Highly potent and selective phenylmorphan-based inverse agonists of the opioid δ receptor

Article abstract of DOI:10.1021/jm060459p

We recently reported the discovery of (+)-5-(3-hydroxyphenyl)-4-methyl-2- (3-phenylpropyl)-2-azabicyclo-[3.3.1]non-7-yl-(1-phenyl-1-cyclopentane) carboxamide [(+)-KF4, (+)-5] as a novel chemotype possessing potent antagonist activity at the δ opioid receptor. Additional SAR studies involving changes to both the 2-amino and 7-amido N-substituents using this same (+)-morphan scaffold have revealed compounds with improved potency and selectivity for the δ opioid receptor. The highly potent and selective 2,2-dimethylphenylacetamide analogue (+)-N-[(1S,4R,5R,7S)-5-(3-hydroxyphenyl)-4- methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-2-methyl-2- phenylpropanamide (13d, delmorphan-A) showed picomolar inhibitory potency (K_e = 0.1 nM) in the [³⁵S]GTPγS functional assay with δ opioid receptor selectivity ratios of 103- and 132-fold versus the μ and κ opioid receptors, respectively. The compounds showed no agonist activity at any of the three opioid receptors; however, measurements of δ inverse agonist activity within this series illustrated a broad range of negative efficacy and IC₅₀ values 650-fold more potent than the prototypical δ opioid receptor inverse agonist ICI 174 864 (22).

Full text of DOI:10.1021/jm060459p

J. Med. Chem. 2006, 49, 5597-5609
5597
Highly Potent and Selective Phenylmorphan-Based Inverse Agonists of the Opioid δ Receptor
James B. Thomas, Li Zhang, Herna´n A. Navarro, and F. Ivy Carroll*
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709
ReceiVed April 18, 2006
We recently reported the discovery of (+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo-
[3.3.1]non-7-yl-(1-phenyl-1-cyclopentane)carboxamide [(+)-KF4, (+)-5] as a novel chemotype possessing
potent antagonist activity at the δ opioid receptor. Additional SAR studies involving changes to both the
2-amino and 7-amido N-substituents using this same (+)-morphan scaffold have revealed compounds with
improved potency and selectivity for the δ opioid receptor. The highly potent and selective 2,2-
dimethylphenylacetamide analogue (+)-N-[(1S,4R,5R,7S)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-
2-azabicyclo[3.3.1]non-7-yl]-2-methyl-2-phenylpropanamide (13d, delmorphan-A) showed picomolar in-
hibitory potency (Ke ) 0.1 nM) in the [35S]GTPγS functional assay with δ opioid receptor selectivity ratios
of 103- and 132-fold versus the µ and κ opioid receptors, respectively. The compounds showed no agonist
activity at any of the three opioid receptors; however, measurements of δ inverse agonist activity within
this series illustrated a broad range of negative efficacy and IC50 values 650-fold more potent than the
prototypical δ opioid receptor inverse agonist ICI 174 864 (22).
It is now well established that opioid receptors belong to the
superfamily of G-protein-coupled receptors (GPCRsa). Distinct
cDNAs encoding the µ, δ, κ, and ORL-1 receptors have been
cloned, and studies with opioid receptor knockout mice have
clarified the role each receptor type plays in mediating effects
of morphine.1,2 Since the discovery of the three distinct opioid
receptors and the ORL-1 orphan receptor, researchers studying
the underlying mechanisms of opioid activity have sought highly
potent and selective agonists and antagonists.3 In recent years,
the δ opioid receptor has received considerable attention.
Numerous studies have been directed toward the development
of δ agonists as potentially new analgesics with reduced side
effects relative to µ opioid agonists.4-7 In addition, studies have
also suggested that δ opioid receptor antagonists can modulate
a number of biological processes.8 For example, δ opioid
receptor antagonists might be useful in the treatment of
L-DOPA-induced dyskinesia in Parkinson’s disease9 and alcohol
abuse,10 as antitussive drugs,11 and in the regulation of tumor
cell growth.12-14 Most importantly, however, are the continued
reports that indicate an intimate involvement of the δ opioid
receptor system in morphine tolerance and dependence.15-17
Very few opioid receptor pure antagonists selective for the
δ receptor have been reported. By applying the message-
address concept of Schwyzer18 to naltrexone, Portoghese
developed antagonists selective for the δ receptor. Attach-
ment of a properly aligned phenyl ring (δ address) to the
nonselective opioid antagonist naltrexone (the opioid message)
to act as a mimic for Phe4 of the enkephalins provided the δ
opioid receptor selective antagonists naltrindole (1a) and
naltriben (1b).19 Compounds 1a and 1b have proven to be highly
useful for the characterization of the δ opioid receptor, even
though Takemori et al. reported that they showed some agonist
effects.20,21 A significant amount of work from several research
groups has been reported with the goal of providing optimal
alignment of the message and address moieties. Two different
approaches to this are illustrated by benzylidenenaltrexone
(BNTX, 2) and the nonopiate SK 205588 (3).22-24 The latter is
remarkable not only because it showed significant enhancement
of selectivity versus 1a but also because it broke tradition using
a nonclassical N-substituent structure to induce antagonist
behavior in a nonopiate scaffold. Beyond this, the SAR of 1a
proper has been surveyed including N-substituent modification,
alkylation of the 14-position, alkylation of the indole nitrogen,
and substitution or heterocyclic replacement of the phenyl
address ring.25-29
* To whom correspondence should be addressed. Telephone: 919 541-
6679. Fax: 919 541-8868. E-mail: fic@rti.org.
a Abbreviations: GPCRs, G-protein-coupled receptors; cDNAs, comple-
mentary deoxyribonucleic acids; ORL-1, opioid-receptor-like; BNTX,
benzylidenenaltrexone; SAR, structure-activity relationship; ACE-Cl,
R-chloroethyl chloroformate; ICI 174,864, (C3H5)2Tyr-AiG-Aib-Phe-Leu
(22); [35S]GTPγS, sulfur-35 guanosine-5′-O-(3-thio)triphosphate; DAMGO,
(D-Ala2,MePhe4,Gly-ol5)enkephalin; DPDPE, [D-Pen2,D-Pen5]enkephalin;
U69,593, (5R,7R,8â)-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]-
dec-8-yl]benzeneacetamide (23); CHO, Chinese hamster ovary; GDP,
guanosine diphosphate; GFB, glass fiber B filter; PTX, pertussis toxin; SK
205583, 3-(2-ethyl-1,2,3,4,5,6,11,11a-octahydro-4aH-pyrido[4,3-b]carbazol-
4a-yl)phenol (3); BOP, (dimethylamino)phosphonium hexafluorophosphate.
10.1021/jm060459p CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/08/2006

5598 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18
Thomas et al.
Scheme 1a
a Reagents: (a) appropriate carboxylic acid, BOP, Et3N, THF; (b) 48% HBr, HOAc, reflux; (c) phthalic anhydride, toluene, Dean-Stark trap; (d) ACE-
Cl, CH2Cl2, MeOH, reflux; (e) NaBH(OAc)3, Ph(CH2)2CHO, CH2Cl2; (f) H2NNH2, EtOH, reflux.
The phenylmorphans are a class of opioid compounds first
described by Ong and May over 30 years ago.30 In recent years
we have shown that this scaffold can produce potent opioid pure
antagonists and can assume the role of “antagonist message”
similar to naltrexone. Furthermore, we have shown that intro-
duction of appropriate 7-amido-linked “address” elements to
this nonselective scaffold confers opioid receptor selectivity to
the resulting ligand. In line with the findings of Portoghese and
co-workers, κ selectivity was achieved with address elements
containing a basic amino group as in 4 [(-)-KAA1] and δ
selectivity was obtained using a phenyl ring as the address
element as in 5 [(+)-KF4].31-33 Herein we report an expanded
SAR survey with the same (+)-phenylmorphan scaffold, which
has revealed analogues with enhanced potency and selectivity
for the δ opioid receptor as well as potent inverse agonist
activity.
sodium triacetoxyborohydride gave N-phenylpropyl derivative
10. Protection of 6 as the phthalimide was required because
7-amido derivatives of 6 failed to react with ACE-Cl or any
other chloroformate N-demethylating reagent. Deprotection of
10 with hydrazine gave the 7-amino derivative 11, which was
converted to the seminal intermediate 12 by treatment with
hydrogen bromide in glacial acetic acid. Preparation of target
compounds from 12 utilized BOP coupling with the appropriate
carboxylic acid. Target compounds 13a-f expanded the SAR
of 5 by introducing diversity in the R and R′ positions of the
phenylacetamide side chain, whereas target compounds 14a-f
incorporated diversity in the aromatic fragment.
Target compounds 18 and 21a-c explored the SAR of the
N-substituent of the 2-amine in 5 and were accessed from
intermediate 9 as shown in Scheme 2. Differentiation of the
amino groups was accomplished by blocking the 2-amino
position as a tert-butyl carbamate followed by selective removal
of the phthalimide from the 7-position to give intermediate 15.
Target compound 18 was prepared by coupling with 2,2-
dimethylphenylacetic acid followed by removing the carbamate
with trifluoroacetic acid to give 16 followed by N-alkylation
with â-bromophenetole to give 17 and finally phenol depro-
tection with boron tribromide. Target compounds 21a-c were
obtained from 15 by first coupling with the appropriate
carboxylic acid derivatives using BOP to give the 7-amido side
chain intermediates 19a,b. Removal of both the isopropyl and
tert-butyloxycarbonyl groups was accomplished with hydrogen
bromide and acetic acid to give secondary amines 20a,b, which
were subsequently converted to the desired target compounds
21a-c via reductive alkylation using sodium triacetoxyboro-
hydride and the appropriate aldehyde.
Chemistry
Preparation of the target compounds began with optically pure
7-aminomorphan 6 prepared as previously described (Scheme
1).34 The N-methyl derivative of 5, compound 7b, was prepared
directly from 6 by coupling with 1-cyclopentanecarboxylic acid
using benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP, Castro’s reagent) followed by
removal of the isopropyl group with hydrogen bromide and
acetic acid. Target compounds 13a-f and 14a-f required a
change to the phenylpropyl N-substituent. This conversion was
accomplished via protection of the 7-amine as the phthalimide
(8) followed by treatment with R-chloroethyl chloroformate
(ACE-Cl) and then refluxing methanol to give N-demethylated
9. Reductive alkylation of 9 with hydrocinnamldehyde using

InVerse Agonists of the Opioid δ Receptor
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18 5599
Scheme 2a
a Reagents: (a) Boc2O, Et3N, CH2Cl2; (b) H2NNH2, EtOH, reflux; (c) 2,2-dimethylphenylacetic acid, BOP, Et3N, THF; (d) TFA, CH2Cl2; (e) PhOCH2CH2Br,
Bu4NI; (f) BBr3, CH2Cl2; (g) PhR1R2CO2H, BOP, Et3N, THF; (h) 48% HBr, HOAc; (i) NaBH(OAc)3, appropriate aldehyde, CH2Cl.
Table 1. Apparent Affinity (Ke) at Cloned Human µ, δ, and κ Opioid
Biology
Receptorsa
Measures of functional antagonism and selectivity of the
target compounds and standards, 1a and ICI 174 864 (22), were
Ke (nM)
compd
µb
δc
κd
µ/δ
κ/δ
obtained by monitoring the ability of test compounds to inhibit
stimulated [35S]GTPγS binding produced by the selective
agonist DAMGO (µ), DPDPE (δ), or U69 593 (23, κ) using
cloned human opioid receptors expressed in CHO cells (Table
1).31 The assays were run in a 96-well array in 1.4 mL
polypropylene tubes. In a final volume of 0.5 mL, each assay
contained 0.5 nM [35S]GTPγS, 20-40 µg of membrane protein,
one of seven concentrations of agonist (0.32-32 000 nM), 1
or 10 µM GDP, test compound, and 1% dimethyl sulfoxide.
The assay concentration of the test compounds were 3-300,
1-50, and 50-300 nM for the µ, δ, and κ assays, respectively.
The assays were run in a 20 mM Hepes buffer (pH 7.4)
containing 100 mM NaCl, 10 mM MgCl2, and incubated at room
temperature for 1 h. The assay was started by the addition of
the membrane homogenate, and it was terminated by rapid
vacuum filtration over GF/B filter plates and washing with three
volumes of ice-cold buffer. The plates were dried, and trapped
radioactivity was determined using a TopCount scintillation
counter. The average ((SEM) percent stimulation of basal
binding for DAMGO, DPDPE, and 23 was 292 ( 10, 246 (
11, and 285 ( 9, respectively. Receptor expression for these
cell lines ranged between 0.4 and 0.6 pmol/mg protein.
Agonist concentration response curves were run in the
presence or absence of a single concentration of test compound
and in the presence of 10 µM GDP. This concentration of GDP
was used to reduce the basal or unstimulated binding of
[35S]GTPγS in order to increase the agonist signal-to-back-
ground ratio. The concentration of test compound was chosen
such that it caused at least a 2-fold increase in the agonist EC50
value. The apparent affinity or Ke values were calculated using
the formula Ke ) [L]/{(A′/A) - 1}, where [L] is the concentra-
5
7b
8.7 ( 2.7
43.2 ( 5.9
10.6 ( 4.8
22.8 ( 6.2
0.15 ( 0.03
76.8 ( 31
17.9 ( 6.3
61 ( 16
58
0.6
62
67
93
103
59
69
18
35
119
0.8
94
30
67
132
74
58
13a
13b
13c
13d
13e
13f
14a
14b
14c
14d
14e
14f
18
0.17 ( 0.04
0.34 ( 0.14
16.0 ( 5.7
10.2 ( 1.5
17.5 ( 4.5
13.2 ( 2.6
14.6 ( 4.7
8.1 ( 1.5
24.4 ( 3.97 0.26 ( 0.16
10.3 ( 3.7
11.7 ( 3.6
9.6 ( 2.5
12.0 ( 3.6
9.1 ( 4.6
27.2 ( 12.8 1.42 ( 0.3
35.0 ( 15.4 0.75 ( 0.23
0.10 ( 0.02
0.20 ( 0.13
0.14 ( 0.04
0.67 ( 0.3
0.26 ( 0.06
2.43 ( 0.02
4.5 ( 1.3
43.6 ( 20.2
56.1 ( 13.4
3.6
17
31
75
77
33
111
22
14
20
77
43
19
47
2.19 ( 0.86 0.31 ( 0.091 24.0 ( 8.4
7.1
8.8
13
7.6
2.2
2.4
2.07 ( 0.91 0.24 ( 0.09
7.77 ( 1.46
96.3 ( 27.8
5.6 ( 2.8
11.4 ( 0.7
0.87 ( 0.24
21a
21b
21c
1a
2.51 ( 0.90 0.33 ( 0.12
1.02 ( 0.27 0.47 ( 0.16
6.7 ( 1.8
1.9 ( 0.3
33 ( 23
42 ( 16
0.81 ( 0.45
0.21 ( 0.06
7.9 ( 3.3
15.8 ( 5.0
16.1 ( 5.3
339 ( 179
157
5.3
22
a The data represent the mean ( SE from at least three independent
experiments. The final GDP assay concentration was 10 µM. b The µ assay
used (D-Ala2,MePhe4,Gly-ol5)enkephalin. Agonist selective for µ opioid
receptor. c The δ assay used [D-Pen2,D-Pen5]enkephalin. Agonist selective
for δ opioid receptor. d The κ assay used [(5R,7R,8â)-(-)-N-methyl-N-[7-
(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzeneacetamide] (23). Agonist
selective for κ opioid receptor.
tion of test compound and A′ and A are the agonist EC50 values
in the presence and absence of antagonist, respectively. No
agonist activity was observed at the δ opioid receptor with any
of the test compounds (maximum assay concentration of 31.6
µM), and none of the compounds displayed intrinsic activity
(agonist or inverse agonist) at either the µ or κ receptor.

5600 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18
Thomas et al.
Table 2. Inverse Agonist Potencies and Efficacies of Compounds at the
Cloned Human δ Receptor
nearly as selective with µ/δ and κ/δ ratios of 62 and 94,
respectively. Increasing the ring size to a six-membered ring as
in 13b, however, resulted in a 2-fold loss of potency for µ and
δ but an increase in potency at κ. The selectivity as a
consequence was maintained at µ but was decreased for κ to
30-fold versus δ. Increasing the ring size to seven members
gave results similar to those of the six-membered ring but
showed lower potency for κ, which combined to improve the
δ/κ selectivity. Overall, changing the size of the cyclopentyl
ring in 5 did not provide any significant improvements in either
the potency or the selectivity of the target compounds.
compd
IC50 (nM)
% of basal binding
5
7b
1.8 ( 0.6
95 ( 28
70 ( 10
79 ( 3.2
65 ( 4.3
65 ( 4.6
70 ( 7
64 ( 7
61 ( 17
78 ( 6
72 ( 7
72 ( 4
46 ( 1.4
69 ( 13
54 ( 6
86 ( 5
83 ( 2
70 ( 4
70 ( 5
78 ( 4
13a
13b
13c
13d
13e
13f
14a
14b
14c
14d
14e
14f
0.42 ( 0.10
0.68 ( 0.21
0.39 ( 0.15
0.40 ( 0.23
1.8 ( 1.0
0.15 ( 0.01
0.48 ( 0.05
0.45 ( 0.03
16 ( 7.5
Three acyclic analogues of 5 were investigated, including the
dimethyl (13d, delmorphan-A), diethyl (13e), and monomethyl
(13f) derivatives. The dimethyl analogue was the most potent
and selective of the three with a Ke of 0.1 nM for the δ receptor
and µ/δ and κ/δ ratios of 103 and 132, respectively. Overall,
this compound represents one of the most potent and selective
δ opioid receptor antagonists yet identified and exceeded the
lead compound 5 in both potency and selectivity. The diethyl
derivative on the other hand was 2-fold less potent than 13d at
roughly 0.2 nM, whereas the monomethyl derivative was only
slightly less potent relative to 13d but equally potent compared
with 5. From a selectivity standpoint, however, neither of the
last two compounds showed the high level of selectivity of 13d.
Together with the cyclic analogues, the results obtained with
this set of compounds indicates that dimethyl substitution has
the best overall combination of potency and selectivity and is
from this standpoint the best compound yet identified in this
series of antagonists.
7.7 ( 2.84
0.80 ( 0.33
0.45 ( 0.18
1.4 ( 1.1
0.50 ( 0.12
0.12 ( 0.01
0.72 ( 0.32
NAb
18
21a
21b
21c
naltrexone
1a
NAb
22
PTX
83 ( 35
75 ( 4
61 ( 7
a The data represent the mean ( SE from at least three independent
experiments. The assays were exactly as described above except the final
GDP assay concentration was 1 µM. See text for rationale. DPDPE typically
caused a 2-fold increase in basal binding under these assay conditions.b No
intrinsic activity.
The potencies and efficacies of the target compounds as
inverse agonists were determined in the [35S]GTPγS binding
assay using wild-type human δ opioid receptors and compared
to the prototypical inverse agonist (22) as well as the oxymor-
phone-based antagonists naltrexone and 1a (Table 2). Intrinsic
activity at all receptors was determined using a final concentra-
tion of 1 µM GDP. In our test system this concentration of GDP
results in an approximate 5-fold increase in basal [35S]GTPγS
binding. This increase in basal binding provides a greater signal
range over which the effect of an inverse agonist can be detected.
A DPDPE concentration response curve was run on each assay
plate to control for the performance of the assay. It is noted
that although the compounds were inverse agonists, their
influence on the basal binding in the δ opioid Ke experiments
was minor because they were reducing an already low basal
activity (∼400 cpm) and it had no apparent effect on the upper
asymptote of the DPDPE curve.
Target compounds 14a-f retained the cyclopentyl ring found
in 5 and focused on variation of the aromatic fragment of the
7-amido side chain substructure. The first two members of this
set explored the electronic character of the aromatic ring looking
at both ends of the spectrum, para fluoro (14b) and para methoxy
(14a) substitution. Remarkably, addition of the methoxy group
to 5 imparts a 7.5-fold increase in potency for the κ opioid
receptor while maintaining roughly the same potency at µ.
Combined with a 5-fold decrease in potency for the δ receptor,
the methoxy group virtually eliminates the selectivity seen in
5. Interestingly, fluoro substitution has a similar effect, though
in this case, the δ potency decreases less than 2-fold and is still
very potent at 0.26 nM. However, 14b was also more potent at
both µ and κ receptors with selectivity ratios of 35 and 17,
respectively, and thus is not a δ selective compound.
Results and Discussion
Target compounds 14c-f include the naphthyl and thienyl
replacement analogues for the phenyl ring in 5 with each of
these being represented by two regioisomeric variations. Target
compound 14c, the 1-naphthyl analogue, showed potency
decreases at all opioid receptors relative to 5. The biggest drop
was at the δ receptor at roughly 10-fold, which resulted in a
nonselective compound. The 2-naphthyl derivative (14d) on the
other hand showed only half as much decrease in δ potency
but relatively greater losses in potency for the remaining
receptors. Overall, however, neither of the naphthyl compounds
represented an improvement compared with 5 toward either
potency or selectivity. The 2-thienyl compound 14e was found
to be very potent for the δ receptor with a Ke of 0.31 nM, but
relative to 5, the µ potency improved roughly 4-fold, thus
eliminating selectivity. The 3-thienyl compound was also very
potent in the δ assay but was not selective because of relatively
good potencies for the µ and κ receptors. On the whole, changes
to either the size or electron density of the side chain aromatic
ring in 5 did not lead to improved compounds but showed a
significant ability to affect both the potency and selectivity of
The results obtained for the measures of [35S]GTPγS in vitro
antagonist potency at the µ, δ, and κ receptors are listed in Table
1 and are described in comparison to the lead compound 5. The
2-(N-methyl) derivative of 5, compound 7b, showed a significant
loss of potency (512-fold) for the δ receptor (76.8 versus 0.15
nM), but as expected, the compound retained its antagonist
activity. Typically, antagonists of this and related phenyl-
piperidine-based systems show much greater potency with
N-substituent groups larger than methyl.33 Compound 7b
showed no receptor preference, suggesting that both the 7-amido
and the basic 2-amino substituent contribute to receptor selectiv-
ity. The phenylacetamide analogues 13a-f on the other hand
showed subnanomolar potency at the δ receptor with Ke of
0.10-0.26 nM compared to 0.21 nM for 1a. All six compounds
showed much improved selectivity relative to 7b. Compounds
13a-c are R,R′-cyclic systems like 5, having fewer (13a) or
more methylene groups (13b,c) in the ring. The four-membered
ring analogue 13a was of equal potency compared with 5 at
nearly all of the opioid receptors and as a consequence was

InVerse Agonists of the Opioid δ Receptor
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18 5601
the target compounds. In general, the analogues possessing an
unsubstituted phenyl ring show greater in vitro potency and
selectivity for the δ opioid receptor.
Changes to the N-substituent of 5 and 13d were also
examined in this study. This included a phenetole derivative
(18) as well as cinnamyl and 2-methyl cinnamyl (21a-c)
derivatives. Target compound 18 was 9-fold less potent than
compound 13d in the δ assay but showed little change for µ.
The compound also lost significant potency (7.6-fold) in the κ
assay. Compound 21a was not selective for the δ receptor
because the compound showed improved potency at both µ and
κ. Thus, while the δ potency was only 2-fold less than 5, its µ
and κ Ke values were 3.5- and 3.2-fold greater. Similar results
were obtained in 21b and 21c where the δ potency decreased
in parallel with improvements in potency for both µ and κ. It is
noted, however, that the cinnamyl N-substituents (as in 21a-
c) had previously shown strong potency for the µ receptor in
the phenylpiperidine analogues [(+)-N-(trans-3′-phenyl-2′-pro-
penyl)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (RTI-
5989-1, 24) and (+)-N-[trans-3′-(2-methylphenyl)-2′-propenyl]-
(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (RTI-5989-25,
25)].31,35,36 Thus, it is not surprising that these compounds
showed a lack of µ/δ receptor selectivity. The significant
decrease in µ receptor potency for 21a,b, however, relative to
the corresponding phenylpiperidines 24 and 25 reveals that the
7-amido side chain moiety exerts a substantial influence over
potency for the µ. However, it is very interesting that all of the
compounds showed subnanomolar potency for the δ receptor,
since the related phenylpiperidines 24 and 25 identified in
previous work showed high µ potency (Ke values at µ are 0.039
and 0.013 nM) for 24 and 25, respectively.35 Similar to the
prototype, all the target compounds were inverse agonists for
the δ receptor. Compound 7b showed very low activity with
an IC50 of 95 nM, which is consistent with the low Ke found as
a δ antagonist. In the other examples studied, the Ke for δ
antagonist activity was usually very similar to the IC50 seen for
inverse agonism. Reduction in the percent of basal binding was
similar for most compounds, with many examples showing
levels equal to that found with PTX (100 ng/mL). The lead
compound 5 with an IC50 value of 1.8 nM was 46 times more
potent than the prototype 22. The most potent inverse agonist
discovered, however, was 21b (delmorphan-B) (IC50 ) 0.12
nM), which was ∼650 times as potent as 22.
Figure 1. Comparison of the relative δ opioid receptor binding for 1a
and 5.
this perspective, the phenylmorphan-based compounds are
similar to their naltrexone-based counterparts. In terms of inverse
agonist behavior, however, the data available in the [35S]GTPγS
assay using wild-type human δ opioid receptors suggest that
the two classes of compounds behave differently. As shown
earlier, all of the phenylmorphans tested in this study were found
to be inverse agonists. This trait is also shared by the structurally
related phenylpiperidine-based antagonists such as 24 and 25,
which have also been found to be inverse agonists.35,37,38 In
contrast, neither 1a nor naltrexone showed inverse agonist
activity. Others using wild-type δ receptors showed that
naltrexone-based compounds did not demonstrate inverse agonist
activity.39
In a recent article, we related our interpretation of the
similarities and differences observed in the SAR for these two
types of antagonist structures as arising from different ways of
binding to the opioid receptors, as depicted in Figure 1.34 As
illustrated, the phenol and protonated amino groups of the two
classes of antagonist were believed to bind to common domains
represented by H and S, respectively. This implied that the
N-substituents would occupy different domains NS1 versus NS2.
Using this comparative analysis as a guide, we were able to
correctly position the phenyl “address” ring on the nonselective
phenylmorphan scaffold to obtain numerous δ opioid receptor
selective compounds. These positive results support our initial
hypothesis regarding the different relative modes of receptor
binding presented by the two classes of antagonist. This in turn
offers a means of rationalizing why one observes inverse agonist
activity in the phenylmorphan series but not in the compounds
derived from naltrexone. In short, the dichotomy in behavior
between the two series could arise from the different modes by
which they interact with the receptor. More specifically, the
analysis suggests that the inverse agonist behavior arises as a
consequence of the interaction of the receptor region NS2 by
the 2-amino N-substituent of the phenylmorphan ligand. Though
speculative, this notion is supported by the observation of inverse
agonist activity in the phenylpiperidine series (24 and 25) and
these compounds are believed to occupy the receptor in a
manner similar to that depicted for the phenylmorphans.
Collectively, the potent and selective phenylmorphan-based
inverse agonists such as 13d not only will provide tools for
elucidating the biological role of constitutive activity but also
are a valuable set of compounds that can provide an understand-
ing of the mechanistic aspects leading to inverse agonist activity.
We have demonstrated in recent years that the addition of a
4â-methyl substituent to the parent N-substituted 5-(3-hydroxy-
phenyl)morphans resulted in compounds that showed pure, albeit
nonselective, opioid antagonist activity.32 In addition to this,
we have demonstrated that this class of antagonist conforms to
the message-address model that Portoghese used to explain
the δ selective properties of 1a.19 In the present case, we found
that the addition of phenyl “address” groups to the (+)-N-
phenylpropyl-4â-methyl-5-(3-hydroxyphenyl)morphan “mes-
sage” fragment resulted in δ selective compounds. Viewed from
Conclusion
This study suggests that using the hypothetical binding model
that compared the receptor binding of phenylmorphan-based
compounds to that of naltrexone-based antagonists such as 1a
can accurately predict structural modifications that impart δ

5602 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18
Thomas et al.
layer was extracted with 3:1 CH2Cl2-THF (30 mL × 3), the organic
layer was collected and dried (Na2SO4), and the solvent was
removed under reduced pressure. The product was purified by
preparative TLC [silica gel plate, 50% (80% CHCl3, 18% CH3OH,
2% NH4OH) in CHCl3] to afford the title compound (55.1 mg, 57%)
as a white foam: 1H NMR (CDCl3) δ 7.35-7.18 (m, 5H), 7.09 (t,
1H, J ) 7.8 Hz), 6.60 (m, 3H), 4.78 (d, 1H, J ) 7.8 Hz), 4.57 (m,
1H), 3.12-3.06 (m, 2H), 2.65 (d, 1H, J ) 12.3 Hz), 2.50-2.21
(m, 8H), 2.14-1.94 (m, 3H), 1.82-1.51 (m, 5H), 0.94-0.72 (m,
2H), 0.63 (d, 3H, J ) 6.6 Hz); 13C NMR (CDCl3) δ 176.4, 157.1,
151.1, 144.1, 129.6, 128.9, 127.2, 127.0, 116.6, 113.2, 112.7, 59.8,
58.5, 55.5, 47.0, 45.5, 43.5, 40.1, 38.0, 37.64, 37.60, 33.1, 31.6,
24.71, 24.68, 19.2; MS (APCI) m/z 433.5 (M + H)+. The free base
(43.2 mg, 0.1 mmol) was dissolved in CH2Cl2. HCl (1 M in diethyl
ether, 110 µL, 1.1 equiv) solution was added to this, and the salt
was precipitated from the solution by adding diethyl ether (5 mL),
filtered, and dried in the vacuum oven at 50 °C overnight: mp
194-200 °C; [R]20D +43.6° (c 0.50, MeOH). Anal. (C28H37ClN2O2‚
H2O) C, H, N.
2-[(1S,4R,5S,7S)-5-(3-Isopropoxyphenyl)-2,4-dimethyl-2-
azabicyclo[3.3.1]non-7-yl]-1H-isoindole-1,3(2H)-dione (8). Amine
6 (800 mg, 2.64 mmol) was dissolved in toluene (25 mL), followed
by the addition of phthalic anhydride (1.19 g, 0.008 mol) and
refluxed under a Dean-Stark trap overnight. The solution was
cooled, washed with 1 N NaOH (25 mL × 3) and water (25 mL)
and dried (Na2SO4). The solvent was removed under reduced
pressure yielding crude product, which was purified by filtering
through a short column of neutral alumina (Brockman activity II-
II), eluting with 50% ethyl acetate in hexanes to afford the title
compound (0.726 g, 64%) as a white solid: 1H NMR (CDCl3) δ
7.80-7.75 (m, 2H), 7.68-7.66 (m, 2H), 7.19 (t, 1H, J ) 7.8 Hz),
6.81-6.76 (m, 2H), 6.70-6.68 (m, 1H), 5.07 (m, 1H), 4.52 (sept,
1H, J ) 6.0 Hz), 3.27-3.18 (m, 2H), 2.73 (d, 1H, J ) 12.3 Hz),
2.48-2.41 (m, 4H), 2.30-2.11 (m, 5H), 2.00-1.96 (m, 1H), 1.32
(d, 6H, J ) 6.0 Hz), 0.78 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3)
δ 168.4, 158.2, 151.3, 134.0, 132.1, 129.3, 123.2, 117.6, 113.8,
112.5, 69.9, 58.6, 55.4, 46.6, 43.4, 42.7, 40.1, 38.0, 32.1, 26.6, 22.3,
18.9; LCMS (APCI) m/z 433.5 (M + H)+.
opioid receptor selectivity to nonselective phenylmorphan-based
compounds. Interestingly, however, the set of analogues of (+)-5
examined revealed that in every instance the compounds are
actually inverse agonists for the δ receptor. While this activity
was narrowly defined within a specific set of structural elements,
we did find that (+)-N-[(1S,4R,5R,7S)-5-(3-hydroxyphenyl)-
4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-2-
methyl-2-phenylpropanamide (13d), the dimethylphenylacet-
amido analogue of 5, is both more potent and more selective
for the δ opioid receptor than the lead compound, showing
picomolar activity (Ke ) 0.1 nM) in the [35S]GTPγS functional
assay and selectivity ratios of 103- and 132-fold for δ versus
the µ and κ opioid receptors, respectively. Finally, the success
of the model in predicting the relative relationship between the
two classes of “antagonists” may be further interpreted to
suggest that it is the occupation of different receptor domains
by the 2-amino N-substituents of these two classes of com-
pounds that underlies the observation of neutral antagonist
activity for the naltrexone-based series and inverse agonist
activity in the phenylmorphan series.
Experimental Section
1H NMR spectra were determined on a Bruker 300 spectrometer
using tetramethylsilane as an internal standard. Mass spectral data
were obtained using a Finnegan LCQ electrospray mass spectrom-
eter in positive ion mode at atmospheric pressure. Silica gel 60
(230-400 mesh) was used for column chromatography. All
reactions were followed by thin-layer chromatography using
Whatman silica gel 60 TLC plates and were visualized by UV or
by charring using 5% phosphomolybdic acid in ethanol. All solvents
were reagent grade. Tetrahydrofuran and diethyl ether were dried
over sodium benzophenone ketyl and distilled prior to use.
Methylene chloride and chloroform were distilled from calcium
hydride if used as reaction solvents. HCl in dry diethyl ether was
purchased from Aldrich Chemical Co. and used while fresh before
discoloration.
2-[(1S,4R,5S,7S)-5-(3-Isopropoxyphenyl)-4-methyl-2-azabicyclo-
[3.3.1]non-7-yl]-1H-isoindole-1,3(2H)-dione (9). Phthalimide 8
(2.67 g, 0.0062 mol) was dissolved in dichloroethane and heated
to reflux under N2 followed by the addition of 1-chloroethyl
chloroformate (0.80 mL, 8.11 mmol). This solution was allowed
to reflux for 4 h. The reaction mixture was allowed to cool to room
temperature and then washed with a saturated sodium bicarbonate
solution (150 mL) and water (250 mL). The solvent was removed
under reduced pressure. The residue was dissolved in methanol (150
mL) and refluxed under N2 overnight. The methanol was removed,
and the crude product was not purified but carried directly to the
next step: 1H NMR (CDCl3) δ 7.78-7.76 (m, 2H), 7.67-7.65 (m,
2H), 7.19 (t, 1H, J ) 7.8 Hz), 6.80-6.68 (m, 3H), 5.33 (m, 1H),
4.52 (sept, 1H, J ) 6.0 Hz), 3.76 (dd, 1H, J ) 13.8, 4.8 Hz), 3.58
(br, 1H), 2.86 (d, 1H, J ) 13.8 Hz), 2.63 (td, 1H, J ) 12.9, 4.2
Hz), 2.18-2.32 (m, 5H), 1.92-1.96 (m, 2H), 1.32 (d, 6H, J ) 6.0
Hz), 0.72 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 168.1, 157.9,
151.3, 133.8, 131.8, 129.1, 122.9, 117.1, 113.4, 112.4, 69.6, 49.5,
48.6, 46.6, 42.3, 40.4, 37.4, 34.6, 31.0, 22.0, 17.1; LCMS (APCI)
m/z 419.9 (M + H)+.
2-[(1S,4R,5S,7S)-5-(3-Isopropoxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1H-isoindole-
1,3(2H)-dione (10). To a solution of amine 9 (2.66 mmol) in
anhydrous 1,2-dichloroethane (60 mL) was added hydrocinnam-
aldehyde (0.34 mL, 2.32 mmol) and NaBH(OAc)3 (736 mg, 3.47
mmol), and the resulting mixture was stirred overnight. The reaction
mixture was washed with saturated NaHCO3 (45 mL), and the
aqueous layer was back-extracted with ethyl acetate (45 mL × 2).
The combined organic layers were dried over MgSO4, and the
solvent was removed at reduced pressure. This material was purified
by flash chromatography (Al2O3, 5% EtOAc in hexanes) to afford
the title compound as a white solid (1.07 g, 75% yield from 8):
1H NMR (CDCl3) δ 7.78-7.76 (m, 2H), 7.68-7.65 (m, 2H), 7.30-
DAMGO, DPDPE, and 23 were obtained from NIDA and were
prepared by Multiple Peptide Systems (San Diego, CA). [35S]-
GTPγS was obtained from Perkin-Elmer Inc. (Boston, MA). GTPγS
and GDP were obtained from Sigma Chemical Company (St. Louis,
MO).
N-[(1S,4R,5R,7S)-5-(3-Isopropoxyphenyl)-2,4-dimethyl-2-
azabicyclo[3.3.1]non-7-yl]-1-phenylcyclopentanecarboxamide (7a).
A 250 mL three-neck round-bottom flask was charged with (+)-
(1S,4R,5R,7S)-5-(3-isopropoxyphenyl)-2,4-dimethyl-2-azabicyclo-
[3.3.1]nonan-7-amine (6) (820 mg, 2.71 mmol), 1-cyclopentane-
carboxylic acid (1.03 g, 0.0054 mol), and dry THF (70 mL),
followed by the addition of triethylamine (1.9 mL, 13.55 mmol)
and BOP reagent (1.32 g, 2.98 mmol). The reaction mixture was
stirred under N2 at room temperature overnight. The mixture was
diluted with diethyl ether (70 mL), washed consecutively with water
(100 mL), saturated NaHCO3 (100 mL), and brine (100 mL × 2),
and dried (Na2SO4). The solvent was removed under reduced
pressure, and the product was purified by flash chromatography
[silica gel, 20% (80% CHCl3, 18% CH3OH, 2% NH4OH) in CHCl3]
to afford the title compound as a white foam (1.01 g, 78%): 1H
NMR (CDCl3) δ 7.38-7.16 (m, 6H), 6.71-6.65 (m, 3H), 4.71-
4.46 (m, 3H), 3.13-3.08 (m, 2H), 2.64-1.52 (m, 18H), 1.32 (d,
6H, J ) 6.0 Hz), 0.99-0.90 (m, 1H), 0.70 (d, 3H, J ) 6.9 Hz);
13C NMR (CDCl3) δ 175.9, 158.0, 151.3, 144.2, 129.2, 128.7,
126.85, 126.81, 117.4, 113.6, 112.2, 69.7, 59.1, 58.0, 54.9, 46.7,
44.8, 43.0, 39.8, 37.4, 37.0, 36.9, 32.7, 31.2, 29.7, 24.1, 22.1, 18.6.
(+)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-2,4-dimethyl-2-
azabicyclo[3.3.1]non-7-yl]-1-phenylcyclopentanecarboxamide (7b).
A solution of 7a (107 mg, 0.225 mmol) in glacial acetic acid (3
mL) and 48% HBr (3 mL) was heated to reflux overnight. The
reaction mixture was allowed to cool to room temperature, added
to ice (10 g), and adjusted to pH 14 with 50% NaOH. The aqueous

InVerse Agonists of the Opioid δ Receptor
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18 5603
7.16 (m, 6H), 6.81-6.77 (m, 2H), 6.70-6.67 (m, 1H), 5.11 (m,
1H), 4.52 (sept, 1H, J ) 6.0 Hz), 3.27 (br, 1H), 3.11 (dd, 1H, J )
12, 4.8 Hz), 2.77 (d, 1H, J ) 11.4 Hz), 2.67 (m, 2H), 2.58-2.52
(m, 2H), 2.46-2.41 (m, 1H), 2.29-2.14 (m, 5H), 1.94 (d, 1H, J )
12.3 Hz), 1.80 (pentet, 2H, J ) 7.5 Hz), 1.32 (d, 6H, J ) 6.0 Hz),
0.77 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 168.2, 157.9, 151.2,
142.5, 133.8, 132.0, 129.1, 128.5, 128.2, 125.6, 123.0, 117.5, 113.7,
112.4, 69.7, 55.7, 54.4, 54.0, 46.5, 42.5, 40.5, 37.9, 33.3, 31.9, 29.4,
27.6, 22.1, 18.6; LCMS (APCI) m/z 537.5 (M + H)+.
(1S,4R,5R,7S)-5-(3-Isopropoxyphenyl)-4-methyl-2-(3-phenyl-
propyl)-2-azabicyclo[3.3.1]nonan-7-amine (11). Hydrazine (295
µL, 9.40 mmol) was added to a solution of phthalimide 10 (1.01 g,
0.0019 mol) in ethanol (70 mL), and the reaction mixture was
refluxed under N2 for 4.5 h. The reaction mixture was allowed to
cool to room temperature. Removal of the solvent yielded a white
solid crude product, which was dissolved in CH2Cl2 (15 mL). The
heterogeneous solution was filtered through a fritted funnel with
several CH2Cl2 washes. The filtrate was concentrated and dried on
the vacuum pump to afford the title compound as a yellow oil in
almost quantitative yield: 1H NMR (CDCl3) δ 7.30-7.18 (m, 6H),
6.81-6.70 (m, 3H), 4.54 (sept, 1H, J ) 6.0 Hz), 3.53 (m, 1H),
3.16 (m, 1H), 2.89 (dd, 1H, J ) 12.0, 4.8 Hz), 2.68-2.62 (m, 3H),
2.52-2.47 (m, 2H), 2.37-2.32 (m, 3H), 2.13 (m, 1H), 1.84-1.59
(m, 5H), 1.33 (d, 6H, J ) 6.0 Hz), 1.17 (dd, 1H, J ) 13.8, 11.4
Hz), 0.97 (m, 1H), 0.74 (d, 3H, J ) 7.2 Hz); LCMS (APCI) m/z
407.7 (M + H)+.
3-[(1S,4R,5R,7S)-7-Amino-4-methyl-2-(3-phenylpropyl)-2-
azabicyclo[3.3.1]non-5-yl]phenol (12). A solution of amine 11
(2.41 mmol) in glacial acetic acid (11 mL) and 48% HBr (11 mL)
was heated to reflux for 17 h. The reaction mixture was allowed to
cool to room temperature. Ice (40 g) was added to the mixture,
and the pH of the mixture was adjusted to 14 with 50% NaOH.
This mixture was extracted with 3:1 CH2Cl2-THF (70 mL × 3),
the organic layer was collected and dried (Na2SO4), and the solvent
was removed under reduced pressure. The product was purified by
flash chromatography [silica gel, 50% (80% CHCl3, 18% CH3OH,
2% NH4OH) in CHCl3] to afford the title compound as an off-
white foam (0.546 g, 62%): 1H NMR (CDCl3) δ 7.29-7.24 (m,
2H), 7.19-7.11 (m, 4H), 6.68-6.60 (m, 3H), 3.59 (m, 1H), 3.17
(br, 2H), 2.86 (dd, 1H, J ) 7.2, 4.8 Hz), 2.69-2.61 (m, 3H), 2.51-
2.46 (m, 2H), 2.42-2.32 (m, 4H), 2.10 (m, 1H), 1.79 (m, 2H),
1.58 (d, 1H, J ) 12.0 Hz), 1.26-1.16 (m, 1H), 1.06-0.98 (m,
1H), 0.72 (d, 3H, J ) 6.9 Hz).
(+)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1-phenyl-1-cyclo-
butanecarboxamide (13a). A 50 mL round-bottom flask was
charged with amine 12 (48 mg, 0.132 mmol) and 1-phenyl-1-
cyclobutanecarboxylic acid (25.6 mg, 0.145 mmol), and then the
mixture was dissolved in dry THF (10 mL), followed by the addition
of triethylamine (40 µL, 0.290 mmol) and BOP reagent (64.1 mg,
0.145 mmol). The reaction mixture was stirred under N2 at room
temperature for 2.5 h. The mixture was diluted with diethyl ether
(10 mL), washed consecutively with water (10 mL), saturated
NaHCO3 (10 mL), and brine (10 mL × 2), and dried (Na2SO4).
The solvent was removed under reduced pressure, and the product
was purified by preparative TLC [silica gel plate, 50% (80% CHCl3,
18% CH3OH, 2% NH4OH) in CHCl3] to afford the title compound
as an off-white solid (50 mg, 73%): 1H NMR (CDCl3) δ 7.35-
7.11 (m, 11H), 6.68-6.65 (m, 3H), 4.68-4.60 (m, 2H), 3.12 (br,
1H), 3.02 (dd, 1H, J ) 7.8, 4.5 Hz), 2.84-2.80 (m, 1H), 2.74-
2.67 (m, 2H), 2.60 (t, 2H, J ) 7.8 Hz), 2.52-2.40 (m, 4H), 2.37-
2.30 (m, 3H), 2.17-2.11 (m, 2H), 1.89-1.75 (m, 3H), 1.51 (d,
1H, J ) 12.0 Hz), 0.92 (m, 1H), 0.76-0.67 (m, 4H); 13C NMR
(CDCl3) δ 175.8, 156.4, 151.5, 144.4, 142.4, 129.4, 128.8, 128.5,
128.2, 126.9, 126.3, 125.6, 116.8, 112.9, 112.4, 55.6, 54.2, 53.3,
52.7, 46.7, 45.0, 40.3, 37.4, 33.4, 32.6, 32.2, 31.8, 29.2, 18.6, 16.6;
LCMS (APCI) m/z 523.8 (M + H)+. The free base (49 mg, 0.0937
mmol) was dissolved in CH2Cl2 (3 mL), and to this solution was
added HCl (1 M in diethyl ether, 103 µL, 1.1 equiv). The solvent
was removed under reduced pressure, and the product was dried
in the vacuum oven at 45 °C overnight to afford the hydrochloride
salt of the title compound as an off-white solid (51.3 mg, 98%):
mp 157.5-159.5 °C; [R]20D +36.5° (c 3.80, CHCl3). Anal. (C35H43-
ClN2O2‚H2O) C, H, N.
(+)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1-phenyl-1-cyclohex-
anecarboxamide (13b). A 50 mL round-bottom flask was charged
with amine 12 (48 mg, 0.132 mmol) and 1-phenyl-1-cyclohexane-
carboxylic acid (29.6 mg, 0.145 mmol), and the mixture was
dissolved in dry THF (10 mL), followed by the addition of
triethylamine (40 µL, 0.290 mmol) and BOP reagent (64.1 mg,
0.145 mmol). The reaction mixture was stirred under N2 at room
temperature for 2.5 h. The mixture was diluted with diethyl ether
(10 mL), washed consecutively with water (10 mL), saturated
NaHCO3 (10 mL), and brine (10 mL × 2), and dried (Na2SO4).
The solvent was removed under reduced pressure, and the product
was purified by preparative TLC [silica gel plate, 50% (80% CHCl3,
18% CH3OH, 2% NH4OH) in CHCl3 and then silica gel plate 49%
hexanes/49% acetone/2% Et3N] to afford the title compound as an
off-white solid (42.9 mg, 59%): 1H NMR (CDCl3) δ 7.33-7.31
(m, 4H), 7.28-7.21 (m, 3H), 7.17-7.11 (m, 4H), 6.71-6.64 (m,
3H), 4.78 (d, 1H, J ) 7.8 Hz), 4.63 (m, 1H), 3.10 (br, 1H), 3.01
(m, 1H), 2.69-2.58 (m, 3H), 2.55-2.44 (m, 2H), 2.32-2.12 (m,
6H), 1.98 (m, 2H), 1.79-1.71 (m, 2H), 1.63-1.36 (m, 8H), 0.92
(m, 1H), 0.75-0.67 (m, 4H); 13C NMR (CDCl3) δ 175.8, 156.7,
151.7, 143.4, 142.6, 129.6, 129.1, 128.7, 128.5, 127.0, 126.9, 125.8,
116.9, 113.2, 112.7, 55.7, 54.4, 53.6, 51.0, 46.8, 46.1, 45.1, 40.5,
37.6, 34.7, 34.5, 33.6, 32.8, 32.0, 29.4, 26.0, 23.0, 18.8; LCMS
(APCI) m/z 551.8 (M + H)+. The free base (42.9 mg, 0.078 mmol)
was dissolved in CH2Cl2 (3 mL), and to this was added HCl (1 M
in diethyl ether, 86 µL, 1.1 equiv). The solvent was removed under
reduced pressure, and the product was dried in the vacuum oven at
50 °C overnight to afford the hydrochloride salt of the title
compound as an off-white solid (43.7 mg, 93%): mp 157.0-159.0
°C; [R]20D +32.0° (c 1.11, CHCl3). Anal. (C37H47ClN2O2‚H2O) C,
H, N.
(+)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1-phenyl-1-cyclohep-
tanecarboxamide (13c). A 50 mL round-bottom flask was charged
with amine 12 (37.4 mg, 0.102 mmol) and 1-phenyl-1-cyclohep-
tanecarboxylic acid (24.6 mg, 0.112 mmol), and the mixture was
dissolved in dry THF (10 mL), followed by the addition of
triethylamine (32 µL, 0.224 mmol) and BOP reagent (51 mg, 0.112
mmol). The reaction mixture was stirred under N2 at room
temperature for 1.5 h. The mixture was diluted with diethyl ether
(10 mL), washed consecutively with water (10 mL), saturated
NaHCO3 (10 mL), brine (10 mL × 2), and dried (Na2SO4). The
solvent was removed under reduced pressure, and the product was
purified twice by preparative TLC (silica gel plate, hexanes-
acetone-triethylamine, 65:33:2) and [silica gel plate, 33% (80%
CHCl3, 18% CH3OH, 2% NH4OH) in CHCl3] to afford the title
compound as a white solid (37.9 mg, 66%): 1H NMR (CDCl3) δ
7.33-7.31 (m, 4H), 7.28-7.20 (m, 3H), 7.17-7.11 (m, 4H), 6.69-
6.64 (m, 3H), 4.78 (d, 1H, J ) 7.8 Hz), 4.63 (m, 1H), 3.10 (br,
1H), 3.01 (m, 1H), 2.69-2.58 (m, 3H), 2.53-2.40 (m, 2H), 2.32-
2.10 (m, 6H), 1.98 (m, 2H), 1.79-1.71 (m, 3H), 1.60-1.36 (m,
8H), 0.92 (m, 1H), 0.75-0.67 (m, 4H); 13C NMR (CDCl3) δ 177.4,
156.1, 151.7, 145.2, 142.5, 129.4, 128.7, 128.5, 128.2, 126.8, 126.7,
125.6, 117.0, 112.8, 112.4, 55.5, 54.2, 53.4, 46.5, 44.8, 40.3, 37.47,
37.42, 37.2, 33.4, 32.6, 31.8, 29.9, 29.3, 24.18, 24.14, 18.6; LCMS
(APCI) m/z 565.6 (M + H)+. The free base (37.9 mg, 0.0671 mmol)
was dissolved in CH2Cl2 (3 mL), and to this was added HCl (1 M
in diethyl ether, 80.5 µL, 1.2 equiv). The solvent was removed
under reduced pressure, and the product was dried in the vacuum
oven at 50 °C overnight to afford the hydrochloride salt of the title
compound as an off-white solid (41.2 mg, 99.9%): mp 152-155
°C; [R]20D +28.5° (c 0.88, CH2Cl2). Anal. (C38H49ClN2O2‚0.75H2O)
C, H, N.
(+)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-2-methyl-2-phenyl-
propanamide (13d). A 50 mL round-bottom flask was charged
with amine 12 (35.5 mg, 0.0974 mmol) and 2-methyl-2-phenyl-

5604 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18
Thomas et al.
propionic acid (17.6 mg, 0.107 mmol), and the mixture was
dissolved in dry THF (10 mL), followed by the addition of
triethylamine (30 µL, 0.214 mmol) and BOP reagent (47.3 mg,
0.107 mmol). The reaction mixture was stirred under N2 at room
temperature for 2.5 h. TLC showed complete consumption of the
starting material (12). The reaction mixture was diluted with diethyl
ether (10 mL), washed consecutively with water (10 mL), saturated
NaHCO3 (10 mL), and brine (10 mL × 2), and dried (Na2SO4).
The solvent was removed under reduced pressure, and the product
was purified by preparative TLC [silica gel plate, 49% hexanes/
49% acetone/2% Et3N and then silica gel plate 50% (80% CHCl3,
18% CH3OH, 2% NH4OH) in CHCl3] to afford the title compound
as an off-white solid (37.0 mg, 74%): 1H NMR (CDCl3) δ 7.31-
7.10 (m, 11H), 6.66 (m, 3H), 4.75-7.63 (m, 2H), 3.15 (br, 1H),
3.04 (dd, 1H, J ) 12, 4.2 Hz), 2.73-2.53 (m, 5H), 2.53 (m, 3H),
2.14 (m, 1H), 1.77 (m, 2H), 1.53 (d, 7H, J ) 6.0 Hz), 0.93 (m,
1H), 0.81-0.69 (m, 4H); 13C NMR (CDCl3) δ 177.1, 156.3, 151.4,
144.8, 142.3, 129.4, 128.7, 128.5, 128.2, 127.1, 126.4, 125.7, 116.9,
112.9, 112.4, 55.6, 54.2, 53.4, 46.9, 46.5, 45.0, 40.2, 37.4, 33.3,
32.5, 31.7, 29.0, 27.2, 27.0, 18.6; LCMS (APCI) m/z 511.5 (M +
H)+. The free base (37.0 mg, 0.0724 mmol) was dissolved in
CH2Cl2 (3 mL), and to this was added HCl (1 M in diethyl ether,
80 µL, 1.1 equiv). The solvent was removed under reduced pressure,
and the product was dried in the vacuum oven at 50 °C overnight
to afford the hydrochloride salt of the title compound as an off-
CH3OH, 2% NH4OH) in CHCl3] to afford the title compound as a
white foam (68 mg, 64%): 1H NMR (CDCl3) δ 7.30-7.07 (m,
11H), 6.66-6.60 (m, 3H), 5.05 (d, 1H, J ) 6.0 Hz), 4.62 (m, 1H),
3.49 (q, 1H, J ) 7.2 Hz), 3.15 (br, 1H), 2.99 (dd, 1H, J ) 12.3,
4.8 Hz), 2.69-2.48 (m, 5H), 2.32-2.04 (m, 4H), 1.78-1.72 (m,
2H), 1.49 (d, 4H, J ) 6.9 Hz), 0.85 (m, 2H), 0.66 (d, J ) 6.9 Hz);
13C NMR (CDCl3) δ 174.2, 156.9, 151.5, 142.5, 141.1, 129.6, 129.2,
128.7, 128.4, 127.8, 127.6, 125.9, 116.7, 113.2, 112.7, 55.9, 54.4,
53.4, 47.4, 46.8, 45.2, 40.4, 37.5, 33.6, 32.6, 32.0, 29.2, 18.8; LCMS
(APCI) m/z 498.0 (M + H)+. The free base (68 mg, 0.137 mmol)
was dissolved in CH2Cl2 (3 mL), and to this was added HCl (1 M
in diethyl ether, 164 µL, 1.2 equiv). The solvent was removed under
reduced pressure, and the product was dried in the vacuum oven at
50 °C overnight to afford the hydrochloride salt of the title
compound as an off-white solid (75 mg, 99.9%): mp 162-165
°C; [R]20D +43.9° (c 0.84, MeOH). Anal. (C33H41ClN2O2‚0.75H2O)
C, H, N.
(+)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1-(4-methoxyphenyl)-
1-cyclopentanecarboxamide (14a). A 50 mL round-bottom flask
was charged with amine 12 (53.8 mg, 0.148 mmol) and 1-(4-
methoxyphenyl)-1-cyclopentanecarboxylic acid (38.0 mg, 0.164
mmol), and the mixture was dissolved in dry THF (10 mL),
followed by the addition of triethylamine (45 µL, 0.326 mmol) and
BOP reagent (73.8 mg, 0.162 mmol). The reaction mixture was
stirred under N2 at room temperature for 2.5 h. The mixture was
diluted with diethyl ether (10 mL), washed consecutively with water
(10 mL), saturated NaHCO3 (10 mL), and brine (10 mL × 2), and
dried (Na2SO4). The solvent was removed under reduced pressure,
and the product was purified by preparative TLC [silica gel, 50%
(80% CHCl3, 18% CH3OH, 2% NH4OH) in CHCl3] to afford the
title compound (82 mg, 98%) as a white foam: 1H NMR (CDCl3)
δ 7.31-7.08 (m, 8H), 6.83-6.80 (m, 2H), 6.68-6.63 (m, 3H),
4.81-4.79 (m, 1H), 4.58 (m, 1H), 3.76 (s, 3H), 3.14 (br, 1H), 3.01
(dd, 1H, J ) 12.0, 4.5 Hz), 2.70-1.52 (m, 21H), 0.90 (t, 1H, J )
12.3 Hz), 0.731 (m, 1H), 0.67 (d, 3H, J ) 6.9 Hz); 13C NMR
(CDCl3) δ 176.7, 158.4, 156.7, 151.4, 142.3, 135.7, 129.3, 128.5,
128.2, 128.0, 125.6, 116.5, 114.1, 112.9, 112.5, 58.4, 55.6, 55.2,
54.2, 53.3, 46.6, 45.0, 40.2, 37.4, 37.15, 37.11, 36.9, 33.4, 32.5,
31.7, 29.0, 24.0, 18.6; MS (APCI) m/z 567.6 (M + H)+. The free
base was dissolved in CH2Cl2, and to this was added HCl (1 M in
diethyl ether, 160 µL, 1.1 equiv). The solvent was removed under
reduced pressure to yield an off-white solid. This product was
purified by dissolving in CH2Cl2, then precipitated from the solution
by adding diethyl ether, filtered, and dried in the vacuum oven at
white solid (40.4 mg, 99%): mp 147.5-149.5 °C; [R]20 +36.5°
D
(c 1.03, CHCl3). Anal. (C34H43ClN2O2‚H2O) C, H, N.
(+)-2-Ethyl-N-[(1S,4R,5R,7S)-5-(3-hydroxyphenyl)-4-methyl-
2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-2-phenylbutan-
amide (13e). A 50 mL round-bottom flask was charged with amine
12 (39.4 mg, 0.108 mmol) and 2-ethyl-2-phenylbutyric acid (22.8
mg, 0.118 mmol), and the mixture was dissolved in dry THF (10
mL), followed by the addition of triethylamine (33 µL, 0.236 mmol)
and BOP reagent (53.8 mg, 0.118 mmol). The reaction mixture
was stirred under N2 at room temperature for 1.5 h. The mixture
was diluted with diethyl ether (10 mL), washed consecutively with
water (10 mL), saturated NaHCO3 (10 mL), and brine (10 mL ×
2), and dried (Na2SO4). The solvent was removed under reduced
pressure, and the product was purified twice by preparative TLC
[silica gel plate, hexanes-acetone-ammonium hydroxide, 49:49:
2, and silica gel plate 50% (80% CHCl3, 18% CH3OH, 2% NH4OH)
in CHCl3] to afford the title compound as a white solid (37.7 mg,
65%): 1H NMR (CDCl3) δ 7.32-7.10 (m, 11H), 6.66 (m, 3H),
4.74 (m, 2H), 3.14 (br, 1H), 3.06 (dd, 1H, J ) 11.7, 3.3 Hz), 2.72-
2.53 (m, 5H), 2.37-2.28 (m, 3H), 2.14 (m, 1H), 2.05-1.88 (m,
4H), 1.77 (m, 2H), 1.52 (d, 1H, J ) 12 Hz), 0.97 (t, 1H, J ) 12
Hz), 0.79-0.61 (m, 10H); 13C NMR (CDCl3) δ 175.9, 156.4, 151.4,
143.1, 142.4, 129.4, 128.5, 128.4, 128.3, 127.4, 126.8, 125.7, 116.7,
113.0, 112.4, 55.6, 54.5, 54.2, 53.5, 46.6, 44.9, 40.3, 37.5, 33.4,
32.5, 31.9, 29.1, 27.41, 27.35, 18.6, 8.5, 8.3; LCMS (APCI) m/z
539.7 (M + H)+. The free base (37.7 mg, 0.07 mmol) was dissolved
in CH2Cl2 (3 mL), and to this was added HCl (1 M in diethyl ether,
84 µL, 1.2 equiv). The solvent was removed under reduced pressure,
and the product was dried in the vacuum oven at 50 °C overnight
to afford the hydrochloride salt of the title compound as an off-
50 °C overnight: mp 142.5-144.5 °C; [R]20 +24.5° (c 0.84,
D
CHCl3). Anal. (C37H47ClN2O3‚1.25H2O) C, H, N.
(+)-1-(4-Fluorophenyl)-N-[(1S,4R,5R,7S)-5-(3-hydroxyphenyl)-
4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1-cy-
clopentanecarboxamide (14b). A 50 mL round-bottom flask was
charged with amine 12 (62.5 mg, 0.171 mmol) and 1-(4-fluoro-
phenyl)-1-cyclopentanecarboxylic acid (40.7 mg, 0.192 mmol), and
the mixture was dissolved in dry THF (10 mL), followed by the
addition of triethylamine (52 µL, 0.376 mmol) and BOP reagent
(85.8 mg, 0.188 mmol). The reaction mixture was stirred under N2
at room temperature for 2.5 h. The mixture was diluted with diethyl
ether (10 mL), washed consecutively with water (10 mL), saturated
NaHCO3 (10 mL), and brine (10 mL × 2), and dried (Na2SO4).
The solvent was removed under reduced pressure, and the product
was purified by preparative TLC [silica gel, 50% (80% CHCl3,
18% CH3OH, 2% NH4OH) in CHCl3] to afford the title compound
(88.3 mg, 93%) as a white foam: 1H NMR (CDCl3) δ 7.36-6.86
(m, 10H), 6.68-6.62 (m, 3H), 4.81 (m, 1H), 4.59 (m, 1H), 3.15
(br, 1H), 2.98 (m, 1H), 2.71-2.30 (m, 10H), 2.08-1.49 (m, 11H),
0.93 (t, 2H, J ) 12.0 Hz), 0.75 (t, 1H, J ) 12.0 Hz), 0.67 (d, 3H,
J ) 6.0 Hz); 13C NMR (CDCl3) δ 175.9, 161.6 (d, JCF ) 246.0
Hz), 156.7, 151.2, 142.2, 139.5, 129.3, 128.4, 128.3, 128.2, 125.6,
116.6, 115.5 (d, JCF ) 21.1 Hz), 112.9, 112.5, 58.6, 55.6, 54.2,
53.2, 46.5, 45.1, 40.1, 37.3, 37.04, 36.99, 33.3, 32.3, 31.6, 28.9,
23.84, 23.81, 18.6; MS (APCI) m/z 556.0 (M + H)+. The free base
was dissolved in CH2Cl2, and to this was added HCl (1 M in diethyl
white solid (39.9 mg, 94%): mp 150-152 °C; [R]20 +31.9° (c
D
1.03, CH2Cl2). Anal. (C36H47ClN2O2‚1.75H2O) C, H, N.
(+)-(2R)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-
(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-2-phenylpropan-
amide (13f). A 50 mL round-bottom flask was charged with amine
12 (77.9 mg, 0.214 mmol) and (R)-2-phenylpropanoic acid (36.4
mg, 0.235 mmol), and the mixture was dissolved in dry THF (20
mL), followed by the addition of triethylamine (66 µL, 0.47 mmol)
and BOP reagent (103.9 mg, 0.235 mmol). The reaction mixture
was stirred under N2 at room temperature for 2.5 h. The mixture
was diluted with diethyl ether (20 mL), washed consecutively with
water (20 mL), saturated NaHCO3 (20 mL), and brine (20 mL ×
2), and dried (Na2SO4). The solvent was removed under reduced
pressure, and the product was purified by silica gel chromatography
using an ISCO chromatography system [0-50% (80% CHCl3, 18%

InVerse Agonists of the Opioid δ Receptor
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18 5605
ether, 175 µL, 1.1 equiv). The solvent was removed under reduced
pressure to yield an off-white solid. This product was purified by
dissolving in CH2Cl2, then precipitated from the solution by adding
diethyl ether, filtered, and dried in the vacuum oven at 50 °C
overnight: mp 148-152 °C; [R]20D +25.1° (c 0.75, CHCl3). Anal.
(C36H44ClFN2O2‚1.25H2O) C, H, N.
(+)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1-(2-thienyl)cyclo-
pentanecarboxamide (14e). A 50 mL round-bottom flask was
charged with amine 12 (35.4 mg, 0.0971 mmol) and 1-(2-thienyl)-
cyclopentanecarboxylic acid (20.96 mg, 0.107 mmol), and the
mixture was dissolved in dry THF (10 mL), followed by the addition
of triethylamine (30 µL, 0.214 mmol) and BOP reagent (47.32 mg,
0.107 mmol). The reaction mixture was stirred under N2 at room
temperature for 3 h. The mixture was diluted with diethyl ether
(10 mL), washed consecutively with water (10 mL), saturated
NaHCO3 (10 mL), and brine (10 mL × 2), and dried (Na2SO4).
The solvent was removed under reduced pressure, and the product
was purified by preparative TLC [silica gel plate, 50% (80% CHCl3,
18% CH3OH, 2% NH4OH) in CHCl3] to afford the title compound
as a white foam (42.9 mg, 81%): 1H NMR (CDCl3) δ 7.28-7.11
(m, 7H), 6.94-6.89 (m, 2H), 6.68-6.65 (m, 3H), 5.08 (d, 1H, J )
7.8 Hz), 4.60 (m, 1H), 3.17 (br, 1H), 3.04 (dd, 1H, J ) 12, 3.9
Hz), 2.73-2.31 (m, 10H), 2.12-2.06 (m, 3H), 1.84-1.52 (m, 8H),
0.97 (t, 1H, J ) 12.6 Hz), 0.84-0.76 (m, 1H), 0.70 (d, 3H, J )
6.9 Hz); 13C NMR (CDCl3) δ 175.1, 156.4, 151.3, 148.4, 142.3,
129.4, 128.5, 128.2, 127.1, 125.7, 125.1, 124.8, 116.8, 112.9, 112.4,
56.6, 55.6, 54.2, 53.4, 46.5, 45.1, 40.2, 39.3, 39.2, 37.4, 33.3, 32.4,
31.6, 29.0, 24.3, 18.6; LCMS (APCI) m/z 543.4 (M + H)+. The
free base (42.9 mg, 0.0790 mmol) was dissolved in CH2Cl2 (3 mL),
and to this was added HCl (1 M in diethyl ether, 87 µL, 1.1 equiv).
The solvent was removed under reduced pressure, and the product
was dried in the vacuum oven at 50 °C overnight to afford the
hydrochloride salt of the title compound as an off-white solid (45.5
(+)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1-(1-naphthyl)cyclo-
pentanecarboxamide (14c). A 50 mL round-bottom flask was
charged with amine 12 (34.1 mg, 0.0933 mmol) and 1-(1-naphthyl)-
cyclopentanecarboxylic acid (24.3 mg, 0.103 mmol), and the
mixture was dissolved in dry THF (10 mL), followed by the addition
of triethylamine (29 µL, 0.206 mmol) and BOP reagent (45.4 mg,
0.103 mmol). The reaction mixture was stirred under N2 at room
temperature for 3 h. The mixture was diluted with diethyl ether
(10 mL), washed consecutively with water (10 mL), saturated
NaHCO3 (10 mL), and brine (10 mL × 2), and dried (Na2SO4).
The solvent was removed under reduced pressure, and the product
was purified by preparative TLC [silica gel plate, 50% (80% CHCl3,
18% CH3OH, 2% NH4OH) in CHCl3] to afford the title compound
as a white solid (45 mg, 82%): 1H NMR (CDCl3) δ 7.93-7.90
(m, 1H), 7.81-7.78 (m, 1H), 7.73 (d, 1H, J ) 8.1 Hz), 7.48-7.35
(m, 4H), 2.27-2.22 (m, 2H), 7.16 (m, 3H), 7.07 (m, 1H), 6.63-
6.56 (m, 3H), 6.02 (br, 1H), 4.63-4.58 (m, 2H), 2.97 (m, 2H),
2.73-2.45 (m, 7H), 2.27-2.10 (m, 6H), 1.87 (m, 2H), 1.74-1.58
(m, 4H), 1.31 (d, 1H, J ) 12.1 Hz), 0.64 (d, 4H, J ) 6.75 Hz),
0.38 (m, 1H); 13C NMR (CDCl3) δ 177.4, 156.1, 151.4, 142.4,
139.7, 134.6, 131.5, 129.3, 129.0, 128.9, 128.5, 128.2, 126.0, 125.8,
125.7, 125.6, 124.9, 123.6, 117.0, 112.7, 112.3, 58.4, 55.4, 54.1,
53.3, 46.3, 45.0, 40.1, 38.0, 37.5, 37.4, 33.3, 32.4, 31.4, 29.2, 25.0,
24.8, 18.5; LCMS (APCI) m/z 587.4 (M + H)+. The free base (45
mg, 0.0767 mmol) was dissolved in CH2Cl2 (3 mL), and to this
was added HCl (1 M in diethyl ether, 84 µL, 1.1 equiv). The solvent
was removed under reduced pressure, and the product was dried
in the vacuum oven at 50 °C overnight to afford the hydrochloride
salt of the title compound as an off-white solid (47.1 mg, 99%):
mg, 96%): mp 154.0-156.0 °C; [R]20 +35.8° (c 1.06, CHCl3).
D
Anal. (C34H43ClN2O2S‚H2O) C, H, N.
(+)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1-(3-thienyl)cyclo-
pentanecarboxamide (14f). A 50 mL round-bottom flask was
charged with amine 12 (36.3 mg, 0.0996 mmol) and 1-(3-thienyl)-
cyclopentanecarboxylic acid (21.5 mg, 0.109 mmol), and the
mixture was dissolved in dry THF (10 mL), followed by the addition
of triethylamine (30 µL, 0.214 mmol) and BOP reagent (48.8 mg,
0.110 mmol). The reaction mixture was stirred under N2 at room
temperature for 3 h. The mixture was diluted with diethyl ether
(10 mL), washed consecutively with water (10 mL), saturated
NaHCO3 (10 mL), and brine (10 mL × 2), and dried (Na2SO4).
The solvent was removed under reduced pressure, and the product
was purified by preparative TLC [silica gel plate, 50% (80% CHCl3,
18% CH3OH, 2% NH4OH) in CHCl3] to afford the title compound
as an off-white solid (42 mg, 78%): 1H NMR (CDCl3) δ 7.29-
7.23 (m, 3H), 7.17-7.12 (m, 4H), 7.06 (m, 1H), 6.92 (dd, 1H, J )
4.8, 0.9 Hz), 6.66 (m, 3H), 4.88 (d, 1H, J ) 7.8 Hz), 4.61 (m, 1H),
3.14 (br, 1H), 3.28 (dd, 1H, J ) 12.0, 3.9 Hz), 2.71-2.51 (m, 5H),
2.43-2.24 (m, 5H), 2.14 (m, 1H), 2.02-1.97 (m, 2H), 1.80-1.76
(m, 4H), 1.67-1.51 (m, 3H), 0.95 (t, 1H, J ) 12.6 Hz), 0.76 (t,
1H, J ) 12 Hz), 0.69 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ
175.7, 156.3, 151.5, 145.0, 142.4, 129.4, 128.5, 128.4, 128.2, 127.2,
126.7, 125.6, 120.9, 112.9, 112.4, 56.4, 55.5, 54.2, 53.4, 46.6, 45.0,
40.2, 37.6, 37.5, 37.4, 33.3, 32.5, 31.8, 29.1, 24.3, 18.6; LCMS
(APCI) m/z 543.4 (M + H)+. The free base (42 mg, 0.0774 mmol)
was dissolved in CH2Cl2 (3 mL), and to this was added HCl (1 M
in diethyl ether, 85 µL, 1.1 equiv). The solvent was removed under
reduced pressure, and the product was dried in the vacuum oven at
50 °C overnight to afford the hydrochloride salt of the title
compound as an off-white solid (46.0 mg, 99%): mp 151.0-153.0
°C; [R]20D +26.2° (c 0.97, CHCl3). Anal. (C34H43ClN2O2‚1.25H2O)
C, H, N.
mp 159-161 °C; [R]20 +18.7° (c 0.98, CHCl3). Anal. (C40H47-
D
ClN2O2‚1.5H2O) C, H, N.
(-)-N-(1S,4R,5R,7S)-{5-(3-Hydroxy)phenyl-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl}-1-(naphthalen-2-yl)-
cyclopentanecarboxamide (14d). A 50 mL round-bottom flask was
charged with amine 12 (39.1 mg, 0.107 mmol) and 1-(naphthalen-
2-yl)cyclopentanecarboxylic acid (28.3 mg, 0.118 mmol), and the
mixture was dissolved in dry THF (10 mL), followed by the addition
of triethylamine (35 µL, 0.236 mmol) and BOP reagent (54 mg,
0.118 mmol). The reaction mixture was stirred under N2 at room
temperature for 3 h. The mixture was diluted with diethyl ether
(10 mL), washed consecutively with water (10 mL), saturated
NaHCO3 (10 mL), and brine (10 mL × 2), and dried (Na2SO4).
The solvent was removed under reduced pressure, and the product
was purified twice by preparative TLC [silica gel plate, 50% (80%
CHCl3, 18% CH3OH, 2% NH4OH) in CHCl3 and silica gel plate
hexanes-acetone-triethylamine, 65:33:2] to afford the title com-
pound as a white solid (40.0 mg, 64%): 1H NMR (CDCl3) δ 7.81-
7.76 (m, 3H), 7.72 (s, 1H), 7.50-7.42 (m, 2H), 7.35 (dd, 1H, J )
8.7, 1.5 Hz), 7.25-7.22 (m, 2H), 7.17-7.05 (m, 4H), 6.62-6.56
(m, 3H), 4.77-4.74 (m, 1H), 4.60 (m, 1H), 3.07 (br, 1H), 2.98 (m,
1H), 2.67-2.41 (m, 7H), 2.27-2.01 (m, 6H), 1.87-1.68 (m, 6H),
4.41 (d, 1H, J ) 11.7 Hz), 0.79-0.63 (m, 5H); 13C NMR (CDCl3)
δ 176.0, 156.2, 151.5, 142.4, 141.3, 133.2, 132.3, 129.4, 128.6,
128.5, 128.2, 128.0, 127.6, 126.4, 126.1, 125.9, 125.6, 124.6, 116.8,
112.8, 112.4, 59.3, 55.5, 54.2, 53.3, 46.5, 45.1, 40.2, 37.3, 37.0,
33.4, 32.4, 31.6, 29.2, 24.2, 18.6; LCMS (APCI) m/z 587.7 (M +
H)+. The free base (40 mg, 0.0682 mmol) was dissolved in CH2Cl2
(3 mL), and to this was added HCl (1 M in diethyl ether, 75 µL,
1.1 equiv). The solvent was removed under reduced pressure, and
the product was dried in the vacuum oven at 50 °C overnight to
afford the hydrochloride salt of the title compound as an off-white
tert-Butyl (1S,4R,5R,7S)-7-Amino-5-(3-isopropoxyphenyl)-4-
methyl-2-azabicyclo[3.3.1]nonane-2-carboxylate (15). Triethyl-
amine (5.25 mL, 37.7 mmol) and di-tert-butyl dicarbonate (8.48 g,
0.038 mol) were added to a solution of 9 (7.88 g, 0.019 mol) in
dichloromethane (250 mL). The reaction mixture was stirred at room
temperature for an hour. TLC showed complete consumption of
the starting material. Removal of the solvent under reduced pressure
afforded a solid crude product. This material was dissolved in
diethyl ether, and the insoluble solid was filtered and washed several
solid (41.6 mg, 95%): mp 159-162 °C; [R]20 -74.3° (c 1.09,
D
CHCl3). Anal. (C40H47ClN2O2‚H2O) C, H, N.

5606 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18
Thomas et al.
times with diethyl ether. The solvent was removed under reduced
pressure, and the residue was purified by flash column chroma-
tography using an ISCO chromatography system (silica gel, 0-50%
ethyl acetate in hexanes) to give 15 as a white solid (7.92 g, 81%).
Rotamers of this compound were observed in the 1H and 13C NMR
spectra: 1H NMR (CDCl3) δ 7.85-7.78 (m, 2H), 7.70-7.67 (m,
2H), 7.19 (t, 1H, J ) 7.8 Hz), 6.80-6.69 (m, 3H), 5.07 (m, 1H),
4.74-4.48 (m, 2H), 3.84-3.59 (m, 2H), 2.52 (ddd, 1H, J1 ) J2 )
12.9 Hz, J3 ) 3.6 Hz), 2.43-2.24 (m, 4H), 2.11-2.02 (m, 1H),
1.89 (m, 1H), 1.48 (d, 9H, J ) 2.7 Hz), 1.32 (d, 6H, J ) 6.0 Hz),
0.63 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 168.6, 158.3, 156.0,
150.4/150.2, 134.3, 132.3, 129.5, 123.5, 117.9, 114.4/114.2, 113.1,
80.0, 70.2, 48.8/48.6, 47.8/47.5, 46.0/45.8, 42.4, 40.6/40.3, 37.5/
37.2, 33.3/32.8, 31.2/30.7, 28.9, 22.5, 18.2/17.9.
Hydrazine (2.9 mL, 91.2 mmol) was added to a solution of the
phthalimide (9.46 g, 0.018 mol) in ethanol (500 mL), and the
reaction mixture was refluxed under N2 for 2.5 h. The reaction
mixture was cooled to room temperature, and TLC [silica gel, 25%
(80% CHCl3, 18% CH3OH, 2% NH4OH) in CHCl3] showed
complete consumption of compound 9. Removal of the solvent
under reduced pressure yielded a white solid residue, which was
dissolved in CH2Cl2 (150 mL). The heterogeneous solution was
filtered through a fritted funnel, and the solid was washed several
times with CH2Cl2. The filtrate was concentrated under reduced
pressure, and the residue was dried on vacuum pump to afford the
title compound (6.94 g, 98%) as a white foam. Rotamers of this
compound were observed in the 1H and 13C NMR spectra: 1H NMR
(CDCl3) δ 7.21 (t, 1H, J ) 7.8 Hz), 6.80-6.71 (m, 3H), 4.60-
4.41 (m, 2H), 3.59-3.43 (m, 3H), 2.44-2.12 (m, 4H), 1.63-1.42
(m, 11H), 1.33 (d, 6H, J ) 6.0 Hz), 1.26-1.12 (m, 3H), 0.60 (d,
3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 158.2, 155.9, 150.8/150.6,
129.4, 117.7, 114.1, 112.9, 79.7, 70.0, 50.3/50.1, 48.6/48.4, 47.8/
47.3, 46.4/46.0, 41.0, 40.6/40.4, 37.2/37.0, 31.5/31.2, 28.7, 22.3,
18.1/18.0.
(m, 1H), 0.74 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 177.0,
158.3, 150.4, 145.1, 129.6, 128.9, 127.2, 126.6, 117.2, 113.5, 112.7,
70.0, 48.7, 48.0, 47.1, 46.4, 44.8, 40.0, 36.5, 30.4, 27.3, 27.2, 22.3,
22.2, 17.6; MS (APCI) m/z 435.6 (M + H)+.
N-[(1S,4R,5R,7S)-5-(3-Isopropoxyphenyl)-4-methyl-2-(2-phe-
noxyethyl)-2-azabicyclo[3.3.1]non-7-yl]-2-methyl-2-phenylpro-
panamide (17). To a solution of amine 16 (125 mg, 0.288 mmol)
in THF (anhydrous, 3 mL) was added â-bromophenetole (57.6 mg,
0.288 mmol), triethylamine (48 µL, 0.346 mmol), and tetrabutyl-
ammonium iodide (106 mg, 0.288 mmol). The reaction mixture
was stirred at room temperature for 3 days. The reaction mixture
was diluted with CH2Cl2 (10 mL), washed with 1 N HCl and water,
and dried over NaSO4. This solution was concentrated under
vacuum, and the residue was purified by flash chromatography
[silica gel, 0-50% (80% CHCl3, 18% CH3OH, 2% NH4OH) in
CHCl3] to afford the title compound as a yellow oil (81 mg, 51%)
and the starting material (56 mg): 1H NMR (CDCl3) δ 7.32-7.17
(m, 8H), 6.97-6.89 (m, 3H), 6.70 (m, 3H), 4.76-4.62 (m, 2H),
4.52 (hep, 1H, J ) 6.0 Hz), 4.22 (br, 2H), 3.40 (br, 1H), 3.31 (dd,
1H, J ) 12.6, 4.8 Hz), 3.08 (m, 2H), 2.92 (d, 1H, J ) 12.0 Hz),
2.34 (m, 2H), 2.40-2.34 (m, 1H), 2.22 (pet, 1H, J ) 6.0 Hz), 1.60
(m, 1H), 1.54 (d, 6H, J ) 3.6 Hz), 1.32 (d, 6H, J ) 6.0 Hz), 1.06-
0.88 (m, 2H), 0.76 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 177.1,
158.8, 158.2, 150.7, 145.1, 129.7, 129.5, 128.9, 127.2, 126.6, 121.1,
117.2, 114.9, 113.7, 70.0, 66.2, 56.5, 55.0, 54.6, 47.1, 46.5, 44.8,
40.0, 37.5, 32.2, 27.4, 27.2, 22.3, 18.9; LCMS (APCI) m/z 555.8
(M + H)+.
(+)-N-[(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-(2-
phenoxyethyl)-2-azabicyclo[3.3.1]non-7-yl]-2-methyl-2-phenyl-
propanamide (18). A solution of compound 17 (81 mg, 0.146
mmol) in CH2Cl2 (anhydrous, 20 mL) at -78 °C was treated with
BBr3 (1 M solution in CH2Cl2, 1.5 mL). After 30 min, the reaction
mixture was warmed to room temperature and was kept stirring
for an additional 2 h. The reaction mixture was cooled to 0 °C,
and the reaction was quenched with saturated NaHCO3 (25 mL).
The aqueous layer was separated and extracted with CH2Cl2 (10
mL × 2). The combined organic layers were washed with water
(30 mL × 2), dried over NaSO4, and concentrated under vacuum.
The residue was purified by preparative TLC [silica gel plate, 25%
(80% CHCl3, 18% CH3OH, 2% NH4OH) in CHCl3] to give the
title compound as a white solid (44.4 mg, 59%): 1H NMR (CDCl3)
δ 7.32-7.23 (m, 7H), 7.12 (t, 1H, J ) 7.8 Hz), 6.93-6.85 (m,
3H), 6.68-6.65 (m, 3H), 4.78-4.66 (m, 2H), 4.06 (t, 2H, J ) 5.4
Hz), 3.22-3.17 (m, 2H), 3.03-2.86 (m, 2H), 2.75 (d, 1H, J )
12.3 Hz), 2.42-2.30 (m, 3H), 2.14 (m, 1H), 1.54 (d, 7H, J ) 6.9
Hz), 0.97-0.76 (m, 2H), 0.67 (d, 3H, J ) 6.9 Hz); 13C NMR
(CDCl3) δ 177.4, 159.0, 156.6, 151.5, 145.1, 129.6, 129.0, 127.4,
126.6, 120.9, 117.0, 114.9, 113.2, 112.6, 66.7, 56.5, 54.4, 54.3,
47.1, 46.7, 45.2, 40.1, 37.6, 32.6, 32.3, 27.4, 27.2, 18.7; LCMS
(APCI) m/z 513.6 (M + H)+. The free base (44.4 mg, 0.0866 mmol)
was dissolved in CH2Cl2 (3 mL), and to this was added HCl (1 M
in diethyl ether, 104 µL, 1.2 equiv). The solvent was removed under
reduced pressure, and the product was dried in the vacuum oven at
50 °C overnight to afford the hydrochloride salt of the title
compound as an off-white solid (41.4 mg, 84%): mp 147-150
N-[(1S,4R,5S,7S)-5-(3-Isopropoxyphenyl)-4-methyl-2-azabicyclo-
[3.3.1]non-7-yl]-2-methyl-2-phenylpropanamide (16). A 500 mL
round-bottom flask was charged with amine 15 (2.02 g, 0.052 mol)
and 2-methyl-2-phenylpropionic acid (1.73 g, 0.01 mol) followed
by dry THF (130 mL), triethylamine (3.60 mL, 26.0 mmol), and
BOP reagent (2.60 g, 0.0057 mol). The reaction mixture was stirred
under N2 at room temperature for 4 h. TLC showed that the starting
material was consumed completely. The mixture was diluted with
diethyl ether (130 mL), washed consecutively with water (150 mL),
saturated NaHCO3 (150 mL), and brine (150 mL × 2), and dried
(Na2SO4). The solvent was removed under reduced pressure, and
the product was purified by Combi Flash chromatography (silica
gel, 10-25% ethyl acetate in hexanes) to afford the title compound
1
(2.60 g, 93%) as a white foam. Rotamers in H and 13C NMR
spectra were observed: 1H NMR (CDCl3) δ 7.36-7.17 (m, 6H),
6.72-6.64 (m, 3H), 4.76-4.63 (m, 2H), 4.58-4.40 (m, 2H), 3.75-
3.57 (m, 2H), 2.47-2.42 (m, 1H), 2.22-2.13 (m, 3H), 1.52 (m,
7H), 1.46 (s, 9H), 1.32 (d, 6H, J ) 6.0 Hz), 1.04-0.96 (m, 2H),
0.58 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 177.1/176.9, 158.2,
155.9/155.5, 150.6/150.5, 145.1, 129.4, 128.9, 127.2, 126.6, 117.6,
113.8, 112.9/112.6, 79.8/79.7, 70.0, 48.4, 47.8/47.4, 47.1/46.8, 46.3,
44.2, 40.3/40.2, 37.4, 36.8/36.7, 31.4/31.0, 28.7, 27.4/27.2, 22.3,
17.8; MS (APCI) m/z 535.7 (M + H)+.
°C; [R]20 + 37.1° (c 0.84, MeOH). Anal. (C33H41ClN2O3‚H2O)
D
C, H, N.
To a solution of the amide (105 mg, 0.196 mmol) in CH2Cl2 (3
mL) at room temperature was added trifluoroacetic acid (230 µL,
2.98 mmol). After 1.5 h, TLC [25% (80% CHCl3, 18% CH3OH,
2% NH4OH) in CHCl3] showed complete consumption of the
starting material. The solvent and excess TFA were removed under
vacuum, the residue was dissolved in CH2Cl2 (10 mL) and made
basic with saturated Na2CO3. The organic layer was dried (Na2SO4)
and concentrated under vacuum. The residue was purified by flash
chromatography [silica gel, 0-50% (80% CHCl3, 18% CH3OH,
2% NH4OH) in CHCl3] to give the title compound as a colorless
film (52.4 mg, 62%): 1H NMR (CDCl3) δ 7.31-7.17 (m, 6H),
6.71 (m, 3H), 4.77 (m, 2H), 4.52 (hep, 1H, J ) 6.0 Hz), 3.73-
3.66 (m, 2H), 2.94 (d, 1H, J ) 13.8 Hz), 2.51-2.21 (m, 4H), 1.58-
1.51 (m, 7H), 1.32 (d, 6H, J ) 6.0 Hz), 1.26-1.16, (m, 1H), 1.05
tert-Butyl (1S,4R,5R,7S)-5-(3-Isopropoxyphenyl)-4-methyl-7-
{[(1-phenyl-1-cyclopentyl)carbonyl]amino}-2-azabicyclo[3.3.1]-
nonane-2-carboxylate (19a). A 100 mL round-bottom flask was
charged with amine 15 (459 mg, 1.18 mmol) and 1-phenyl-1-
cyclopentanecarboxylic acid (449 mg, 2.36 mmol), and the mixture
was dissolved in dry THF (30 mL), followed by the addition of
triethylamine (0.82 mL, 5.9 mmol) and BOP reagent (574 mg, 1.3
mmol). The reaction mixture was stirred under N2 at room
temperature for 4 h. The mixture was diluted with diethyl ether
(50 mL), washed consecutively with water (30 mL), saturated
NaHCO3 (30 mL), and brine (30 mL × 2), and dried (Na2SO4).
The solvent was removed under reduced pressure, and the product
was purified by flash chromatography (silica gel, 20% ethyl acetate
in hexanes) to afford the title compound (0.606 g, 92%) as a white

InVerse Agonists of the Opioid δ Receptor
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18 5607
1
foam. Rotamers of this compound were observed in the H and
13C NMR spectra: 1H NMR (CDCl3) δ 7.34-7.14 (m, 6H), 6.72-
6.63 (m, 3H), 4.77-4.39 (m, 4H), 3.73-3.57 (m, 2H), 2.43-1.45
(m, 22H), 1.32 (d, 6H, J ) 6.0 Hz), 0.97 (t, 2H, J ) 12.5 Hz),
0.57 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 176.0/175.8, 157.9,
155.6/155.3, 150.4, 144.1/144.0, 129.2, 128.7, 126.9, 126.8, 117.4,
113.6, 112.7/112.4, 79.6/79.4, 69.8, 59.1, 48.2, 47.6/47.1, 46.5/
46.0, 44.0, 40.1/39.9, 37.2, 37.0/36.9, 36.7/36.6, 36.5, 31.1, 30.8,
28.4, 24.1, 22.0, 17.6.
1H), 2.18 (d, 1H, J ) 12.0 Hz), 2.09 (m, 1H), 1.70 (d, 7H), 1.48-
1.39 (m, 4H), 0.79 (d, 3H, J ) 6.9 Hz); 13C NMR (C5D5N) δ 176.7,
159.6, 153.4, 147.5, 130.3, 129.3, 127.3, 127.2, 116.8, 113.9, 113.8,
50.0, 49.4, 47.62, 47.58, 46.2, 41.4, 40.1, 38.2, 32.6, 28.5, 27.8,
18.0.
(+)-N-{(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-[3-(2-
methylphenyl)prop-2-en-1-yl]-2-azabicyclo[3.3.1]non-7-yl}-1-
phenylcyclopentanecarboxamide (21a). Amine 20a (126 mg,
0.301 mmol) was suspended in DCE (15 mL) under N2. Then trans-
2-methylcinnamaldehyde (46 mg, 0.301 mmol) and sodium tri-
acetoxyborohydride (82.9 mg, 0.391 mmol) were added to the
reaction mixture. The reaction mixture was stirred at room
temperature for 2 days and became a clear solution. The reaction
mixture was transferred to a separatory funnel and washed with
saturated NaHCO3. The aqueous layer was extracted with 3:1
CH2Cl2-THF (15 mL × 2). The combined organic layers were
dried (MgSO4) and concentrated to give a solid crude product. The
crude product was purified by preparative TLC [silica gel plate,
35% (80% CHCl3, 18% CH3OH, 2% NH4OH) in CHCl3] to afford
the title compound (0.126 g, 76%) as a white solid: 1H NMR
(CDCl3) δ 7.38-7.07 (m, 10H), 6.76 (d, 1H, J ) 15.9 Hz), 6.66-
6.60 (m, 3H), 6.14-6.04 (m, 1H), 4.79-4.63 (m, 2H), 3.35-2.24
(m, 3H), 3.08-3.03 (m, 1H), 2.75 (d, 1H, J ) 12.3 Hz), 2.52-
2.22 (m, 8H), 2.10-1.95 (m, 3H), 1.83-1.65 (m, 4H), 1.50-1.46
(m, 1H), 0.87-0.64 (m, 5H). 13C NMR (CDCl3) δ 176.8, 157.1,
151.5, 144.3, 136.5, 135.7, 130.6, 129.8, 129.2, 127.7, 127.4, 127.2,
126.4, 126.2, 126.1, 117.1, 113.4, 112.9, 59.6, 58.4, 56.4, 53.6,
46.8, 45.4, 40.5, 37.8, 37.42, 37.38, 32.8, 31.9, 24.5, 24.4, 20.2,
19.0; MS (APCI) m/z 549.7 (M + H)+. The free base (126 mg,
0.230 mmol) was dissolved in CH2Cl2 (8 mL), and to this was added
HCl (1 M solution in diethyl ether, 255 µL, 0.255 mmol). The
reaction mixture was stirred for 15 min, and the solvent was
removed under vacuum. The salt was purified twice by adding
diethyl ether (8 mL) to its CH2Cl2 (3 mL) solution. The precipitate
was filtered and dried in the vacuum oven at 50 °C overnight to
afford the hydrochloride salt of the title compound as a white
powder (98.5 mg, yield 73%): mp 168.5-170.5 °C; [R]20D +25.6°
(c 1.04, CHCl3). Anal. (C37H45ClN2O2‚H2O) C, H, N.
tert-Butyl (1S,4R,5R,7S)-5-(3-Isopropoxyphenyl)-4-methyl-7-
[(2-methyl-2-phenylpropanoyl)amino]-2-azabicyclo[3.3.1]nonane-
2-carboxylate (19b). A 500 mL round-bottom flask was charged
with 15 (2.02 g, 0.0052 mol) and 2-methyl-2-phenylpropionic acid
(1.73 g, 0.01 mol), and the mixture was dissolved in dry THF (130
mL), followed by the addition of triethylamine (3.60 mL, 26.0
mmol) and BOP reagent (2.60 g, 0.0057 mol). The reaction mixture
was stirred under N2 at room temperature for 4 h. TLC showed
that the starting material was completely consumed. The mixture
was diluted with diethyl ether (130 mL), washed consecutively with
water (150 mL), saturated NaHCO3 (150 mL), and brine (150 mL
× 2), and dried (Na2SO4). The solvent was removed under reduced
pressure, and the product was purified by flash chromatography
(silica gel, 10-25% ethyl acetate in hexanes) to afford the title
compound (2.60 g, 93%) as a white foam. Rotamers of this
compound were observed in the 1H and 13C NMR spectra: 1H NMR
(CDCl3) δ 7.36-7.17 (m, 6H), 6.72-6.64 (m, 3H), 4.76-4.63 (m,
2H), 4.58-4.40 (m, 2H), 3.75-3.57 (m, 2H), 2.47-2.42 (m, 1H),
2.22-2.13 (m, 3H), 1.52 (m, 7H), 1.46 (s, 9H), 1.32 (d, 6H, J )
6.0 Hz), 1.04-0.96 (m, 2H), 0.58 (d, 3H, J ) 6.9 Hz); 13C NMR
(CDCl3) δ 177.1/176.9, 158.2, 155.9/155.5, 150.6/150.5, 145.1,
129.4, 128.9, 127.2, 126.6, 117.6, 113.8, 112.9/112.6, 79.8/79.7,
70.0, 48.4, 47.8/47.4, 47.1/46.8, 46.3, 44.2, 40.3/40.2, 37.4, 36.8/
36.7, 31.4/31.0, 28.7, 27.4/27.2, 22.3, 17.8; MS (APCI) m/z 535.7
(M + H)+.
N-[(1S,4R,5S,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-azabicyclo-
[3.3.1]non-7-yl]-1-phenyl-1-cyclopentanecarboxamide (20a). A
solution of amide 19a (231 mg, 0.412 mmol) in glacial acetic acid
(4 mL) and 48% HBr (4 mL) was heated to reflux for 15 h. The
reaction mixture was allowed to cool to room temperature, and ice
(10 g) was added. The pH of the reaction mixture was adjusted to
14 with 50% NaOH. The aqueous layer was extracted with 3:1
CH2Cl2-THF (30 mL × 3). The organic layer was collected and
dried (Na2SO4), and the solvent was removed under reduced
pressure. The product was purified by flash chromatography [silica
gel, 50% (80% CHCl3, 18% CH3OH, 2% NH4OH) in CHCl3] to
afford the title compound (0.126 g, 73%) as a white solid: 1H NMR
(CD3OD) δ 7.38-7.06 (m, 6H), 6.62-6.57 (m, 3H), 4.79 (m, 1H),
3.60 (dd, 1H, J ) 9.0 Hz, 5.1 Hz), 3.31 (m, 1H), 2.72 (d, 1H, J )
14.1 Hz), 2.49-2.40 (m, 2H), 2.25-1.87 (m, 6H), 1.70-1.56 (m,
5H), 1.48-1.40 (m, 1H), 1.28-1.15 (m, 2H), 0.64 (d, 3H, J ) 7.2
Hz); 13C NMR (CD3OD) δ 177.9, 158.6, 152.7, 145.4, 130.3, 129.4,
127.6, 127.6, 117.0, 113.8, 113.0, 60.7, 49.6, 46.9, 46.3, 41.0, 38.1,
37.9, 37.3, 37.2, 32.0, 24.39, 24.37, 17.6; MS (APCI) m/z 419.7
(M + H)+.
(+)-N-{(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-[3-(2-
methylphenyl)prop-2-en-1-yl]-2-azabicyclo[3.3.1]non-7-yl}-2-
methyl-2-phenylpropanamide (21b). Amine 20b (50 mg, 0.127
mmol) was suspended in DCE (5 mL) under N2, and then trans-
2-methylcinnamaldehyde (18.6 mg, 0.127 mmol) and sodium
triacetoxyborohydride (41 mg, 0.19 mmol) were added to the
reaction mixture. The reaction mixture was stirred at room
temperature for 3 h, when it became a clear solution. The reaction
mixture was diluted with CH2Cl2 and washed with saturated
NaHCO3. The aqueous layer was extracted with CH2Cl2 (10 mL
× 2). The combined organic layers were dried (Na2SO4) and
concentrated under vacuum. The residue was purified by preparative
TLC [silica gel plate, 33% (80% CHCl3, 18% CH3OH, 2% NH4OH)
in CHCl3] to afford the title compound (52 mg, 78%) as a white
solid: 1H NMR (CDCl3) δ 7.40-7.08 (m, 10H), 6.78 (d, 1H, J )
15.9 Hz), 6.64 (m, 3H), 6.11 (dt, 1H, J ) 15.6, 6.3 Hz), 4.78-
4.68 (m, 2H), 4.78-4.68 (m, 2H), 3.36 (m, 2H), 3.27 (br, 1H),
3.08 (m, 1H), 2.78 (d, 1H, J ) 12.0 Hz), 2.43-2.43 (m, 6H), 2.14
(m, 1H), 1.59-1.50 (m, 8H), 0.91 (t, 1H, J ) 12.0 Hz), 0.78 (t,
1H, J ) 12.0 Hz), 0.68 (d, 3H, J ) 6.0 Hz); 13C NMR (CDCl3) δ
177.4, 156.7, 151.4, 145.1, 136.4, 135.5, 130.4, 129.7, 129.0, 128.8,
127.5, 127.3, 126.6, 126.3, 125.9, 117.0, 113.7, 113.1, 112.6, 58.2,
56.2, 53.5, 47.2, 46.8, 45.2, 40.4, 37.7, 32.7, 31.8, 27.4, 27.3, 20.1,
18.8; MS (APCI) m/z 523.4 (M + H)+. The free base (42 mg, 0.080
mmol) was dissolved in CH2Cl2 (3 mL), and to this was added
HCl (1 M solution in diethyl ether, 96 µL, 0.096 mmol). The
reaction mixture was stirred for 15 min, and the solvent was
removed under vacuum. The residue was dried in the vacuum oven
at 50 °C overnight to afford the hydrochloride salt of the title
compound as an off-white powder (40.1 mg, yield 87%): mp
N-[(1S,4R,5S,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-azabicyclo-
[3.3.1]non-7-yl]-2-methyl-2-phenylpropanamide (20b). A solution
of amide 19b (530 mg, 0.991 mmol) in glacial acetic acid (9 mL)
and 48% HBr (9 mL) was heated to reflux for 17.5 h. The reaction
mixture was allowed to cool to room temperature, and ice (25 g)
was added. The pH of the reaction mixture was adjusted to 14 with
50% NaOH. The aqueous layer was extracted with 3:1 CH2Cl2-
THF (50 mL × 3). The organic layer was collected and dried
(Na2SO4), and the solvent was removed under reduced pressure.
The product was purified by flash chromatography [silica gel, 50%
(80% CHCl3, 18% CH3OH, 2% NH4OH) in CHCl3] to afford the
title compound (0.164 g, 42%) as a white solid. The 1H NMR and
13C NMR spectra showed several small peaks, indicating pyridine
impurities: 1H NMR (C5D5N) δ 7.53-7.48 (m, 2H), 7.33-7.28
(m, 3H), 7.24-7.22 (m, 1H), 7.10-7.05 (m, 2H), 6.79 (m, 1H),
6.69 (d, 1H, J ) 8.1 Hz), 5.43-5.28 (m, 1H), 3.78 (dd, 1H, J )
13.5, 4.8 Hz), 3.34 (br, 1H), 2.72-2.62 (m, 2H), 2.36-2.30 (m,
148.5-151.5 °C; [R]20 +27.8° (c 0.74, MeOH). Anal. (C35H43-
D
ClN2O2‚H2O) C, H, N.

5608 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18
Thomas et al.
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(+)-N-{(1S,4R,5R,7S)-5-(3-Hydroxyphenyl)-4-methyl-2-[3-
phenylprop-2-en-1-yl]-2-azabicyclo[3.3.1]non-7-yl}-2-methyl-2-
phenylpropanamide (21c). Amine 20b (51.8 mg, 0.132 mmol)
was suspended in DCE (5 mL) under N2, and then cinnamaldehyde
(17 µL, 0.132 mmol) and sodium triacetoxyborohydride (42 mg,
0.198 mmol) were added to the reaction mixture. The reaction
mixture was stirred at room temperature overnight and became a
clear solution. The reaction mixture was diluted with CH2Cl2 and
washed with saturated NaHCO3. The aqueous layer was extracted
with CH2Cl2 (10 mL × 2). The combined organic layers were dried
(Na2SO4) and concentrated under vacuum. The residue was purified
by preparative TLC [silica gel plate, 25% (80% CHCl3, 18%
CH3OH, 2% NH4OH) in CHCl3] to afford the title compound (60.2
mg, 90%) as a white solid: 1H NMR (CDCl3) δ 7.33-7.06 9m,
11H), 6.66-6.51 (m, 4H), 6.20 (dt, 1H, J ) 8.7, 6.6 Hz), 4.78-
4.65 (m, 2H), 3.34-3.30 (m, 2h), 3.23 (br, 1H), 3.07 (dd, 1H), J
) 12.3, 4.8 Hz), 2.74 (d, 1H, J ) 12.6 Hz), 2.40-2.10 (m, 4H),
1.57-1.45 (m, 7H), 0.83-0.62 (d, 5H); 13C NMR (CDCl3) δ 177.5,
156.8, 151.4, 145.0, 137.2, 132.6, 129.6, 129.0, 128.8, 128.4, 127.6,
127.3, 126.62, 126.55, 116.8, 113.2, 112.7, 57.9, 56.4, 53.1, 47.2,
46.7, 45.2, 40.3, 37.6, 32.6, 31.7, 27.4, 27.3, 18.8; MS (APCI) m/z
509.6 (M + H)+. The free base (60.2 mg, 0.118 mmol) was
dissolved in CH2Cl2 (4 mL), and to this was added HCl (1 M
solution in diethyl ether, 142 µL, 0.142 mmol). The reaction mixture
was stirred for 15 min, and the solvent was removed under vacuum.
The salt was purified twice by adding diethyl ether (8 mL) to its
MeOH (3 mL) solution. The precipitate was filtered and dried in
the vacuum oven at 50 °C overnight to afford the hydrochloride
salt of the title compound as a white powder (52.2 mg, yield
78%): mp 152.5-155 °C; [R]20 +28.8° (c 0.82, MeOH). Anal.
D
(C34H41ClN2O2‚1.25H2O).
Acknowledgment. The National Institute on Drug Abuse
supported this research under Grant DA09045. IUPAC names
for the final compounds and intermediates were obtained from
using ACD software. We thank Dr. Lee-Yuan Liu-Chen, Temple
University School of Medicine, for supplying us the human κ
cell line, and we thank Dr. Larry Toll, SRI International, for
supplying the µ and δ human cell lines.
Supporting Information Available: Results from elemental
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.
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