calcd for
C25H30NO2 (M þ H)þ 376.2277, found 376.2273.
((1R,5S)-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-
2-yl)((10R,20S)-2-phenylcyclopropyl)methanone ((-)-24). Yield,
75% as a colorless resin; [R]2D0 -138.1° (c 0.65, EtOH); 1H NMR
(CDCl3) δ 7.10-7.28 (m, 6H), 6.67-6.86 (m, 3H), 4.42-
4.54 (m, 1H), 3.36-4.02 (m, 2H), 3.79 (s, 3H), 2.40-2.50 (m,
1H), 2.10-2.24 (m, 1H), 1.62-2.05 (m, 7H), 1.02-1.44 (m, 4H),
0.60-0.78 (m, 1H); HRMS (TOF MS ESþ) calcd for C25H30-
NO2 (M þ H)þ 376.2277, found 376.2278.
General Procedure for the Synthesis of the Enantiomers of 5-(3-
Methoxyphenyl)-2-(((trans or cis)-2-phenylcyclopropyl)methyl)-
2-azabicyclo[3.3.1]nonane ((þ)- and (-)-25 through 28).2 Red-Al
(65%, 2.0 equiv) was added dropwise to a solution of chiral
amide (2-3 mmol) in anhydrous THF (80 mL) under argon at
room temperature, and the mixture was stirred for 1 h at room
temperature. The reaction was quenched with saturated Na2-
CO3 (20 mL), and the organic layer was separated. The aqueous
layer was extracted with Et2O (3 ꢀ 20 mL). The combined
organic layers were washed with brine and dried over Na2SO4.
After removal of solvent in vacuo, the residue was purified by
silica gel column chromatography using hexanes/EtOAc/acet-
one (60/35/5).

Article
(1R,5S)-5-(3-Methoxyphenyl)-2-(((10S,20S)-2-phenylcyclopro-
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4 967
light yellow oil; [R]2D0 -15.2° (c 0.50, EtOH); 1H NMR (CDCl3) δ
7.15-7.31 (m, 6H), 6.89-6.94 (m, 1H), 6.87 (t, 1H, J = 2.4 Hz),
6.71 (ddd, 1H, J = 7.8, 2.4, 0.9 Hz), 3.79 (s, 3H), 3.23 (m, 1H),
2.70-2.79 (m, 2H), 2.49 (dd, 1H, J = 12.9, 5.4 Hz), 1.64-2.22
(m, 9H), 1.50-1.62 (m, 2H), 1.22-1.36 (m, 2H), 1.08 (dt, 1H,
J = 4.8, 8.1 Hz), 0.84 (q, 1H, J = 6.0 Hz); 13C NMR (CDCl3)
δ 159.66, 154.26, 139.31, 129.21, 129.18, 128.06, 125.92, 117.46,
111.52, 110.41, 55.32, 54.62, 51.76, 49.57, 38.95, 38.63, 37.57,
35.30, 24.82, 22.92, 20.51, 17.62, 9.75; HRMS (TOF MS ESþ)
calcd for C25H32NO (M þ H)þ 362.2484, found 362.2485.
(1S,5R)-5-(3-Methoxyphenyl)-2-(((10S,20R)-2-phenylcyclopro-
pyl)methyl)-2-azabicyclo[3.3.1]nonane ((þ)-28). Yield, 95% as a
light yellow oil; [R]2D0 þ48.5° (c 0.60, EtOH); 1H NMR (CDCl3) δ
7.14-7.32 (m, 6H), 6.90-6.95 (m, 1H), 6.88 (t, 1H, J = 2.4 Hz),
6.72 (ddd, 1H, J = 7.8, 2.4, 0.9 Hz), 3.79 (s, 3H), 2.82-3.04 (m,
3H), 2.54 (dd, 1H, J = 12.9, 5.1 Hz), 1.64-2.23 (m, 9H),
1.48-1.62 (m, 2H), 1.04-1.36 (m, 3H), 0.83 (q, 1H, J = 6.0
Hz); 13C NMR (CDCl3) δ 159.66, 154.25, 139.27, 129.29,
129.22, 128.09, 125.92, 117.47, 111.55, 110.39, 55.53, 55.33,
52.70, 49.58, 38.98, 38.69, 37.54, 35.27, 25.03, 23.03, 20.49,
17.61, 10.16; HRMS (TOF MS ESþ) calcd for C25H32NO
(M þ H)þ 362.2484, found 362.2489.
pyl)methyl)-2-azabicyclo[3.3.1]nonane ((þ)-25)). Yield, 98% as a
light yellow oil; [R]D20 þ204.0° (c 0.83, MeOH); 1H NMR
(CDCl3) δ 7.19-7.28 (m, 3H), 7.10-7.16 (m, 1H), 7.03-7.08
(m, 2H), 6.91-6.96 (m, 1H), 6.89 (t, 1H, J = 2.4 Hz), 6.72 (ddd,
1H, J = 8.1, 2.7, 0.90 Hz), 3.79 (s, 3H), 3.26 (m, 1H), 2.98-3.06
(m, 2H), 2.79 (dd, 1H, J = 12.6, 5.7 Hz), 2.49 (dd, 1H, J = 12.6,
7.2 Hz), 1.84-2.18 (m, 7H), 1.56-1.76 (m, 3H), 1.20-1.42 (m,
2H), 0.95 (dt, 1H, J = 8.4, 5.1 Hz), 0.86 (dt, 1H, J = 8.4, 5.1 Hz);
13C NMR (CDCl3) δ 158.64, 154.11, 143.30, 129.26, 128.47,
125.89, 125.58, 117.48, 111.55, 110.47, 60.47, 55.34, 52.95, 49.63,
39.12, 38.63, 37.61, 35.33, 25.07, 23.21, 23.09, 22.16, 14.99;
HRMS (TOF MS ESþ) calcd for C25H32NO (M þ H)þ 362.-
2484, found 362.2495.
(1S,5R)-5-(3-Methoxyphenyl)-2-(((10R,20R)-2-phenylcyclopro-
pyl)methyl)-2-azabicyclo[3.3.1]nonane ((-)-25). Yield, 94% as a
light yellow oil; [R]D20 -202.5° (c 1.0, MeOH); 1H NMR (CDCl3)
δ 7.19-7.28 (m, 3H), 7.10-7.16 (m, 1H), 7.03-7.08 (m, 2H),
6.91-6.96 (m, 1H), 6.89 (t, 1H, J = 2.4 Hz), 6.71 (ddd, 1H, J =
8.1, 2.7, 0.90 Hz), 3.79 (s, 3H), 3.25 (m, 1H), 2.97-3.06 (m, 2H),
2.79 (dd, 1H, J = 12.6, 5.7 Hz), 2.49 (dd, 1H, J = 12.6, 7.2 Hz),
1.84-2.18 (m, 7H), 1.56-1.76 (m, 3H), 1.20-1.42 (m, 2H), 0.94
(dt, 1H, J = 8.4, 5.1 Hz), 0.85 (dt, 1H, J = 8.4, 5.1 Hz); 13C
NMR (CDCl3) δ 159.46, 153.93, 143.11, 129.00, 128.22, 125.66,
125.32, 117.24, 111.30, 110.22, 60.27, 55.09, 52.72, 49.39, 38.95,
38.41, 37.43, 35.10, 24.88, 22.96, 22.87, 22.01, 14.77; HRMS
(TOF MS ESþ) calcd for C25H32NO (M þ H)þ 362.2484, found
362.2495.
(1R,5S)-5-(3-Methoxyphenyl)-2-(((10R,20S)-2-phenylcyclopro-
pyl)methyl)-2-azabicyclo[3.3.1]nonane ((-)-28)). Yield, 94% as a
light yellow oil; [R]2D0 -49.1° (c 0.60, EtOH); 1H NMR (CDCl3) δ
7.14-7.32 (m, 6H), 6.90-6.95 (m, 1H), 6.88 (t, 1H, J = 2.4 Hz),
6.71 (ddd, 1H, J = 7.8, 2.4, 0.9 Hz), 3.79 (s, 3H), 2.82-3.04 (m,
3H), 2.54 (dd, 1H, J = 12.9, 5.1 Hz), 1.64-2.23 (m, 9H),
1.48-1.62 (m, 2H), 1.04-1.36 (m, 3H), 0.83 (q, 1H, J = 6.0
Hz); 13C NMR (CDCl3) δ 159.66, 154.28, 139.32, 129.30, 129.22,
128.09, 125.92, 117.47, 111.56, 110.39, 55.54, 55.33, 52.72,
49.58, 39.02, 38.71, 37.58, 35.29, 25.07, 23.03, 20.51, 17.67,
10.15; HRMS (TOF MS ESþ) calcd for C25H32NO (M þ H)þ
362.2484, found 362.2491.
General Procedure for the Synthesis of the N-(2-Phenylcyclo-
propyl)methyl enantiomers of (þ)- and (-)-2-azabicyclo[3.3.1]-
nonan-5-yl)phenol ((þ)- and (-)-29 through 32). The enantio-
meric methoxyphenyl ether (1-2 mmol, ((þ)- and (-)-25
through 28), 48% hydrogen bromide (2 mL), and acetic acid
(3 mL) were refluxed for 30 min to 1 h under argon. The acetic
acid was removed in vacuo, and the residue was neutralized with
saturated NaHCO3 to pH 10. The mixture was extracted with
5% propan-2-ol in CH2Cl2 (3 ꢀ 30 mL). The combined extracts
were washed with H2O and brine and dried over Na2SO4. After
removal of solvent, the residue was purified by silica gel column
chromatography using hexanes/EtOAc/EtOH (40/28/2) to give
the phenolic amide products.
(1S,5R)-5-(3-Methoxyphenyl)-2-(((10S,20S)-2-phenylcyclopro-
pyl)methyl)-2-azabicyclo[3.3.1]nonane ((þ)-26)). Yield, 98% as
light yellow oil; [R]D20 þ230.1° (c 0.90, MeOH); 1H NMR
(CDCl3) δ 7.20-7.28 (m, 3H), 7.12-7.17 (m, 1H), 7.03-7.07
(m, 2H), 6.92-6.96 (m, 1H), 6.89 (t, 1H, J = 2.4 Hz), 6.72 (ddd,
1H, J = 8.4, 2.4, 0.9 Hz), 3.79 (s, 3H), 3.27 (m, 1H), 3.02 (dd, 2H,
J = 9.6, 3.9 Hz), 2.74 (dd, 1H, J = 12.6, 6.3 Hz), 2.56 (dd, 1H,
J = 12.6, 6.3 Hz), 1.80-2.20 (m, 8H), 1.56-1.76 (m, 3H),
1.20-1.44 (m, 2H), 0.98 (dt, 1H, J = 8.4, 5.1 Hz), 0.87 (dt,
1H, J = 8.4, 5.1 Hz); 13C NMR (CDCl3) δ 159.70, 154.15,
143.39, 129.27, 128.51, 125.83, 125.58, 117.46, 111.52, 110.50,
59.99, 55.35, 51.95, 49.99, 39.11, 38.61, 37.66, 35.33, 24.82,
23.12, 22.46, 22.29, 15.60; HRMS (TOF MS ESþ) calcd for
C25H32NO (M þ H)þ 362.2484, found 362.2480.
(1R,5S)-5-(3-Methoxyphenyl)-2-(((10R,20R)-2-phenylcyclopro-
pyl)methyl)-2-azabicyclo[3.3.1]nonane ((-)-26). Yield, 97% as a
light yellow oil; [R]D20 -232.0° (c 1.0, MeOH); 1H NMR (CDCl3)
δ 7.20-7.29 (m, 3H), 7.10-7.18 (m, 1H), 7.02-7.08 (m, 2H),
6.91-6.96 (m, 1H), 6.89 (t, 1H, J = 2.4 Hz), 6.71 (ddd, 1H, J =
8.4, 2.4, 0.9 Hz), 3.79 (s, 3H), 3.27 (m, 1H), 3.02 (dd, 2H, J = 9.6,
3.9 Hz), 2.74 (dd, 1H, J = 12.6, 6.3 Hz), 2.56 (dd, 1H, J = 12.6,
6.3 Hz), 1.80-2.20 (m, 8H), 1.56-1.76 (m, 3H), 1.20-1.40 (m,
2H), 0.98 (dt, 1H, J = 8.4, 5.1 Hz), 0.87 (dt, 1H, J = 8.4, 5.1 Hz);
13C NMR (CDCl3) δ 159.48, 153.97, 143.21, 129.04, 128.28,
125.60, 125.35, 117.25, 111.30, 110.27, 59.81, 55.12, 51.75, 49.77,
38.93, 38.41, 37.49, 35.13, 24.64, 22.90, 22.22, 22.13, 15.39;
HRMS (ESI) calcd for C25H32NO (M þ H)þ 362.2484, found
362.2469.
3-((1R,5S)-2-(((10S,20S)-2-Phenylcyclopropyl)methyl)-2-azabi-
cyclo[3.3.1]nonan-5-yl)phenol ((þ)-29). Yield, 60% as HCl salt;
mp 232-234 °C (dec); [R]2D0 þ62.0° (c 0.38, MeOH); 1H NMR
(CDCl3, free base) δ 7.22 (br-s, 1H), 7.19 (br-s, 1H), 7.08-7.16
(m, 1H), 7.03 (br-s, 1H), 7.01 (br-s, 1H), 6.99 (d, 1H, J = 8.1 Hz),
6.76 (d, 1H, J = 8.1 Hz), 6.70 (t, 1H, J = 1.8 Hz), 6.48 (dd, 1H,
J = 7.8, 2.4 Hz), 3.30 (br-s, 1H), 2.90-3.10 (m, 2H), 2.83 (dd,
1H, J = 12.6, 5.7 Hz), 2.49 (dd, 1H, J = 12.6, 5.7 Hz), 2.15 (br-t,
2H, J = 12.6 Hz), 1.50-2.02 (m, 8H), 1.24-1.46 (m, 2H), 0.96
(dt, 1H, J = 8.7, 5.1 Hz), 0.87 (dt, 1H, J = 8.7, 5.1 Hz); 13C
NMR (CDCl3, free base) δ 156.61, 153.59, 142.95, 129.31,
128.51, 125.89, 125.65, 116.93, 113.88, 113.20, 60.15, 52.77,
49.69, 38.35, 37.06, 34.89, 24.50, 23.31, 23.07, 21.46, 14.95;
HRMS (TOF MS ESþ) calcd for C24H30NO (M þ H)þ
348.2327, found 348.2327. Anal. (C23H29NO HCl 0.25H2O)
(1R,5S)-5-(3-Methoxyphenyl)-2-(((10S,20R)-2-phenylcyclopro-
pyl)methyl)-2-azabicyclo[3.3.1]nonane ((þ)-27)). Yield, 93% as a
light yellow oil; [R]2D0 þ15.4° (c 0.35, EtOH); 1H NMR (CDCl3) δ
7.14-7.32 (m, 6H), 6.90-6.95 (m, 1H), 6.87 (t, 1H, J = 2.4 Hz),
6.71 (ddd, 1H, J = 7.8, 2.4, 0.9 Hz), 3.79 (s, 3H), 3.23 (m, 1H),
2.70-2.80 (m, 2H), 2.50 (dd, 1H, J = 12.9, 5.1 Hz), 1.64-2.22
(m, 9H), 1.48-1.62 (m, 2H), 1.22-1.36 (m, 2H), 1.09 (dt, 1H,
J = 5.1, 8.1 Hz), 0.84 (q, 1H, J = 6.0 Hz); 13C NMR (CDCl3) δ
159.67, 154.27, 139.32, 129.22, 129.19, 128.07, 125.92, 117.47,
111.53, 110.41, 55.33, 54.62, 51.77, 49.58, 38.95, 38.64, 37.58,
35.30, 24.83, 22.93, 20.51, 17.62, 9.75; HRMS (TOF MS ESþ)
calcd for C25H32NO (M þ H)þ 362.2484, found 362.2490.
(1S,5R)-5-(3-Methoxyphenyl)-2-(((10R,20S)-2-phenylcyclopro-
pyl)methyl)-2-azabicyclo[3.3.1]nonane ((-)-27). Yield, 94% as a
3
3
C, H, N.
3-((1S,5R)-2-(((10R,20R)-2-Phenylcyclopropyl)methyl)-2-aza-
bicyclo[3.3.1]nonan-5-yl)phenol ((-)-29). Yield, 60% as HCl
1
salt; mp 222-224 °C (dec); [R]2D0 -62.6° (c 0.52, MeOH); H
NMR (CDCl3, free base) δ 7.08-7.30 (m, 4H), 6.96-7.06 (m,
2H), 6.68-6.80 (m, 2H), 6.49 (dd, 1H, J = 8.1, 2.1 Hz), 3.30 (br,
1H), 2.90-3.10 (m, 2H), 2.84 (dd, 1H, J = 12.6, 5.7 Hz), 2.49
(dd, 1H, J = 12.6, 7.2 Hz), 2.15 (br-t, 2H, J = 12.6 Hz),

968 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4
Cheng et al.
1.50-2.02 (m, 8H), 1.20-1.46 (m, 2H), 0.94 (dt, 1H, J = 8.7, 5.1
Hz), 0.87 (dt, 1H, J = 8.7, 5.1 Hz); 13C NMR (CDCl3, free base)
δ 156.64, 153.52, 142.92, 129.31, 128.51, 125.89, 125.66, 116.90,
113.90, 113.21, 60.13, 52.77, 49.70, 38.34, 37.01, 34.87, 24.46,
23.32, 23.06, 21.40, 14.97; HRMS (TOF MS ESþ) calcd for
C24H30NO (M þ H)þ 348.2327, found 348.2330. Anal. (C23H29-
Mp 157-160 °C; [R]D20 þ69.5° (c 0.60, MeOH); 1H NMR
(CDCl3, free base) δ 7.14-7.30 (m, 4H), 7.10 (t, 1H, J = 8.1
Hz), 6.77 (d, 1H, J = 8.1 Hz), 6.71 (br-t, 1H, J = 2.1 Hz), 6.58
(dd, 1H, J = 8.1, 2.1 Hz), 3.13 (br-s, 1H), 2.98-3.08 (m, 1H),
2.87 (dt, 1H, J = 5.1, 12.3 Hz), 2.65 (dd, 1H, J = 12.9, 4.2 Hz),
2.04-2.22 (m, 2H), 1.70-2.00 (m, 7H), 1.44-1.62 (m, 2H),
1.30-1.40 (m, 1H), 1.16-1.24 (m, 1H), 1.09 (dt, 1H, J = 5.1, 8.4
Hz), 0.87 (q, 1H, J = 5.7 Hz); 13C NMR (CDCl3, free base) δ
156.80, 153.70, 138.99, 129.34, 129.23, 128.22, 126.07, 116.66,
113.62, 113.00, 55.49, 52.61, 49.75, 38.50, 38.31, 36.92, 34.92,
24.40, 23.03, 20.37, 16.74, 10.41; HRMS (TOF MS ESþ) calcd
for C24H30NO (M þ H)þ 348.2327, found 348.2334. Anal.
(C23H29NO HCl 1.25H2O) C, H, N.
NO HCl 0.25H2O) C, H, N.
3
3
3-((1S,5R)-2-(((10S,20S)-2-Phenylcyclopropyl)methyl)-2-aza-
bicyclo[3.3.1]nonan-5-yl)phenol ((þ)-30). Yield, 58% as HCl
salt; mp 255-260 °C (dec); [R]2D0 þ69.8° (c 0.38, MeOH); H
1
NMR (CDCl3, free base) δ 7.22 (br-s, 1H), 7.19 (br-s, 1H),
7.09-7.16 (m, 1H), 7.05 (d, 1H, J = 8.1 Hz), 7.02 (d, 1H, J = 1.5
Hz), 6.99 (br-s, 1H), 6.76 (d, 1H, J = 8.1 Hz), 6.70 (t, 1H, J = 1.8
Hz), 6.56 (dd, 1H, J = 7.8, 2.4 Hz), 3.34 (br-s, 1H), 2.93-3.10
(m, 2H), 2.76 (dd, 1H, J = 12.6, 6.3 Hz), 2.60 (dd, 1H, J = 12.6,
6.3 Hz), 2.14 (br-t, 2H, J = 12.6 Hz), 1.50-2.02 (m, 8H),
1.24-1.46 (m, 2H), 0.96 (dt, 1H, J = 8.7, 5.1 Hz), 0.88
(dt, 1H, J = 8.7, 5.1 Hz); 13C NMR (CDCl3, free base) δ
156.76, 153.49, 142.94, 129.37, 128.51, 125.85, 125.68, 116.61,
113.68, 112.93, 59.59, 51.82, 49.96, 38.36, 38.21, 36.96, 34.88,
24.28, 22.99, 22.63, 21.24, 15.61; HRMS (TOF MS ESþ) calcd
for C24H30NO (M þ H)þ 348.2327, found 348.2307. Anal.
(C23H29NO HCl 0.25H2O) C, H, N.
3
3
3-((1R,5S)-2-(((10R,20S)-2-Phenylcyclopropyl)methyl)-2-azabi-
cyclo[3.3.1]nonan-5-yl)phenol ((-)-32). Yield, 66% as HCl salt;
mp 158-162 °C; [R]D20 -70.0° (c 0.58, MeOH); 1H NMR
(CDCl3, free base) δ 7.14-7.30 (m, 4H), 7.10 (t, 1H, J = 8.1
Hz), 6.77 (d, 1H, J = 8.1 Hz), 6.71 (br-t, 1H, J = 2.1 Hz), 6.58
(dd, 1H, J = 8.1, 2.1 Hz), 3.13 (br-s, 1H), 2.98-3.08 (m, 1H),
2.87 (dt, 1H, J = 5.1, 12.3 Hz), 2.65 (dd, 1H, J = 12.9, 4.2 Hz),
2.06-2.22 (m, 2H), 1.70-2.00 (m, 7H), 1.44-1.62 (m, 2H),
1.30-1.40 (m, 1H), 1.16-1.24 (m, 1H), 1.09 (dt, 1H, J = 5.1, 8.4
Hz), 0.87 (q, 1H, J = 5.7 Hz); 13C NMR (CDCl3, free base) δ
156.77, 153.71, 139.00, 129.33, 129.23, 128.22, 126.06, 116.68,
113.60, 112.99, 55.49, 52.60, 49.75, 38.51, 38.32, 36.94, 34.93,
24.41, 23.04, 20.38, 16.76, 10.41; HRMS (TOF MS ESþ) calcd
for C24H30NO (M þ H)þ 348.2327, found 348.2328. Anal.
(C23H29NO HCl 1.5H2O) C, H, N.
3
3
3-((1R,5S)-2-(((10R,20R)-2-Phenylcyclopropyl)methyl)-2-azabi-
cyclo[3.3.1]nonan-5-yl)phenol ((-)-30). Yield, 62% as HCl salt;
mp 250-255 °C (dec); [R]2D0 -70.4° (c 0.44, MeOH); 1H NMR
(CDCl3, free base) δ 7.22 (br-s, 1H), 7.20 (br-s, 1H), 7.09-7.16
(m, 2H), 7.06 (d, 1H, J = 8.1 Hz), 7.02 (d, 1H, J = 1.5 Hz), 6.78
(d, 1H, J = 8.1 Hz), 6.70 (t, 1H, J = 1.8 Hz), 6.56 (dd, 1H, J =
7.8, 2.4 Hz), 3.32 (m, 1H), 2.93-3.06 (m, 2H), 2.75 (dd, 1H, J =
12.6, 6.3 Hz), 2.59 (dd, 1H, J = 12.6, 6.3 Hz), 2.13 (br-t, 2H, J =
12.6 Hz), 1.50-2.02 (m, 8H), 1.24-1.46 (m, 2H), 0.97 (dt, 1H,
J = 8.7, 5.1 Hz), 0.88 (dt, 1H, J = 8.7, 5.1 Hz); 13C NMR
(CDCl3, free base) δ 156.73, 153.56, 142.98, 129.35, 128.50,
125.83, 125.65, 116.64, 113.68, 112.96, 59.63, 51.75, 49.98, 38.38,
38.26, 37.01, 34.90, 24.28, 23.03, 22.62, 21.33, 15.62; HRMS
(TOF MS ESþ) calcd for C24H30NO (M þ H)þ 348.2327, found
3
3
Quantum Chemistry and Superposition Study. The starting
geometries of the NPCM compounds (Figure 2) and the N-
phenylalkenyl compounds (Figure 3) were constructed from the
respective X-ray structure of naltrexone and naloxone. The
geometry optimization for these compounds, in their proton-
ated form, was done in the gaseous phase with the density
functional theory at the level of B3LYP/6-31G*.16 The con-
formation of the cyclopropyl moiety in (þ)-29 and (þ)-31 as well
as the alkenyl in (-)-6 (1R,5S)-(E) and (-)-9 (1R,5S)-(Z) was
assumed to resemble the respective conformation of these
moieties shown in the X-ray structure of naltrexone and nalox-
one; thus, a conformation search was not carried out to find the
lowest energy conformer for these compounds. However, the
conformation of the N-cyclopropylmethyl moiety in (þ)-30 and
(-)-32 was varied by changing the dihedral angles of
C1-N-C-C10 and N-C-C10-C20, and their respective low
energy conformers were chosen after the geometry optimiza-
tion. For the superposition study, the optimized structures of the
NPCM compounds (þ)-29, (-)-30, (þ)-31, and (-)-32 in Fig-
ure 2 were overlaid onto naltrexone while the N-phenylalkenyl
compounds (-)-6 (1R,5S)-(E) and (-)-9 (1R,5S)-(Z) were over-
laid onto naloxone with the rigid fit of Quanta 2008 (Accelrys)
using the nine heavy atoms of the phenylmorphan as a common
docking site. The root-mean-square deviations of such fit for
348.2332. Anal. (C23H29NO HCl) C, H, N.
3
3-((1R,5S)-2-(((10S,20R)-2-Phenylcyclopropyl)methyl)-2-azabi-
cyclo[3.3.1]nonan-5-yl)phenol ((þ)-31). Yield, 64% as HCl salt;
mp 135-138 °C; [R]D20 þ4.6° (c 0.41, MeOH); 1H NMR (CDCl3,
free base) δ 7.24-7.32 (m, 2H), 7.16-7.23 (m, 2H), 7.10 (t, 1H,
J = 8.1 Hz), 6.76 (d, 1H, J = 8.1 Hz), 6.70 (br-t, 1H, J = 2.1
Hz), 6.58 (dd, 1H, J = 8.1, 2.1 Hz), 3.31 (br-s, 1H), 2.78-2.88
(m, 1H), 2.67 (dt, 1H, J = 5.1, 12.3 Hz), 2.57 (dd, 1H, J = 12.9,
4.8 Hz), 2.04-2.22 (m, 2H), 1.70-2.00 (m, 7H), 1.44-1.62 (m,
2H), 1.28-1.40 (m, 2H), 1.09 (dt, 1H, J = 5.1, 8.4 Hz), 0.87 (q,
1H, J = 5.7 Hz); 13C NMR (CDCl3, free base) δ 156.79, 153.73,
139.03, 129.33, 129.14, 128.16, 126.06, 116.73, 113.61, 113.02,
54.41, 51.82, 49.53, 38.44, 38.22, 36.98, 34.91, 24.26, 22.87,
20.46, 16.84, 9.81; HRMS (TOF MS ESþ) calcd for C24H30-
NO (M þ H)þ 348.2327, found 348.2339. Anal. (C23H29-
NO HCl 0.75H2O) C, H, N.
˚
each compound were all less than 0.12 A. The root-mean-square
deviation for the rigid fit of the optimized naloxone to the
3
3
3-((1S,5R)-2-(((10R,20S)-2-Phenylcyclopropyl)methyl)-2-azabi-
cyclo[3.3.1]nonan-5-yl)phenol ((-)-31). Yield, 61% as HCl salt;
mp 136-138 °C; [R]D20 -4.8° (c 0.42, MeOH); 1H NMR (CDCl3,
free base) δ 7.24-7.32 (m, 2H), 7.16-7.23 (m, 2H), 7.10 (t, 1H,
J = 8.1 Hz), 6.76 (d, 1H, J = 8.1 Hz), 6.71 (br-t, 1H, J = 2.1
Hz), 6.59 (dd, 1H, J = 8.1, 2.1 Hz), 3.31 (br-s, 1H), 2.78-2.88
(m, 1H), 2.67 (dt, 1H, J = 4.8, 12.3 Hz), 2.57 (dd, 1H, J = 12.9,
4.8 Hz), 2.02-2.22 (m, 3H), 1.70-2.02 (m, 6H), 1.44-1.62 (m,
2H), 1.26-1.40 (m, 2H), 1.08 (dt, 1H, J = 5.1, 8.1 Hz), 0.87 (q,
1H, J = 5.7 Hz); 13C NMR (CDCl3, free base) δ 156.75, 153.76,
139.05, 129.34, 129.14, 128.16, 126.06, 116.77, 113.60, 113.02,
54.43, 51.82, 49.54, 38.45, 38.24, 37.00, 34.93, 24.27, 22.88,
20.46, 16.87, 9.81; HRMS (TOF MS ESþ) calcd for C24H30-
NO (M þ H)þ 348.2327, found 348.2321. Anal. (C23H29-
NO HCl 1.0H2O) C, H, N.
˚
optimized naltrexone was less than 0.01 A.
Binding and Efficacy Assays. Cell Culture and Membrane
Preparation. As noted previously,17 the recombinant CHO cells
(hMOR-CHO, hDOR-CHO, and hKOR-CHO) were produced
by stable transfection with the respective human opioid receptor
cDNA and were provided by Dr. Larry Toll (SRI International,
CA). The cells were grown on plastic flasks in DMEM (100%)
(hDOR-CHO and hKOR-CHO) or DMEM/F-12 (50%/50%)
medium (hMOR-CHO) containing 10% FBS, and G-418
(0.10-0.2 mg/mL) under 95% air/5% CO2 at 37 °C. Cell
monolayers were harvested and frozen at -80 °C.
[35S]GTP-γ-S Binding Assays. The assays were conducted
with minor modifications of published methods.18 In this de-
scription, buffer “A” is 50 mM Tris-HCl, pH 7.4, containing 100
mM NaCl, 10 mM MgCl2, 1 mM EDTA and buffer “B” is buffer
A plus 1.67 mM DTT and 0.15% BSA. On the day of the assay,
3
3
3-((1S,5R)-2-(((10S,20R)-2-Phenylcyclopropyl)methyl)-2-azabi-
cyclo[3.3.1]nonan-5-yl)phenol ((þ)-32). Yield, 61% as HCl salt.

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4 969
cells were thawed on ice for 15 min and homogenized using a
Polytron in 50 mM Tris-HCl, pH 7.4, containing 4 μg/mL
leupeptin, 2 μg/mL chymostatin, 10 μg/mL bestatin, and
100 μg/mL bacitracin. The homogenate was centrifuged at
30000g for 10 min at 4 °C and the supernatant discarded. The
membrane pellets were resuspended in buffer B and used for
[35S]GTP-γ-S binding assays. Test tubes received the following
additions: 50 μL of buffer A plus 0.1% BSA, 50 μL of GDP in
buffer A/0.1% BSA (final concentration of 40 μM), 50 μL of
drug in buffer A/0.1% BSA, 50 μL of [35S]-GTP-γ-S in buffer A/
0.1% BSA (final concentration of 50 pM), and 300 μL of cell
membranes (50 μg of protein) in buffer B. The final concentra-
tions of reagents in the [35S]GTP-γ-S binding assays were 50 mM
Tris-HCl, pH 7.4, containing 100 mM NaCl, 10 mM MgCl2,
1 mM EDTA, 1 mM DTT, 40 μM GDP, and 0.1% BSA.
Incubations proceeded for 3 h at 25 °C. Nonspecific binding
was determined using GTP-γ-S (40 μM). Bound and free
[35S]GTP-γ-S were separated by vacuum filtration (Brandel)
through GF/B filters. The filters were punched into 24-well
plates to which was added 0.6 mL of LSC-cocktail (Cytoscint).
Samples were counted, after an overnight extraction, in a Trilux
liquid scintillation counter at 27% efficiency.
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Acknowledgment. The work of the Drug Design and
Synthesis Section, CBRB, NIDA, and NIAAA, was sup-
ported by the NIH Intramural Research Programs of the
National Institute on Drug Abuse (NIDA) and the National
Institute of Alcohol Abuse and Alcoholism, and the Clinical
Psychopharmacology Section, CBRB, NIDA, was supported
by the NIH Intramural Research Program of the National
Institute on Drug Abuse (NIDA). We also thank Dr. Klaus
Gawrisch and Dr. Walter Teague (Laboratory of Membrane
Biochemistry and Biophysics, NIAAA, for NMR spectral
data. The authors also express their thanks to Noel Whittaker
and Wesley White, Laboratory of Analytical Chemistry,
NIDDK, for mass spectral data and 1H NMR spectral data.
The quantum chemical study utilized PC/LINUX clusters
at the Center for Molecular Modeling of the NIH (http://cit.
nih.gov), and this research was supported by the NIH In-
tramural Research Program through the Center for Informa-
tion Technology.
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Supporting Information Available: Elemental analysis for
compounds (þ)- and (-)-6, (þ)- and (-)-9, and (þ)- and (-)-
29-32; additional data for Table 1 on opioid receptor binding.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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