Opioid affinity and selectivity of 4-hydroxy-3-methoxyindolomorphinan analogues related to naltrindole

Article abstract of DOI:10.1021/jm9807003

To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (μ, κ, δ), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7:2',3'- indolomorphinan (13) was an exception, displaying excellent 5 binding selectivity (δ K(i) = 7 nM, μ/δ = 1900, μ/κ = 1130). GTP-χ-S functional assays showed 13 to be a selective δ antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce μ activity, to obtain increased δ selectivity.

Full text of DOI:10.1021/jm9807003

J . Med. Chem. 1999, 42, 1673-1679
1673
δ Op ioid Affin ity a n d Selectivity of 4-Hyd r oxy-3-m eth oxyin d olom or p h in a n
An a logu es Rela ted to Na ltr in d ole
Andrew Coop,§ Richard B. Rothman,† Christina Dersch,† J ohn Partilla,† Frank Porreca,‡ Peg Davis,‡
Arthur E. J acobson, and Kenner C. Rice*
Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes, Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, Maryland 20892, Clinical Psychopharmacology Section, National Institute on
Drug Abuse, Addiction Research Center, Baltimore, Maryland 21224, and Department of Pharmacology,
University of Arizona Health Sciences Center, Tuscon, Arizona 85724
Received December 11, 1998
To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinity
and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were
prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor
affinity for all three opioid receptors (µ, κ, δ), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-
3-methoxy-6,7:2′,3′-indolomorphinan (13) was an exception, displaying excellent δ binding
selectivity (δ Ki ) 7 nM, µ/δ ) 1900, µ/κ ) 1130). GTP-γ-S functional assays showed 13 to be
a selective δ antagonist, albeit with lower potency than naltrindole. Although the reason for
the unique profile of 13 could not be determined, these results validate our approach of
introducing groups into the indolomorphinans that are known to reduce µ activity, to obtain
increased δ selectivity.
In tr od u ction
indolomorphinans, a series of moderately δ-selective
ligands developed by Portoghese.21 The prototypical
member of this series is the antagonist naltrindole (1)
(Chart 1),21 an indolomorphinan which was prepared
from the nonselective naltrexone (2) by the introduction
of an indolic moiety. This group served to reduce µ and
κ affinity and increase δ affinity, thereby giving a ligand
of moderate binding selectivity (µ/δ ) 120 in our binding
assays).22 Although 1 has found many uses as a phar-
macological tool,23 its high affinity at both µ and κ
receptors limits its utility. Indeed, the κ agonist profile
of 1 can easily be observed in vivo,24 a possible compli-
cation in such studies when high doses are employed.
The discovery of the opioid receptor subtypes mu,
kappa, and delta (µ, κ, δ) and the finding that traditional
opioid analgesics act through the µ receptor1 initially
prompted research into the possibility that κ and δ
agonists could be clinically useful analgesics lacking the
detrimental side effects of µ agonists.2,3 Studies on the
δ receptor have, however, shown that in addition to
analgesia,4,5 the δ receptor is involved in many biological
processes.6 δ Agonists have been shown to have a
stimulatory effect on respiration,7 appear to act as
antidiarrheals without affecting motility in the GI
tract,8,9 and are immunoregulators acting through δ-like
binding sites on the surface of immune cells.10-12 Unlike
Studies aimed at improving the selectivity of the
indolomorphinans have mainly concentrated on modify-
ing the indolic region, as this moiety is the portion of
the ligand that confers the δ selectivity.25-29 However,
it has also been shown that changes in functionality in
the opioid nucleus of the indolomorphinans modify their
degree of selectivity. Loew30 showed that an N-cyclo-
propylmethyl (N-CPM) substituent is superior to an
N-methyl (N-Me) in terms of δ selectivity and, in the
agonist N-Me series, ligands with a 14-hydroxyl group
tend to be 2-3-fold more δ-selective than the corre-
sponding 14-unsubstituted analogues, the latter re-
cently corroborated by Portoghese in the antagonist
N-CPM series.31 On the basis of this work, we became
interested in the systematic introduction of functionality
into the opioid nucleus of 1 that is known to be
detrimental to µ affinity, with the aim of discovering a
group that reduces µ and κ affinity, but not δ, thereby
increasing δ selectivity.
δ agonists which tend to be immunostimulants,13-15
δ
antagonists display potent immunosuppression and
have the potential to be useful medications in transplant
therapy.16-18 It has also been shown that δ antagonists
prevent the development of tolerance and dependence
to µ agonists such as morphine,19 a finding that has
implications for the use of δ antagonists in the treat-
ment of patients requiring chronic administration with
µ agonists. In addition, recent findings that lung cancer
cells express δ receptors, whereas normal lung cells do
not, may allow for novel δ opioid-based diagnostic and
therapeutic strategies in this area.20
Further studies to increase our understanding of the
δ receptor system and its interactions with other
systems in vivo require the development of metabolically
stable non-peptide ligands with high δ selectivity and
good CNS penetration. One of our approaches toward
this goal has been to modify the structure and investi-
gate the structure-activity relationship (SAR) of the
One obvious example would be masking the 3-phenol
as a 3-methoxyl group, a modification shown in other
classes of opioids to reduce µ affinity,32 but previous
work on 3-ethers of the indolomorphinans has led to
conflicting results. In the N-Me series, Loew reported
† National Institute on Drug Abuse.
‡ University of Arizona Health Sciences Center.
§ Current address: Department of Pharmaceutical Sciences, Uni-
versity of Maryland School of Pharmacy, Baltimore, MD 21201.
10.1021/jm9807003 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/14/1999

1674 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9
Brief Articles
Ch a r t 1. Structures of Naltrexone and Naltrindole
Sch em e 1a
Analogues
that 4 lost affinity at all three sites compared to phenol
3 (Chart 1), but the decrease at µ and κ was far greater
than at δ giving rise to increased selectivity,30 whereas
Portoghese reported that in the N-CPM series, masking
the 3-phenol of 1 as a methyl ether led to a ligand with
poor selectivity and activity.21 Although these reports
appear to be contradictory, it is obvious that functional-
ity in the A-ring can influence the δ affinity and
selectivity in the naltrindole series of ligands. This led
us to investigate the effect of introducing both a
4-phenolic and a 3-methoxyl substituent into this series,
as 4-phenolic/3-methoxyl-substituted opioid ligands are
known to possess extremely poor opioid activity in in
vivo assays that predominantly measure µ agonism.33,34
Because of the poor activity, in vitro assays have rarely
been performed, but low µ affinity has been observed.35
It was therefore expected that the combination of a
4-phenolic and 3-methoxyl group would lead to ex-
tremely low µ affinity in the indolomorphinans; because
of the conflicting data above for the 3-ethers, the effect
at δ receptors could not be predicted. This paper
describes the synthesis, binding affinities, and µ/δ
selectivities of a series of 4-phenolic analogues of nal-
trindole leading to the discovery of 13, a highly δ-selec-
tive opioid ligand.
a
Conditions: (a) BuLi, THF; (b) H2/Pd/C (10%), AcOH; (c)
PhNHNH2‚HCl, TsOH, EtOH.
Sch em e 2a
a
Conditions: (a)Zn,HCl,AcOH;(b)Zn,NH4Cl;(c)PhNHNH2‚HCl,
TsOH, EtOH; (d) EtI, DMF, NaHCO3.
Biologica l Resu lts
Ch em istr y
Codeine (5), N-ethylnorcodeine (6),36 and N-cyclopro-
pylmethylnorcodeine (7)37 were converted to the corre-
sponding dihydrothebainones 8-10 by treatment with
BuLi, followed by catalytic hydrogenation.38 Simple
Fischer indole reaction with PhNHNH2‚HCl and TsOH
in EtOH22 gave only the 6,7-fused products 11-13
(Scheme 1). The regiochemistry of the products was
Op ioid Recep tor Bin d in g Assa ys. The binding
affinities of the target compounds for µ and δ receptors
were determined by inhibition of binding of [3H]-
DAMGO44 and [3H]DADLE45 to rat brain membranes.
The affinities of the compounds for κ receptors were
determined by inhibition of binding of [3H]U69,59346 to
guinea pig brain membranes. The results are shown in
Table 1. These data show that the introduction of
both a 4-phenolic and a 3-methyl ether group has a
detrimental effect on affinity at all three opioid recep-
tors for all members of this series compared to the
parent indolomorphinans (1, 3). However, 13 is unique
in this series, the loss of affinity compared to 1 at µ
and κ receptors being greater than the loss at δ, giving
a ligand of excellent selectivity (µ/δ ) 1900, κ/δ )
1130).
1
determined by the presence of a doublet in the H NMR
spectra at 4.75 ppm, a signal that is known to cor-
respond to the equatorial H-5 proton in 4-phenolic
opioids.39
Oxycodone (14) was treated with Zn/HCl/AcOH to give
the corresponding phenol 15,40 and again indole forma-
tion gave only the 6,7-fused isomer 16. N-Norphenol 18
was prepared from noroxycodone (17)41,42 by treatment
with Zn/NH4Cl and converted to N-norindole 19, which
was ethylated to give the N-ethyl (N-Et) analogue 20.
Naltrexone 3-methyl ether (21)43 was converted to 23
under the same conditions as for 14 (Scheme 2).
Bioa ssa ys in Sm ooth Mu scle P r ep a r a tion s a n d
GTP -γ-S Assa ys. Being the most selective compound
in binding assays, 13 was chosen for further evaluation

Brief Articles
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9 1675
Ta ble 1. Opioid Receptor Binding Affinity of 4-Phenolic Analogues of Naltrindole
Ki (nM) ( SEM
selectivity ratio
µ/δ
compound
µa
δb
κc
κ/δ
1, naltrindole
3, oxymorphindole
27.0 ( 1.3
66 ( 5.6
0.22 ( 0.13
0.80 ( 0.10
94 ( 9
515 ( 65
7.0 ( 1.3
218 ( 33
684 ( 40
21.8 ( 7.0
30.4 ( 3.6
123
83
30
138
2700
72
2170 ( 440
11
12
13
16
20
23
2820 ( 850
1350 ( 99
13300 ( 695
2850 ( 25
797 ( 48
>6800
3640 ( 254
7920 ( 890
>6700
>5300
3160 ( 205
3
7
1900
13
1130
31
8
145
1850 ( 382
85
a
b
Displacement of [3H]DAMGO. Displacement of [3H]DADLE. c Displacement of [3H]U69,593.
Ta ble 2. Agonist Activity of 13 in Mouse Vas Deferens and
Guinea Pig Ileum Preparations
in the relative position of the indolic ring by about 2.3
Å,48 possibly explaining the differences observed in the
SAR of the current 4-phenolic ligands and the indolo-
morphinans. For both the N-Me (11, 16) and N-CPM
(13, 23) analogues, it was observed that the presence
of a 14-hydroxyl group was detrimental to δ selectivity
and affinity, an effect particularly marked between the
N-CPM analogues: 14-unsubstituted 13 possesses 3-fold
higher δ affinity and 7-fold lower µ affinity than the 14-
hydroxy 23, leading to a difference in µ/δ selectivity of
22-fold. This contrasts with the findings of both Loew30
and Portoghese,31 who found that a 14-hydroxyl group
enhanced δ selectivity and affinity in the indolomor-
phinans. In addition, we recently reported that an N-Et-
substituted indolomorphinan possessed greater δ bind-
ing selectivity than either the N-Me or N-CPM ana-
logues,49 a finding consistent with the high selectivity
found by Dondio in a related set of N-Et-substituted
opioid ligands.50 In contrast, the N-Et-substituted 4-phe-
nolic ligands (12, 20) display poor δ affinity and
selectivity. These findings suggest that the SAR of the
parent indolomorphinans does not generally apply to the
4-phenolic derivatives.
MVD IC50
GPI IC50
compound
13
SNC80
1, naltrindole
(nM) ( SEM
(nM) ( SEM
187.5 ( 57.9a
2.73 ( 0.48
c, d
532 ( 48b
5457 ( 2052
c
a
Dose-response curve shifted 12.9-fold by 1 mM ICI-174,864.
b Dose-response curve shifted 6-fold by 1 µM naloxone. c Less than
d
20% inhibition. 1 µM naltrindole shifted DPDPE dose-response
curve 2698-fold.
of antagonist and agonist activity on electrically stimu-
lated guinea pig ileal longitudinal muscle myenteric
plexus (GPI) and mouse vas deferens (MVD) smooth
muscle preparations using previously described bioas-
says.47 As can be seen from Table 2, 13 displayed weak
agonist activity in the MVD and very weak agonist
activity in the GPI. The agonist activity in GPI was
somewhat reversed with the µ-preferring antagonist
naloxone (6-fold shift in the dose-response curve)
indicating that the extremely weak agonism in this
tissue was mediated through µ receptors. Challenging
13 in MVD with the δ-selective antagonist ICI-174,864
caused a 12.9-fold shift in the dose-response curve,
indicating a δ agonist effect. The ability of 13 to inhibit
GTP-γ-S binding in guinea pig caudate stimulated by
selective opioid agonists was also determined. As can
be seen from Table 3, 13 acts as a moderately potent δ
antagonist with a selectivity equal to or greater than
that of naltrindole.
The poor activity of 13 in the MVD assay is at odds
with its δ binding affinity. However, it has been noted
that δ-selective opioid ligands with similar binding
affinity in other series also display poor activity in
MVD.51,52 These results suggest that MVD may not be
a reliable functional assay for δ-selective ligands with
single-digit nanomolar affinity. A further complication
of the MVD is the highly oxygenated assay conditions,
possibly giving rise to para-aromatic oxidation53 of 13,
and offers an alternative explanation for the poor
activity of 13. Thus, MVD was not considered a useful
assay for the 4-phenolic ligands, and 13 was evaluated
in the GTP-γ-S assays, which appears to be the func-
tional assay of choice as 13 was shown to be a selective
δ opioid antagonist (>56-fold µ/δ and µ/κ). Consistent
with the binding assays, 13 possessed lower antagonist
potency at all three sites compared to naltrindole.
Unlike the binding assays, the reduction in antagonist
potency was similar at all three receptors (ca. 350-fold),
thereby resulting in a ligand of similar antagonist
selectivity to naltrindole, but greatly reduced potency.
Comparing naltrindole and 13, it can be seen that the
difference in δ antagonist potency (350-fold) is far
greater than their difference in δ binding affinity (30-
fold); thus there also appears to be some discrepancy
between the binding and GTP-γ-S assays. Indeed, all
three assays appear somewhat inconsistent: weak
nonselective δ agonism in MVD, weak selective δ
antagonism in GTP-γ-S, and highly selective δ binding
Discu ssion
The 4-phenolic ligands displayed the expected poor
affinity for µ receptors; however, in general they also
had poor affinity for both κ and δ receptors giving rise
to ligands of reduced affinity and selectivity compared
to the parent indolomorphinans. This would tend to
suggest that the combination of 4-phenol and 3-meth-
oxyl groups is detrimental to δ activity; however, this
is not the case for 13, which has a 30-fold lower δ affinity
than naltrindole but almost 500-fold lower µ affinity,
rendering it one of the most δ opioid-selective non-
peptide ligands yet described as determined in displace-
ment assays (µ/δ ) 1900, κ/δ ) 1130). The reason that
13 possesses such high selectivity whereas the other
members of the series possess poor selectivity is unclear;
molecular modeling (Tripos’ Sybyl) showed negligible
differences between the 4-phenolic ligands, in terms of
the distances between the A-ring, basic nitrogen, and
indolic group. However, it was noted that differences
exist between the 4-phenolic ligands and the indolo-
morphinans; opening of the 4,5-bridge causes a change

1676 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9
Brief Articles
Ta ble 3. Inhibition of Antagonists of GTP-γ-35S Binding in Guinea Pig Caudate Stimulated by µ-, δ-, and κ-Selective Agonists
Ki (nM) ( SD
selectivity ratio
compound
13
1, naltrindole
µa
>1250
3.20 ( 0.20
δb
κc
>1250
8.85 ( 0.82
µ/δ
κ/δ
22.1 ( 2.1
0.062 ( 0.006
>56
52
>56
140
a
b
Antagonism of DAMGO. Antagonism of SNC80. c Antagonism of U69,593.
17-Cyclop r op ylm eth yl-17-n or d ih yd r oth eba in on e (10).
Following the procedure described for 8, compound 737 (3.3 g,
9.7 mmol) was treated with BuLi (2.5 equiv) and hydrogenated
to give the crude product. Column chromatography (SiO2,
CHCl3:MeOH, 19:1) gave 10 (2.5 g, 89%): 1H NMR (CDCl3) δ
6.68 (d, 1H, J ) 8.8 Hz, H-2), 6.59 (d, 1H, J ) 8.8 Hz, H-1),
6.12 (s, 1H, 4-OH), 4.23 (dd, 1H, J ) 13.5, 2.2 Hz, H-5), 3.82
(s, 3H, 3-OCH3), 2.94 (d, 1H, J ) 18.5 Hz, H-10b), 0.92 (m,
1H, H-19), 0.60 (m, 2H, H-20 and H-21), 0.21 (m, 2H, H-20
and H-21); MS m/z (EI) 341 (M+).
in displacement assays. Although the data from MVD
cannot be relied upon due to the reasons given above,
it is possible that 13 is actually a δ agonist but that the
agonism cannot be detected in GTP-γ-S assays con-
ducted with membranes. Indeed, a similar profile was
reported by Childers for µ agonists in GTP-γ-S assays,
where µ partial agonists behaved as µ antagonists in
rat thalamic membranes.54 However, both GTP-γ-S and
binding assays agree that 13 is a δ-selective ligand with
a selectivity equal to or greater than that of naltrindole,
but with reduced δ activity, making 13 a useful new
lead for the discovery of highly selective δ opioid ligands.
In conclusion, our approach to the design of highly
selective δ opioid ligands by introducing groups known
to be detrimental to µ affinity has led to the discovery
of 13, one of the most selective non-peptide δ opioid
ligands yet described.
6,7-Dideh ydr o-4-h ydr oxy-3-m eth oxy-17-m eth yl-6,7:2′,3′-
in d olom or p h in a n (11). A solution of 8 (310 mg, 1.0 mmol),
phenylhydrazine‚HCl (160 mg, 1.1 mmol), and TsOH‚H2O (200
mg, 1.0 mmol) in EtOH (20 mL) was heated at reflux for 3 h.
The cooled reaction mixture was diluted with water (20 mL)
and the solution basified (pH 9) with NH4OH. After removal
of the EtOH, the products were extracted into CHCl3 (3 × 30
mL) and the organic extracts were washed with brine, dried,
and concentrated to give the crude product. Purification by
column chromatography (Al2O3, EtOAc:MeOH, 95:5), followed
by formation of the fumaric acid salt from MeOH, gave 11‚
C4H4O4 (220 mg, 44%): mp 270-272 °C dec; 1H NMR (CDCl3)
δ 7.74 (s, 1H, H-1′), 7.31 (m, 1H, indole ring), 7.23 (m, 1H,
indole ring), 7.09 (m, 2H, indole ring), 6.58 (m, 2H, H-1 and
H-2), 5.93 (s, 1H, 4-OH), 4.75 (d, 1H, J ) 16.7 Hz, H-5), 3.78
(s, 3H, 3-OCH3), 2.43 (s, 3H, H-18); MS m/z (EI) 374 (M+). Anal.
(C26H30N2O6) C, H, N.
Exp er im en ta l Section
Melting points were determined on a Thomas-Hoover capil-
lary melting point apparatus and are uncorrected. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded
in CDCl3 with tetramethylsilane (TMS) as the internal stan-
dard on a Varian Gemini-300 spectrometer. Mass spectra (EI)
were recorded on a VE Analytical 7070E mass spectrometer.
Thin-layer chromatography (TLC) was performed on Analtech
silica gel GHLF-0.25-mm plates. Column chromatography was
performed with Fluka silica gel 60 (mesh 220-240) or neutral
alumina (Brockmann 1, mesh 150). Elemental analyses were
performed by Atlantic Microlabs, Inc., Norcross, GA, and the
results were within (0.4% of the theoretical values. All
extracted solutions were dried over Na2SO4 and concentrated
to dryness on a rotary evaporator under reduced pressure.
With the exception of the preparation of dihydrothebainone,
all reactions are unoptimized.
Dih yd r oth eba in on e (8).38,55 BuLi (1.3 M, 2.8 mL, 3.6
mmol) was added to a solution of codeine (5) (470 mg, 1.6
mmol) in THF (20 mL) at -78 °C. After stirring at -78 °C for
1 h, the light-orange solution was warmed to room tempera-
ture to give a dark-red solution, which was stirred at room
temperature for 20 min and then rapidly quenched with water
(40 mL). The THF was removed, the organic components were
extracted into CHCl3 (3 × 30 mL), and the extracts were then
washed with brine and dried. Removal of the solvent gave
crude thebainone-A (450 mg). The crude thebainone-A was
hydrogenated in AcOH (10 mL) with Pd/C (10%, 40 mg) at 30
psi for 4 h. After completion of the reaction (TLC), the mixture
was diluted with water (20 mL), filtered through Celite, and
basified (pH 9) with NH4OH. The products were extracted into
CHCl3 (3 × 40 mL), and the extracts were washed with brine
and dried. Removal of the solvent and purification as the
hydrochloride salt from acetone gave 8‚HCl (415 mg, 78%):
mp >250 °C. Anal. (C18H24NO3Cl‚0.25H2O) C, H, N.56
6,7-Did eh yd r o-17-et h yl-4-h yd r oxy-3-m et h oxym et h yl-
6,7:2′,3′-in d olom or p h in a n (12). Following the procedure
described for 11, compound 9 (450 mg, 1.4 mmol) was treated
with phenylhydrazine‚HCl (1.1 equiv) and TsOH‚H2O (1 equiv)
for 2 h. The crude product was purified as the hydrated oxalic
acid salt from 2-PrOH/CH2Cl2 (280 mg, 51%): mp 172-173
°C dec; 1H NMR (CDCl3) δ 7.73 (s, 1H, H-1′), 7.30 (m, 1H,
indole ring), 7.23 (m, 1H, indole ring), 7.07 (m, 2H, indole ring),
6.58 (m, 2H, H-1 and H-2), 5.93 (s, 1H, 4-OH), 4.75 (d, 1H, J
) 16.5 Hz, H-5), 3.78 (s, 3H, 3-OCH3), 2.62 (m, 2H, H-18), 1.15
(t, 3H, J ) 6.6 Hz, H-19); MS m/z (EI) 388 (M+). Anal.
(C27H30N2O6‚H2O‚0.25CH2Cl2) C, H, N.
17-Cyclopr opylm eth yl-6,7-dideh ydr o-4-h ydr oxy-3-m eth -
oxy-6,7:2′,3′-in d olom or p h in a n (13). Following the procedure
described for 11, compound 10 (2.5 g, 7.3 mmol) was treated
with phenylhydrazine‚HCl (1.1 equiv) and TsOH‚H2O (1 equiv)
for 2 h. The crude product was purified by column chroma-
tography (SiO2, CHCl3:MeOH:NH3, 19:1:0.1) and then con-
verted to the hydrated (-)-malic acid salt from acetone (1.7 g,
42%): mp 210-211 °C dec; 1H NMR (CDCl3) δ 7.74 (s, 1H,
H-1′), 7.30 (m, 1H, indole ring), 7.23 (m, 1H, indole ring), 7.02
(m, 2H, indole ring), 6.58 (m, 2H, H-1 and H-2), 5.94 (s, 1H,
4-OH), 4.75 (d, 1H, J ) 16.6 Hz, H-5), 3.75 (s, 3H, 3-OCH3),
0.95 (m, 1H, H-19), 0.58 (m, 2H, H-20 and H-21), 0.18 (m, 2H,
H-20 and H-21); MS m/z (EI) 414 (M+). Anal. (C31H36N2O7‚
0.33H2O) C, H, N.
14-Hyd r oxyd ih yd r oth eba in on e (15).55 Zinc dust (2.0 g,
31 mmol) was added in portions over 20 min to a solution of
14‚HCl (2.2 g, 6.3 mmol) in HCl (37%, 2 mL) and AcOH (20
mL) at reflux. After heating at reflux for a further 10 min,
the reaction was cooled by the addition of ice/water (50 mL)
and basified (pH 9) with NH4OH, and the products were
extracted into CHCl3 (3 × 50 mL). The organic extracts were
washed with brine (100 mL), dried, concentrated, and purified
by column chromatography (SiO2, EtOAc:MeOH:NH3, 19:1:0.1)
to give 15 (1.4 g, 71%): 1H NMR (CDCl3) δ 6.67 (d, 1H, J )
8.3 Hz, H-2), 6.58 (d, 1H, J ) 8.3 Hz, H-1), 6.12 (s, 1H, 4-OH),
17-Eth yl-17-n or d ih yd r oth eba in on e (9). Following the
procedure described for 8, compound 636 (3.1 g, 10 mmol) was
treated with BuLi (2.5 equiv) and hydrogenated to give the
crude product. Column chromatography (SiO2, EtOAc:MeOH:
NH3, 19:1:0.1) gave 9 (2.2 g, 71%): 1H NMR (CDCl3) δ 6.68 (d,
1H, J ) 8.8 Hz, H-2), 6.59 (d, 1H, J ) 8.8 Hz, H-1), 6.09 (s,
1H, 4-OH), 4.23 (dd, 1H, J ) 14.2, 2.2 Hz, H-5), 3.83 (s, 3H,
3-OCH3), 2.92 (d, 1H, J ) 18.7 Hz, H-10b), 2.62 (m, 2H, H-18),
1.13 (t, 3H, J ) 6.6 Hz, H-19); MS m/z (EI) 315 (M+).

Brief Articles
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9 1677
3.93 (dd, 1H, J ) 14.2, 2.2 Hz, H-5), 3.62 (s, 3H, 3-OCH3), 2.38
(s, 3H, H-18); MS m/z (EI) 317 (M+).
2H, H-20 and H-21), 0.19 (m, 2H, H-20 and H-21); MS m/z
(EI) 430 (M+). Anal. (C31H36N3O9‚0.5H2O) C, H, N.
6,7-Did eh yd r o-4,14-d ih yd r oxy-3-m et h oxy-17-m et h yl-
6,7:2′,3′-in d olom or p h in a n (16). Following the procedure
described for 11, compound 15 (700 mg, 2.2 mmol) was treated
with phenylhydrazine‚HCl (1.1 equiv) and TsOH‚H2O (1 equiv)
for 2 h. The crude product was purified by column chroma-
tography (SiO2, CHCl3:MeOH:NH3, 19:1:0.1) and then con-
Biologica l Assa ys. 1. Recep tor Bin d in g Assa ys. µ Bind-
ing sites were labeled using [3H]DAMGO (2.0 nM) as previ-
ously described44 with several modifications. Rat membranes
were prepared each day using a partially thawed-frozen rat
brain which was polytroned in 10 mL/brain of ice-cold 10 mM
Tris-HCl, pH 7.0. Membranes were then centrifuged twice at
30000g for 10 min each centrifugation. After the second
centrifugation, the membranes were resuspended in 50 mL/
brain of 25 °C 50 mM Tris-HCl, pH 7.4. Incubations proceeded
for 2 h at 25 °C in 50 mM Tris-HCl, pH 7.4, along with a
protease inhibitor cocktail. The nonspecific binding was de-
termined using 20 µM levallorphan. δ Binding sites were
labeled using [3H]DADLE (2.0 nM) as previously described45
with several modifications. Rat membranes were prepared
each day using a partially thawed-frozen rat brain which was
polytroned in 10 mL/brain of ice-cold 10 mM Tris-HCl, pH 7.0.
Membranes were then centrifuged twice at 30000g for 10 min
each centrifugation. After the second centrifugation, the
membranes were resuspended in 50 mL/brain of 25 °C 50 mM
Tris-HCl, pH 7.4. Incubations proceeded for 2 h at 25 °C in 50
mM Tris-HCl, pH 7.4, containing 100 mM choline chloride, 3
mM MnCl2, 100 nM DAMGO to block µ binding sites, and a
protease inhibitor cocktail. Nonspecific binding was deter-
mined using 20 µM levallorphan. κ 1 binding sites were labeled
using [3H]U69,593 (2.0 nM) as previously described46 with
several modifications. Guinea pig brain membranes were
prepared each day using a partially thawed guinea pig brain
which was polytroned in 10 mL/brain of ice-cold 10 mM Tris-
HCl, pH 7.0. The membranes were then centrifuged twice at
30000g for 10 min each centrifugation. After the second
centrifugation, the membranes were resuspended in 75 mL/
brain of 25 °C 50 mM Tris-HCl, pH 7.4. Incubations proceeded
for 2 h at 25 °C in 50 mM Tris-HCl, pH 7.4, containing 1 µg/
mL captopril and a protease inhibitor cocktail. Nonspecific
binding was determined using 1 µM U69,593. Each tritiated
ligand was displaced by 10 concentrations of test drug, two
times. All drug dilutions were done in 10 mM Tris-HCl, pH
7.4, containing 1 mg/mL bovine serum albumin. The IC50 and
slope factor (N) were obtained by using the program MLAB.
IC50 values were converted to Ki values according to the
equation Ki ) IC50/(1 + [L]/Kd).
2. GP I a n d MVD Bioa ssa ys.47 Electrically induced smooth
muscle contractions of mouse vas deferens and strips of guinea
pig ileum longitudinal muscle myenteric plexus were used.
Tissues came from male ICR mice weighing 25-40 g and male
Hartley guinea pigs weighing 250-500 g. The tissues were
tied to gold chain with suture silk, suspended in 20-mL baths
containing 37 °C oxygenated (95% O2, 5% CO2) Krebs bicar-
bonate solution (magnesium free for the MVD), and allowed
to equilibrate for 15 min. The tissues were then stretched to
optimal length previously determined to be 1 g tension (0.5 g
for MVD) and allowed to equilibrate for 15 min. The tissues
were stimulated transmurally between platinum wire elec-
trodes at 0.1 Hz, 0.4-ms pulses (2-ms pulses for MVD), and
supramaximal voltage. An initial dose-response curve of
DPDPE or PL-017 was constructed at the start of each assay
to establish tissue effects, allowing each tissue to be used as
its own control. Tissues not producing typical results were not
used. Experimental compounds were added to the baths in 14-
60-µL volumes. Succeeding doses of agonist were added
cumulatively to the bath at 3-min intervals to produce a
concentration-response curve. The tissues were then washed
extensively with fresh buffer until the original contraction
height was reestablished. Agonist effects of the compounds at
1 µM were measured as percent inhibition of contraction height
10 min after addition to the bath. Antagonist effects to DPDPE
and PL-017 were assayed after incubation of the tissues with
1 µM concentration of the compound in the bath for 30 min.
The tissues were then washed with fresh buffer for 30 min,
and the agonist dose-response curve was repeated. Rightward
shifts in the dose-response curves were calculated by dividing
the antagonized dose-response curve IC50 value by the un-
i
verted to the fumaric acid salt from PrOH/MeOH (250 mg,
22%): mp >270 °C dec; 1H NMR (CDCl3) δ 7.75 (s, 1H, H-1′),
7.28 (m, 1H, indole ring), 7.22 (m, 1H, indole ring), 7.02 (m,
2H, indole ring), 6.58 (m, 2H, H-1 and H-2), 5.95 (s, 1H, 4-OH),
4.52 (d, 1H, J ) 15.2 Hz, H-5), 3.73 (s, 3H, 3-OCH3), 2.40 (s,
3H, H-18); MS m/z (EI) 390 (M+). Anal. (C28H30N2O7‚0.5MeOH)
C, H, N.
14-Hyd r oxy-17-n or d ih yd r oth eba in on e (18). A mixture
of noroxyoxycodone‚HI (17)41,42 (4.0 g, 9.3 mmol), NH4Cl (5.0
g, 93 mmol), zinc dust (4.0 g, 62 mmol), and EtOH (95%, 60
mL) was heated at reflux for 2.5 h. After cooling, the mixture
was filtered and the solids was washed with NH4OH (8 mL).
The combined filtrate and washings were concentrated, redis-
solved in a mixture of water (12 mL) and NH4OH (8 mL), and
extracted with CHCl3 (25 mL, then 6 × 15 mL). The organic
extracts were dried (MgSO4), and the solvent was removed to
i
give the crude product. Crystallization from PrOH gave 18
1
(1.71 g, 61%): mp 203-205 °C dec; H NMR (CDCl3) δ 6.68
(d, 1H, J ) 8.8 Hz, H-2), 6.57 (d, 1H, J ) 8.8 Hz, H-1), 3.89 (d,
1H, J ) 13.2 Hz, H-5), 3.82 (s, 3H, 3-OCH3); MS m/z (EI) 303
(M+). Anal. (C17H21NO4‚0.2H2O) C, H, N.
6,7-Did eh yd r o-4,14-d ih yd r oxy-3-m eth oxy-6,7:2′,3′-in d o-
lom or p h in a n (19). Following the procedure described for 11,
compound 18 (1.35 g, 4.45 mmol) was treated with phenylhydra-
zine‚HCl (1.1 equiv) and TsOH‚H2O (1 equiv) for 2 h. The crude
product was purified as the hydrated hydrochloride salt from
water (1.05 g, 50%): mp >250 °C dec; 1H NMR (CDCl3) δ 7.80
(s, 1H, H-1′), 7.26 (m, 1H, indole ring), 7.22 (m, 1H, indole
ring), 7.00 (m, 2H, indole ring), 6.59 (m, 2H, H-1 and H-2),
4.59 (d, 1H, J ) 16.5 Hz, H-5), 3.77 (s, 3H, 3-OCH3); MS m/z
(EI) 376 (M+). Anal. (C23H25N2O3‚2.75H2O) C, H, N.
6,7-Did eh yd r o-17-eth yl-4,14-d ih yd r oxy-3-m eth oxy-6,7:
2′,3′-in d olom or p h in a n (20). A mixture of iodoethane (0.07
mL, 0.88 mmol), the hydrochloride salt of 19 (700 mg, 1.5
mmol), NaHCO3 (1 g, 11.9 mmol), and DMF (15 mL) was
stirred at room temperature for 2 h. After quenching with NH4-
OH (20 mL), the products were extracted into Et2O (3 × 30
mL); the organic extracts were washed with brine (3 × 50 mL),
dried, and concentrated to give the crude product. The product
was purified by column chromatography (SiO2, EtOAc), fol-
lowed by formation of the hydrochloride salt from water (245
mg, 59%): mp 210-212 °C dec; 1H NMR (CDCl3) δ 7.76 (s,
1H, H-1′), 7.26 (m, 1H, indole ring), 7.21 (m, 1H, indole ring),
7.02 (m, 2H, indole ring), 6.57 (m, 2H, H-1 and H-2), 5.96 (s,
1H, 4-OH), 4.50 (d, 1H, J ) 15.4 Hz, H-5), 3.77 (s, 3H, 3-OCH3),
2.58 (m, 2H, H-18), 1.13 (t, 3H, J ) 6.6 Hz, H-19); MS m/z
(EI) 404 (M+). Anal. (C25H29N2O3Cl‚2H2O) C, H, N.
17-Cyclop r op ylm eth yl-14-h yd r oxy-17-n or d ih yd r oth e-
ba in on e (22).55 Naltrexone 3-methyl ether‚HCl (21)43 (2.0 g,
5.1 mmol) was treated as 14 above. The crude product was
purified by column chromatography (SiO2, CHCl3:MeOH, 19:
1) to give 22 (1.4 g, 76%): 1H NMR (CDCl3) δ 6.67 (d, 1H, J )
8.3 Hz, H-2), 6.57 (d, 1H, J ) 8.3 Hz, H-1), 6.13 (s, 1H, 4-OH),
3.94 (d, 1H, J ) 12.9 Hz, H-5), 3.81 (s, 3H, 3-OCH3), 0.83 (m,
1H, H-19), 0.55 (m, 2H, H-20 and H-21), 0.18 (m, 2H, H-20
and H-21); MS m/z (EI) 357 (M+).
17-Cyclop r op ylm eth yl-6,7-d id eh yd r o-4,14-d ih yd r oxy-
3-m eth oxy-6,7:2′,3′-in d olom or p h in a n (23). Following the
procedure described for 11, compound 22 (1.4 g, 3.9 mmol) was
treated with phenylhydrazine‚HCl (1.1 equiv) and TsOH‚H2O
(1 equiv) for 2 h. The crude product was purified as the (+)-
i
tartaric acid salt from PrOH (700 mg, 31%): mp 210 °C dec;
1H NMR (CDCl3) δ 7.75 (s, 1H, H-1′), 7.28 (m, 1H, indole ring),
7.22 (m, 1H, indole ring), 6.98 (m, 2H, indole ring), 6.56 (m,
2H, H-1 and H-2), 5.96 (s, 1H, 4-OH), 4.50 (d, 1H, J ) 15.6
Hz, H-5), 3.77 (s, 3H, 3-OCH3), 0.92 (m, 1H, H-19), 0.59 (m,

1678 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9
Brief Articles
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Matsumoto, S. The Immunosuppressive Effect of Delta-Opioid
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1992, 32, 239-269.
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antagonized IC50 value. IC50 values represent the mean of two
to four tissues. IC50 estimates and their associated standard
errors were determined by using a computerized nonlinear
least-squares method.57
3. GTP -γ-35S F u n ction a l Assa ys. Guinea pig caudate
membranes (10 µg) were suspended in 300 µL of buffer
containing 59 mM Tris (pH 7.7 at 25 °C), 100 mM NaCl, 5 µM
MgCl2, 1 mM EDTA, 1 mM DTT, 100 µM GDP, 0.1% BSA,
0.05-0.1 nM [35S]GTP-γ-S, 500 nM or 10 µM agonists, and
varying concentrations (at least 10 different concentrations)
of antagonists. The reaction was initiated by the addition of
membranes and terminated after 4 h by the addition of 3 mL
of cold (4 °C) purified water (Milli-Q UV-Plus, Millipore)
followed by rapid vacuum filtration through Whatman GF/B
filters. The filters were then washed once with 5 mL of cold
water. Bound radioactivity was counted by liquid scintillation
spectroscopy using a Taurus (Micromedic) liquid scintillation
counter at 40% efficiency. Nonspecific binding was determined
in the presence of 10 µM GTP-γ-S. Assays were performed in
triplicate and each experiment was performed at least three
times. The Ki and slope factor were determined using the
program MLAB on a total of 33-44 data points.
Ack n ow led gm en t. We thank Noel Whittaker and
Wesley White for technical assistance and Mallinckrodt
and Co. for the generous gift of the opiates used in this
work.
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(48) Sybyl, version 6.4; Tripos Inc., St. Louis, MO. Compounds were
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Gasteiger-Huckel charges. The A-rings and basic nitrogens of
1 and 13 were overlapped, and the distances between the
centroids of the indolic benzene rings were measured using Sybyl
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(56) Detailed spectral analysis of 8 can be found in ref 39.
(57) MINSQ Least Squares Parameter Estimation, version 3.05;
MicroMath, Inc., 1989.
J M9807003