Pyrrolomorphinans as δ opioid receptor antagonists. The role of steric hindrance in conferring selectivity

Article abstract of DOI:10.1021/jm970189y

A series of 2',3'-disubstituted pyrrolomorphinans (5a-i) were synthesized to determine the role of steric hindrance at μ and γ receptors in promoting δ opioid receptor antagonist selectivity. In smooth muscle preparations, five members of the series (5a-c,e,f) possessed K(e) values in the range 2-15 nM and were 6 selective. Since the unsubstituted analogue 4 possessed δ antagonist potency of similar magnitude, but was not δ selective, it is suggested that the 2',3'substitution confers δ selectivity by hindering the interaction of the pharmacophore at μ and γ receptors, while not affecting δ receptors.

Full text of DOI:10.1021/jm970189y

J . Med. Chem. 1997, 40, 1977-1981
1977
P yr r olom or p h in a n s a s δ Op ioid Recep tor An ta gon ists. Th e Role of Ster ic
Hin d r a n ce in Con fer r in g Selectivity
F. Farouz-Grant and P. S. Portoghese*
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455
Received March 19, 1997X
A series of 2′,3′-disubstituted pyrrolomorphinans (5a -i) were synthesized to determine the
role of steric hindrance at µ and κ receptors in promoting δ opioid receptor antagonist selectivity.
In smooth muscle preparations, five members of the series (5a -c,e,f) possessed Ke values in
the range 2-15 nM and were δ selective. Since the unsubstituted analogue 4 possessed δ
antagonist potency of similar magnitude, but was not δ selective, it is suggested that the 2′,3′-
substitution confers δ selectivity by hindering the interaction of the pharmacophore at µ and
κ receptors, while not affecting δ receptors.
In tr od u ction
substituents attached to the pyrrole moiety in a series
of pyrrolomorphinans (5a -i). Here we describe the
results of this study which support the idea that part
of the δ selectivity of NTI (1) arises from steric hin-
drance by the indolic benzene moiety at µ and δ
receptors.
The design of the prototypical nonpeptide opioid δ
antagonist, naltrindole1 (1, NTI), was based on the
attachment of a “δ address” to the opiate pharmacoph-
ore to confer selectivity. Structure-activity studies in
this series have indicated that two factors contribute
to the high affinity and selectivity for δ receptors.2,3 The
indolic benzene moiety is believed to confer selectivity
by (1) enhancing affinity for the δ receptor and (2) by
decreasing recognition at µ and κ opioid receptors.
The report that the N-methyl-NTI analogue 2 is 9-fold
more potent than its tetrahydro derivative 3 has dem-
onstrated that an aromatic system or its equivalent
plays an important role in the recognition process.3
Moreover, the fact that pyrrolomorphinan 4 is not a δ
selective antagonist and is substantially more potent
at µ and κ receptors than either NTI, 2, or 3 illustrates
that the substitution on the pyrrole “spacer” is essential,
but need not be aromatic to confer δ antagonist selectiv-
ity.4 Thus, it appears that δ selectivity could be
conferred in the absence of an aromatic “address” simply
through a mechanism that involves inhibition of binding
to µ and κ receptors.
Ch em istr y
The rationale for the design of target compounds
involved the attachment of alkyl and phenyl substitu-
ents to the pyrrole moiety in an effort to hinder
recognition at µ and κ receptors. Phenyl substituents
were also introduced for the purpose of mimicking the
“address” of the δ antagonist, BNTX (9).5
The target compounds (5a -i) were synthesized from
the condensation of naltrexone with the corresponding
amino ketones (8a -i) under acidic conditions via the
Knorr reaction6 (Scheme 1). Typically, the reaction was
conducted in a mixture of benzene/DMF and refluxed
in a Dean-Stark apparatus overnight.
The amino ketones (8a -f,h ,i) were derived from the
corresponding N-benzoyl derivatives of alanine, leucine,
and glycine. Ketone 8g was synthesized from N-
acetylphenylglycine. Each N-acyl amino acid was re-
acted with the appropriate organolithium or Grignard
reagent to afford the acylamino ketone (7), which was
then converted to the desired ketone 8 by hydrolysis of
the amide group in 5 N HCl. The synthesis of the
R-amino ketones 8 is similar to that reported by Rapo-
port.7
Biologica l Resu lts
Sm ooth Mu scle P r ep a r a tion s. Pyrrolomorphinans
5a -i were evaluated for antagonist and agonist activi-
ties on the electrically stimulated guinea pig ileum8
(GPI) and mouse vas deferens9 preparations (Table 1).
The ligands (100 nM) were incubated with the prepara-
tions for 15 min prior to testing. The standard agonists,
morphine (M), ethylketazocine (EK), and [D-Ala2,D-
Leu5]enkephalin10 (DADLE) were employed for testing
antagonist potency. They possess pharmacologic selec-
tivity for µ, δ, and κ opioid receptors, respectively. The
antagonist potency is expressed as an IC50 ratio or as a
Ke value. The IC50 ratio represents the agonist potency
in the presence of the test compound divided by the
control IC50 in the same preparation. The Ke values
were calculated from [antagonist]/[ IC50 ratio - 1].
Because the tetramethylene group attached to the
pyrrole “spacer” in 3 appears to confer δ antagonist
selectivity by reducing antagonist potency at µ and κ
receptors, we have investigated the effect of other
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
S0022-2623(97)00189-1 CCC: $14.00 © 1997 American Chemical Society

1978 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Farouz-Grant and Portoghese
Sch em e 1
Ta ble 1. Antagonist Potencies of Pyrrolomorphinans in the MVD and GPI Preparations
DADLE (δ)a
IC50 ratio
M (µ)b
IC50 ratio
EK (κ)b
IC50 ratio
IC50 selectivity ratioc
compound
Ke (nM)
Ke
29
11
158
0.65
Ke
46
20
254
3.2
δ/µ
δ/κ
1 (NTI)d
0.13
0.99
9.2
3.2
6.7
223e
354e
2d
11e
17e
0.03e
8
20e
28e
0.17e
17
3f
4g
5a
5b
5c
5d
5e
5f
5g
5h
16.8 ( 3.2 (5)
50 ( 12 (6)
7.7 ( 2.2 (9)
1.6 ( 0.3 (3)
9.8 ( 2.5 (6)
32 ( 8 (3)
1.4 ( 0.6 (3)
0.76 ( 0.12 (3)
1.5 ( 0.4 (3)
2.1 ( 0.3 (4)
1.3 (2)
1.5 ( 1.0 (3)
0.90 ( 0.19 (3)
0.76 (2)
0.95 ( 0.36 (4)
1.3 (2)
1.4 ( 0.4 (3)
0.98 ( 0.02 (3)
0.99 (2)
2.1
14.8
50
50
5
7
1.6
10
1.6
10
11.4
3.3
h
h
1.2 ( 0.6 (3)
4.1 ( 0.7 (3)
2.3 ( 0.7 (5)
1.1 ( 0.4 (3)
1.3 (2)
2.1 ( 0.8 (5)
1
1
0.2
0.7
2.7
0.2
0.7
18
5i
9i (BNTX)
2.9
8.3
100
a
b
MVD preparation. Morphine (M) or ethylketozacine (EK) in the GPI preparation. c The δ IC50 ratio divided by the µ or κ IC50 ratio.
The IC50 ratio in this calculation is designated as 1 when it is not significantly different from 1. Reference 2. e Ke selectivity ratio ) Keµ
or Keκ divided by Keδ
d
g
h
i
.
f Data from ref 3. Data from ref 4. Full agonist in the GPI, IC50 ) 380 nM (3), 0.68 × morphine. Data from ref
5.
Ta ble 2. Opioid Receptor Binding of Pyrrolomorphinan Derivatives
Ki (nM)a
Ki selectivity ratio
κ/δ
8375
3.3
compound
δ
µ
κ
µ/δ
153
4.8
80
95
7.8
1 (NTI)b
0.040 ( 0.030
12 ( 7
0.35 ( 0.14
0.41 ( 0.10
2.7 ( 1.1
6.1 ( 3.4
57 ( 4
28 ( 3
39 ( 8
21 ( 7
355 ( 22
39 ( 6
41 ( 1
22 ( 2
45 ( 5
5a
5b
5c
5i
117
53.7
16.7
a
b
Values are means ( standard error of the mean of at least three determinations. Data taken from re. 2.
Ligands that were not full agonists were tested at 1 µM,
and the agonist activity was expressed as a percent of
the maximal response.
(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneaceta-
mide14 (U69593) (κ).
The Ki values for the binding of target compounds 5b
and 5c to δ receptors were in the range of 0.3 nM, while
the remaining ligands bound with an order of magni-
tude lower affinity (Table 2). All four compounds were
δ selective, with 5b having the highest selectivity.
Two of the more potent members of the series (5b,f)
exhibited Ke values in the range 2-3 nM, and others
(5a ,c,e) had values in the vicinity of 7-15 nM. The
remainder (5d ,g,h ,i) were virtually inactive as antago-
nists. Except for 5f, which was a full agonist in the GPI
(0.7 × morphine), the compounds were either partial
agonists (GPI or MVD) with not more than 30% maxi-
mal effect or they (5c,d ) induced enhanced contraction
(20-30%) in the MVD.
Bin d in g. Opioid receptor binding for compounds
5a -c,1 were carried out using ICR mouse brain mem-
branes and a modification of an established procedure.11
Binding was determined by competition of the com-
pounds with the selective radioligands: [3H]Naltrin-
dole12 ([3H]NTI) (δ); [3H][D-Ala2,Glyol5]enkephalin13
([3H]DAMGO) (µ); and [3H]-(-)-(5R,7R,8â)-N-methyl[7-
Discu ssion
The results of the present study are in harmony with
an earlier report3 which revealed that the tetrahydroin-
dole 3 is a δ selective opioid antagonist with a potency
one-tenth that of its indole analogue 2. We have found
that members of the pyrrolomorphinan series containing
only alkyl substituents (5a -c,e,f) possessed signifi-
cantly lower antagonist potency at µ and κ receptors
when compared to the unsubstituted analogue 4 (Table
1). Given the fact that the nonselective ligand 4 is as
potent as or more potent than the above compounds as

Pyrrolomorphinans as δ Opioid Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 1979
a δ antagonist,4 it appears that the alkyl substituents
in this series confer δ selectivity by reducing the
antagonism at non δ opioid receptors without signifi-
cantly increasing antagonism at δ receptors.
Interestingly, none of the phenyl-substituted mem-
bers of the series (5d ,g-i) were active as δ opioid
antagonists. This was surprising in view of the struc-
tural similarity to the δ antagonist, BNTX (9). It can
be noted that the phenyl-substituted compounds also
are virtually inactive at µ and κ receptors. These data
suggest that the pyrrolomorphinans and naltrexone
congeners may not interact with δ opioid receptors in
the same way.
In contrast to the phenyl congeners, the benzyl-
substituted derivative 5b was the most potent δ an-
tagonist in the pyrrolomorphinan series and in the
range of BNTX (9). The data suggests that the greater
conformational flexibility of a benzyl versus a phenyl
group may be responsible for the increased potency and
selectivity, and it is consistent with the the idea that
the pyrrole moiety and 6-keto group induce different
modes of interaction of the morphinan component with
δ opioid receptors.
In conclusion, this study supports the idea that the
combination of enhanced affinity for δ receptors and
steric hindrance at µ and κ receptors conferred by the
indolic benzene moiety of NTI (1) is responsible for its
high potency and selectivity. In this regard, alkyl
groups that reduce interaction with µ and κ receptors
(i.e., pyrrolomorphinans 5a -c,e,f) are δ selective, but
they have reduced δ antagonist potency and selectivity
relative to NTI due to the absence of an appropriately
oriented “address” to enhance the binding to δ receptors.
NH), 4.80 (m, 1H, CHCO), 2.60 (m, 2H, CH2CO), 1.66 (m, 2H),
1.47 (d, 3H, J ) 7.50 Hz), 1.33 (m, 2H), 0.91 (t, 3H, J ) 7.50
Hz); 13C NMR (75 MHz, CDCl3) δ 210.22, 167.35 134.70,
132.34, 129.24, 127.62, 55.05, 39.66, 26.36, 22.97, 18.58, 14.50;
HRMS (FAB) 234 (M + H+), calcd 234.1494, obsvd 234.1457;
IR (neat) 3318, 1721, 1637 cm-1
.
(()-4-P h en yl-2-ben za m id o-3-bu ta n on e (7b). Benzoyl-
DL-alanine (1.00 g, 5.2 mmol) was dissolved in 50 mL of dry
THF at -78 °C. To this was added in this order, via syringe,
n-BuLi, 2.5 M in hexane (2.0 equiv 4.2 mL), and BnMgCl, 1.0
M in Et2O (2.0 equiv, 10.4 mL). The experimental and
purification procedures are identical to the ones described for
7a . The desired material was isolated as a white solid in 64%
yield (880 mg, 3.33 mmol): mp 93-95 °C; 1H NMR (300 MHz,
CDCl3) δ 7.80 (d, 2H, J ) 7.20 Hz, Ph), 7.50-7.10 (m, 8H, Ph),
4.90 (m, 1H, CHCO), 3.87 (m, 2H, CH2Ph), 1.49 (d, 3H, J )
7.20 Hz); LRMS (FAB) 268 (M + H+) observed 268.1000.
(()-2-Ben za m id o-3-b u t a n on e (7c). Benzoyl-DL-alanine
(1.00 g, 5.3 mmol) was dissolved in 150 mL of dry THF at -78
°C under N2. To this was added, via a syringe, 11.1 mL (3.0
equiv) of MeLi, 1.4 M in ether. The reaction mixture was
allowed to stir at room temperature overnight. The workup
and purification steps were identical to those for 7a . The
desired amino ketone was isolated as a white-yellowish oil in
58% yield (573 mg, 3 mmol): 1H NMR (300 MHz, CDCl3) δ
7.77 (d, 2H, J ) 7.50 Hz, Ph), 7.34 (m, 3H, Ph), 4.70 (m, 1H,
CH), 2.19 (s, 3H, Me), 1.37 (d, 3H, J ) 7.50 Hz, Me);
HRMS(FAB) 192 (M + H+), calcd 192.1024, obsvd 192.1016.
(()-2-Ben za m id op r op iop h en on e (7d ). Benzoyl-DL-ala-
nine (1.00 g, 5.2 mmol) was dissolved in dry THF (100 mL) at
-78 °C under N2. To this was added, via syringe, n-BuLi, 2.5
M in hexane (2.0 equiv, 4.1 mL), and PhMgBr, 3.0 M in ether,
(2.0 equiv, 3.5 mL). The subsequent experimental conditions
have been described for 7a . The desired product was isolated
in 53% yield (697 mg, 2.8 mmol) as a white oil: 1H NMR (300
MHz, CDCl3) δ 8.06 (d, 2H, J ) 8.40 Hz, Ph), 7.87 (d, 2H, J )
8.40 Hz, Ph), 7.52 (m, 6H, Ph), 5.76 (m, 1H, CHCO), 1.55 (d,
3H, J ) 6.00 Hz); 13C NMR (75 MHz, CDCl3) δ 199.85, 167.28,
134.76, 134.44, 132.37, 129.64, 129.49, 129.27, 129.07, 127.73,
127.46, 126.28, 51.23, 20.63; HRMS (FAB) 254 (M + H+), calcd
254.1181, obsvd 254.1161.
L-2-Meth yl-4-ben za m id o-5-n on a n on e (7e). Benzoyl-L-
leucine (614 mg, 2.8 mmol) was dissolved in dry THF (50 mL)
under N2 at -78 °C. n-BuLi, 2.5 M in hexane (3.0 equiv, 3.4
mL), was syringed in this mixture, and the temperature was
slowly raised to room temperature. The reaction mixture was
stirred for 12 h. The workup and purification steps have been
described for 7a . The desired amino ketone was isolated as
an oil, in 16% yield (116 mg, 0.4 mmol): 1H NMR (300 MHz,
CDCl3) δ 7.81 (d, 1H, J ) 7.50 Hz, Ph), 7.44 (m, 3H, Ph), 6.95
(d, 1H, J ) 7.80 Hz), 4.90 (td, 1H, J ) 3.60, 18.30 Hz, CH),
2.58 (td, 2H, J ) 2.40, 7.20 Hz, CH2), 1.58 (m, 6H, CH2’s), 1.37
(m, 1H, CH), 1.02 (d, 6H, J ) 6.30 Hz, CH3), 0.94 (t, 3H, J )
6.30 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 210.87, 167.86,
134.66, 132.32, 129.24, 127.75, 56.97, 40.99, 39.91, 25.73,
25.19, 23.43, 22.36, 22.02, 13.88.
Exp er im en ta l Section
Melting points were determined in open capillary tubes with
a Thomas-Hoover melting point apparatus and are uncor-
rected. Elemental analyses were performed by M-H-W Labo-
ratories, Phoenix, AZ, and are within 0.4% of the theoretical
values. IR spectra were obtained on a Perkin-Elmer 281
infrared spectrometer, and peak positions are expressed in
cm-1
. NMR spectra were recorded at ambient temperature
on GE-300 MHz and Bruker AC-200 MHz, and chemical shifts
are reported as δ values (ppm) relative to TMS. Mass spectra
were obtained on a VG 7070E-HF instrument. All TLC data
were determined with E. Merck Art. 5554 DC-Alufolien
Kieselgel 60 F254
. Column chromatography was carried out
on E. Merck silica gel 60 (230-400 mesh). The eluents used
during column chromatography and reverse phase HPLC,
CHCl3-MeOH-NH4OH and MeOH-H2O-CH3CN, are de-
noted by CMA and MWA, respectively. Tetrahydrofuran and
benzene were distilled from Na/benzophenone. Dimethylfor-
mamide was distilled from calcium hydride. All other solvents
and reagents were used without any further purifications
unless specified. Benzoylated amino acids were obtained from
Aldrich. Naltrexone hydrochloride salt was provided by
Mallinckrodt.
(()-2-N-Ben za m id o-3-h ep t a n on e (7a ). N-Benzoyl-DL-
alanine (500 mg, 2.64 mmol) was dissolved in 50 mL of dry
THF under N2 at -78 °C. To this was added n-BuLi, 2.5 M in
hexane (3.0 equiv, 3.0 mL), and the reaction mixture was
stirred at -78 °C for 20 min. The reaction mixture was stirred
at room temperature for 2 h. Citric acid 10% was added to
quench the reaction, and ethyl acetate (50 mL) was added. The
organic layer was washed with water, saturated with NaHCO3,
and dried over MgSO4. Upon filtration of MgSO4, the solvent
was evaporated under reduced pressure and the crude material
was eluted on a column chromatography (silica gel) with ethyl
acetate/hexanes (1:5). The desired product was isolated in 52%
yield (70 mg, 0.3 mmol) as a white oil: 1H NMR (300 MHz,
CDCl3) δ 7.81 (m, 2H), 7.44 (m, 3H), 7.13 (d, 1H, J ) 6.00 Hz,
(()-3-Ben za m id o-5-m eth yl-2-h exa n on e (7f). Benzoyl-
DL-leucine (500 mg, 2.1 mmol) was dissolved in dry THF (50
mL) at -78 °C, under N2. To this was added MeLi (4.0 eq,
6.1 mL), and the reaction mixture was allowed to warm up to
room temperature. The experimental conditions have already
been described for 7a . The desired amino ketone was obtained
as an oil in 65% yield (320 mg, 1.4 mmol): 1H NMR (300 MHz,
CDCl3) δ 7.80 (d, 1H, J ) 7.20 Hz, Ph), 7.43 (m, 4H, J ) 7.20
Hz), 4.92 (td, 1H, J ) 3.60, 8.70 Hz, CHN), 2.27 (s, 3H), 1.64
(m, 3H), 1.03 (d, 3H, J ) 6.00 Hz), 0.91 (d, 3H, J ) 6.05 Hz).
(()-Acet a m id op h en yla cet op h en on e (7g). Acetyl-DL-
phenylglycine (1.00 g, 5.3 mmol) was dissolved in 100 mL of
dry THF, under N2, and the temperature was lowered to -78
°C. To this was added, via a syringe, n-BuLi, 2.5 M in hexane
(2.0 equiv, 4.1 mL), and PhMgBr, 3.0 M in Et2O (2.0 equiv,
3.5 mL). The desired product was isolated as a yellow oil in
45% yield (427 mg, 2.12 mmol): 1H NMR (300 MHz, CDCl3) δ
7.98 (d, 2H, J ) 8.70 Hz), 7.50 (m, 8H), 6.59 (d, 1H, J ) 7.20
Hz, CHCO), 2.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 196.50,
169.83, 137.96, 134.89, 134.52, 129.90, 129.87, 129.40, 129.06,

1980 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Farouz-Grant and Portoghese
128.88, 128.64, 128.54, 126.68, 126.09, 59.50, 23.99; HRMS
(FAB) 254 (M + H+), calcd 254.1181, obsvd 254.1163.
1H NMR (300 MHz, methanol-d4) δ 7.96 (d, 2H, J ) 8.40 Hz),
7.45 (m, 8H), 6.24 (s, CHCO); HRMS (FAB) 212 (M+), calcd
212.1075, obsvd 212.1085.
L-2-Meth yl-4-N-ben zoylp en ta p h en on e (7h ). Benzoyl-L-
leucine (1.68 g, 7.2 mmol) was dissolved in dry THF (100 mL)
under N2 at -78 °C. n-BuLi, 2.5 M in hexane, (2.0 equiv, 5.7
mL) was syringed in this mixture, followed by PhMgBr, 3.0
M in ether (2.0 equiv, 4.8 mL), and the temperature was slowly
raised to room temperature. The desired amino ketone was
obtained as an oil (400 mg, 20%): 1H NMR (300 MHz, CDCl3)
δ 8.06 (d, 1H, J ) 7.20 Hz, Ph), 7.86 (d, 1H, J ) 7.20 Hz), 7.43
(m, 8H, aromatic), 5.92 (td, 1H, J ) 3.60, 8.70 Hz, CHN), 1.58
(m, 3H), 1.13 (d, 3H, J ) 6.30 Hz), 0.91 (d, 3H, J ) 6.20 Hz);
HRMS (FAB) 296 (M + H+), calcd 296.1650, obsvd 296.1639.
Ben za m id oa cetop h en on e (7i). Benzoylglycine (1.50 g,
8.4 mmol) was dissolved in dry THF (100 mL) under N2 at
-78 °C. n-BuLi, 2.5 M in hexane (2.0 equiv, 6.7 mL), was
syringed in this mixture, followed by PhMgBr, 3.0 M in ether
(2.0 equiv, 5.6 mL), and the temperature was slowly raised to
room temperature. The desired amino ketone was obtained
as a solid (450 mg, 23%): mp 115-118 °C; 1H NMR (300 MHz,
CDCl3) δ 8.06 (d, 1H, J ) 7.20 Hz), 7.86 (d, 1H, J ) 7.20 Hz),
7.43 (m, 8H, aromatic), 5.51 (d, 1H, J ) 8.70 Hz, CHN); HRMS
(FAB) 240 (M + H+), calcd 240.1024, obsvd 240.1019.
(()-2-Am in o-3-h ep t a n on e H yd r oclor id e (8a ). Com-
pound 7a (70 mg, 0.3 mmol) was dissolved in 35 mL of 6 N
HCl and 5 mL of MeOH. The solution was refluxed for 9 h.
After the aqueous layer was washed with ethyl acetate, water
was removed under vacuum from the aqueous fraction acidic
extracts to afford 8a (27 mg, 55%): 1H NMR (300 MHz,
methanol-d4) δ 4.14 (q, 1H, J ) 7.20 Hz, CH), 2.60 (m, 2H,
COCH2), 1.56 (m, 3H), 1.47 (d, 3H, J ) 7.20 Hz), 0.90 (t, 3H,
J ) 7.50 Hz); 13C NMR (75 MHz, methanol-d4) δ 206.68, 55.05,
38.15, 25.60, 22.42, 14.97, 13.42; HRMS (FAB) 130 (M+) calcd
130.1231, obsvd 130.1240.
L-2-Meth yl-4-a m in op en ta p h en on e Hyd r och lor id e (8h ).
Compound 7h (400 mg, 1.4 mmol) was dissolved in 6 N HCl
(25 mL), refluxed overnight, and worked up as described for
8a to afford 8h (78 mg, 26%): mp 190-192 °C (dec at 180 °C);
1H NMR (300 MHz, methanol-d4) δ 7.43 (m, 5H, Ph), 5.00 (bt,
1H, CHN), 1.55 (m, 3H), 1.10 (d, 6H, J ) 6.30 Hz, CH3); HRMS
(FAB) 192 (M+), calcd 192.1388, obsvd 192.1385.
Am in oa cetop h en on e Hyd r och lor id e (8i). Compound 5i
(210 mg, 0.9 mmol) was dissolved in 6 N MeOH/HCl (1:2),
refluxed overnight, and worked up as described for 8a to afford
8i (150 mg, 95%): mp >210 °C; 1H NMR (300 MHz, CDCl3) δ
8.05-7.50 (m, 10H, Ph), 5.00 (d, 1H, J ) 8.70 Hz, CHN).
17-(Cyclop r op ylm eth yl)-6,7-d eh yd r o-4,5r-ep oxy-3,14-
d ih yd r oxy-2′-m e t h yl-3′-b u t ylp yr r olo[6,7:4′,5′]m or p h i-
n a n (5a ). Compound 8a (220 mg, 1.3 mmol) and naltrexone
hydrochloride (250.9 mg) were dissolved in 70 mL of benzene/
DMF (1:1) in the presence of methanesulfonic acid (1.25 equiv,
107 µL). The reaction mixture was equipped with a Dean-
Stark apparatus and refluxed for 19 h. Upon cooling, ethyl
acetate was added and the organic layer was washed with
saturated NaHCO3 (20 mL) and brine (10 mL). The organic
layer was dried (MgSO4) and filtered, and the solvent was
evaporated under reduced pressure. A TLC plate eluted with
CMA (98:2:0.5) showed a single major product, Rf ) 0.15.
Purification of the crude product was accomplished on a silica
gel column using CMA (99:1:0.5), followed by a florisil column
eluted with CHCl3. The desired product 5a was isolated as
an oil and was crystallized from chloroform/hexane (123.3 mg,
1
49%): mp 118-121 °C; H NMR (300 MHz, CDCl3) δ 8.19 (s,
1H, PhOH), 6.62 (d, 1H, J ) 8.40 Hz, H2, 6H10), 2.71 (m, 2H),
2.53-2.19 (m, 8H), 2.05 (s, 3H, Me-2′), 1.33 (m, 4H, CH2′s),
0.88 (m, 4H, Me H19), 0.55 (m, 2H, H20 H21), 0.16 (m, 2H, H20
H21); 13C NMR (75 MHz, CDCl3) δ 143.26, 139.54, 131.75,
127.05, 125.94, 120.08, 119.38, 119.12, 118.20, 117.65, 87.49,
74.00, 63.07, 60.19, 48.43, 44.33, 34.18, 32.21, 30.01, 24.75,
23.76, 23.45, 14.70 , 11.94, 10.11, 4.68, 4.52; HRMS (FAB) 435
(M + H+), calcd 435.2647, obsvd 435.2644. Anal. (C27H34O3N2)
C, H, N.
1-P h en yl-3-a m in o-2-b u t a n on e H yd r och lor id e (8b ).
Compound 7b (140 mg, 0.5 mmol) was dissolved in a mixture
of 6 N MeOH:HCl (1:3), refluxed for 5 h, and worked up as
described for 8a . The desired product 8b was isolated as a
solid (61 mg, 62%): 1H NMR (300 MHz, methanol-d4) δ 7.26
(m, 5H, Ph), 4.26 (q, 1H, J ) 6.30 Hz), 3.94 (s, 2H), 1.56 (d,
3H, J ) 6.30 Hz); 13C NMR (75 MHz, methanol-d4) δ 204.57,
134.55, 130.45, 129.86, 127.44, 55.07, 46.07, 15.32; HRMS
(FAB) 164 (M + H+) calcd 164.1075, obsvd 164.1072.
17-(Cyclop r op ylm eth yl)-6,7-d eh yd r o-4,5r-ep oxy-3,14-
d ih yd r oxy-2′-m et h yl-3′-b en zylp yr r olo[6,7:4′,5′]m or p h i-
n a n (5b). Compound 8b (200 mg, 1.1 mmol) and naltrexone
hydrochloride (201 mg) were dissolved in 50 mL of benzene/
DMF (1:1) in the presence of methanesulfonic acid (87 µL) and
treated as described for 5a to afford pyrrole 5b (75 mg, 20%):
mp 125-128 °C; 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H,
PhOH), 7.18 (m, 5H, Ph), 6.62 (d, 1H, J ) 8.40 Hz, H2), 6.49
(d, 1H, J ) 8.40 Hz, H1), 5.63 (s, 1H, H5), 3.64 (s, 2H, CH2Ph),
3.21 (d, 1H, J ) 6.30 Hz, H9), 3.08 (d, 1H, J ) 18.30 Hz, H10),
2.75-2.22 (m, 10H), 2.05 (s, 3H, Me-2′), 1.72 (d, 1H, J ) 12.30
Hz, H15), 0.89 (m, 1H, H19), 0.56 (m, 2H, H20 H21), 0.11 (m, 2H,
H20 H21); 13C NMR (75 MHz, CDCl3) δ 142.45, 139.43, 128.86,
128.83, 127.99, 120.54, 119.74, 119.32, 117.49, 116.01, 87.17,
73.84, 62.98, 60.14, 48.51, 44.26, 32.21, 30.70, 30.01, 23.70,
12.15, 10.05, 4.68, 4.52; HRMS (FAB) 469 (M + H+), calcd
469.2491, obsvd 469.2496. Anal. (C30H32N2O3) C, H, N.
17-(Cyclop r op ylm eth yl)-6,7-d eh yd r o-4,5r-ep oxy-3,14-
d ih yd r oxy-2′,3′-d im eth ylp yr r olo[6,7:4′,5′]m or p h in a n (5c).
Compound 8c (300 mg, 2.4 mmol) and naltrexone hydrochlo-
ride (458 mg) were dissolved in 100 mL of benzene/DMF (1:1)
in the presence of methanesulfonic acid (87 µL) and treated
as described for 5a to afford the desired pyrrole 5c (282 mg,
(()-2-Am in o-3-b u t a n on e H yd r och lor id e (8c). Com-
pound 7c (573 mg, 3 mmol) was dissolved in a mixture of 6 N
MeOH:HCl (2:3), refluxed for 10 h, and worked up as described
for 7a to afford the desired product 8c: yield 230 mg (75%);
1
mp 115-117 °C; H NMR (300 MHz, methanol-d4) δ 3.65 (m,
1H, CH), 3.24 (s, 3H, Me), 1.35 (d, 3H, J ) 6.35 Hz, Me); LRMS
(FAB) 73.3 (M+ - Me).
(()-2-Am in op r op iop h en on e Hyd r och lor id e (8d ). Com-
pound 7d (697 mg, 2.8 mmol) was dissolved in 6 N HCl (30
mL), refluxed for 2 days, and worked up as described for 7a
to afford 8d : yield 310 mg (60%); mp 166-170 °C, 1H NMR
(300 MHz, methanol-d4) δ 8.04 (d, 2H, J ) 8.70 Hz, Ph), 7.69
(m, 1H, Ph), 7.59 (m, 2H, Ph), 5.15 (bq, 1H, J ) 6.90 Hz, CHN),
1.53 (d, 1H, J ) 7.20 Hz); 13C NMR (75 MHz, methanol-d4) δ
196.60, 135.04, 133.47, 129.92, 129.46, 52.133, 17.01; HRMS
(FAB) 150 (M+), calcd 150.0918, obsvd 150.0915.
(()-2-Meth yl-4-a m in o-5-n on a n on e Hyd r och lor id e (8e).
Compound 7e (108 mg, 0.4 mmol) was dissolved in 6 N HCl
(30 mL), refluxed for 10 h, and worked up as described for 7a
to afford the desired compound 8e as a gum (40 mg, 50%): 1H
NMR (300 MHz, methanol-d4) δ 3.99 (dd, 1H, J ) 3.60, 8.40
Hz, CH), 2.51 (m, 2H, CH2), 1.55 (m, 6H, CH2’s), 1.28 (m, 1H,
CH), 0.98 (t, 6H, J ) 6.30 Hz, CH3), 0.87 (t, 3H, J ) 7.20 Hz,
CH3); HRMS (FAB) 172 (M+), calcd 172.1701, obsvd 172.1699.
(()-2-Meth yl-4-a m in o-5-h exa n on e Hyd r och lor id e (8f).
Compound 7f (300 mg, 1.3 mmol) was dissolved in 6 N HCl
(20 mL), refluxed for 12 h, and worked up as described for 8a
to afford 8f (213 mg, 99%) as a plastic solid: 1H NMR (300
MHz, methanol-d4) δ 3.95 (t, 1H, J ) 3.65 Hz), 2.86 (s, 3H,
Me), 1.54 (m, 3H), 0.95 (t, 6H, J ) 6.45 Hz).
1
30%): mp 130-132 °C; H NMR (300 MHz, CDCl3) δ 8.09 (s,
1H, PhOH), 6.64 (d, 1H, J ) 8.40 Hz, H2), 6.53 (d, 1H, J )
8.40 Hz, H1), 5.58 (s, 1H, H5), 3.29 (d, 1H, J ) 6.00 Hz, H9),
3.11 (d, 1H, J ) 18.30 Hz, H10), 2.72 (m, 2H), 2.45-2.28 (m,
10H), 2.04 (s, 3H, Me-2′), 1.79 (s, 3H, Me-3′), 1.28 (m, 1H),
0.85 (m, 1H, H19), 0.56 (m, 2H, H20 H21), 0.13 (m, 2H, H20 H21);
13C NMR (75 MHz, CDCl3) δ 143.39, 139.62, 131.76, 127.04,
125.94, 120.16, 119.38, 119.27, 117.54, 112.68, 87.30, 73.79,
62.99, 60.13, 48.46, 44.37, 32.18, 29.98, 23.76, 11.84, 10.06,
9.32, 4.71, 4.44; HRMS (FAB) 393 (M + H+) calcd 393.2178,
obsvd 393.2185. Anal. (C24H28O3N2) C, H, N.
(()-2-(Am in op h en yla cetyl)a cetop h en on e Hyd r och lo-
r id e (8g). Compound 7g (327 mg, 1.3 mmol) was dissolved
in 6 N HCl (30 mL), refluxed for 12 h, and worked up as
described for 8a to afford 8g (180 mg, 56%): mp 210-215 °C;
17-(Cyclop r op ylm eth yl)-6,7-d eh yd r o-4,5r-ep oxy-3,14-
d ih yd r oxy-2′-m et h yl-3′-p h en ylp yr r olo[6,7:4′,5′]m or p h i-

Pyrrolomorphinans as δ Opioid Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 1981
n a n (5d ). Compound 8d (310 mg, 1.7 mmol) and naltrexone
hydrochloride (315 mg) were dissolved in 50 mL of benzene/
DMF (1:1) in the presence of methanesulfonic acid (135 µL)
and treated as detailed for 5a to afford pyrrole 5d (93 mg,
13%): mp 164-166 °C (start dec 157 °C); 1H NMR (300 MHz,
CDCl3) δ 8.64 (s, 1H, PhOH), 7.29 (m, 2H), 7.17 (m, 3H), 6.68
(d, 1H, J ) 7.50 Hz, H2), 6.57 (d, 1H, J ) 7.55 Hz, H1), 5.72 (s,
1H, H5), 3.28 (d, 1H, J ) 6.30 Hz, H9), 3.12 (d, 1H, J ) 18.30
Hz, H10), 2.79-2.27 (m, 10H), 2.13 (s, 3H, Me-2′), 1.75 (m, 1H),
0.87 (m,1H, H19), 0.54 (m, 2H, H21 and H20), 0.13 (m, 2H, H21
and H20); 13C NMR (75 MHz, CDCl3) δ 143.49, 139.68, 136.55,
131.70, 130.05, 128.73, 127.95, 125.95, 121.30, 120.36, 119.58,
118.52, 117.84, 87.04, 74.06, 62.65,60.03, 48.47, 44.43, 32.25,
30.63, 23.72, 12.70, 10.02, 4.85, 4.30; HRMS (FAB) 455 (M +
H+), calcd 455.2334, obsvd 455.2345. Anal. (C29H30O3N2) C,
H, N.
17-(Cyclop r op ylm eth yl)-6,7-d eh yd r o-4,5r-ep oxy-3,14-
d ih yd r oxy-2′-isob u t yl-3′-b u t ylp yr r olo[6,7:4′,5′]m or p h i-
n a n (5e). Compound 8e (40 mg, 0.2 mmol) and naltrexone
hydrochloride salt (72 mg) were dissolved in 20 mL of benzene/
DMF (1:1) in the presence of methanesulfonic acid (12 µL) and
treated as described for 5a to afford pyrrole 5e as an oil (28
mg, 30%): 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H, PhOH),
6.68 (d, 1H, J ) 8.70 Hz, H2), 6.57 (d, 1H, J ) 8.60 Hz, H1),
5.59 (s, 1H, H5), 3.28 (d, 1H, J ) 5.10 Hz, H9), 3.12 (d, 1H, J
) 19.50 Hz, H10), 2.80-2.69 (m, 2H), 2.51-2.14 (m, 10H), 1.71
(m, 2H), 1.30 (m, 5H, CH CH2’s), 0.87 (m, 10H, 3Me H19), 0.54
(m, 2H, H20 H21), 0.14 (m, 2H, H20 H21); 13C NMR (75 MHz,
CDCl3) δ 143.26, 139.42, 131.76, 130.80, 126.12, 120.21, 119.30,
119.15, 118.61, 117.27, 87.70, 73.81, 63.02, 60.13, 48.43, 44.34,
36.04, 34.39, 32.29, 30.08, 29.93, 24.86, 23.73, 23.63, 23.36,
14.68, 10.08, 4.71, 4.46; HRMS (FAB) 477 (M + H+), calcd
477.3117, obsvd 477.3136. Anal. (C30H40O3N2).
8.40 Hz, H2), 6.57 (d, 1H, J ) 8.40 Hz, H1), 5.62 (s, 1H, H5),
3.25 (d, 1H, J ) 6.00 Hz, H9), 3.10 (d, 1H, J ) 18.30 Hz, H10),
2.74 (m, 2H), 2.48-2.29 (m, 10H), 1.75 (m, 1H, H15), 0.86 (m,
1H, H19), 0.84 (d, 3H, J ) 6.00 Hz, CH3), 0.80 (d, 3H, J ) 6.00
Hz, CH3), 0.53 (m, 2H, H20 H21), 0.12 (m, 2H, H20 H21); 13C NMR
(75 MHz, CDCl3) δ 139.28, 136.62, 135.25, 131.68, 131.53,
130.29, 128.57, 126.30, 125.99, 121.19, 121.05, 119.30, 118.59,
117.17, 87.15, 73.68, 62.56, 59.95, 48.51, 44.39, 36.01, 32.19,
30.40, 29.80, 23.60, 23.32, 23.11, 9.93, 4.81, 4.18; HRMS (FAB)
497 (M + H+), calcd 497.2804, obsvd 497.2786. Anal.
(C32H36O3N2).
17-(Cyclop r op ylm eth yl)-6,7-d eh yd r o-4,5r-ep oxy-3,14-
d ih yd r oxy-2′,3′-p h en ylp yr r olo[6,7:4′,5′]m or p h in a n (5i).
Compound 8i (150 mg, 0.9 mmol) and naltrexone hydrochloride
(167 mg) were dissolved in 50 mL of benzene/DMF (1:1) in the
presence of methanesulfonic acid (60 µL) and treated as
described for 8a to afford pyrrole 5i (25 mg, 13%): mp 168-
1
171 °C (155 °C); H NMR (300 MHz, CDCl3) δ 8.60 (bs, 1H,
PhOH), 7.15 (m, 5H, Ph), 6.84 (bs, 1H, H2′), 6.65 (d, 1H, J )
8.40 Hz, H2), 6.58 (d, 1H, J ) 8.40 Hz, H1), 5.66 (s, 1H, H5),
3.32 (d, 1H, J ) 6.00 Hz, H9), 3.14 (d, 1H, J ) 18.30 Hz, H10),
2.70 (m, 4H), 2.38 (m, 5H), 1.75 (d, 1H, J ) 10.20 Hz), 0.86
(m, 1H, H19), 0.56 (m, 2H, H20 H21), 0.13 (m, 2H, H20 H21); 13
C
NMR (300 MHz, CDCl3) δ 143.53, 139.54, 136.49, 131.45,
128.95, 128.10, 126.09, 124.16, 123.99, 119.66, 118.70, 117.77,
86.67, 73.79, 62.63, 60.01, 48.35, 44.42, 32.16, 30.97, 23.71,
9.95, 4.91, 4.26; HRMS (FAB) 441 (M + H+), calcd 441.2178,
obsvd 441.2207. Anal. (C28H28O3N2).
Ack n ow led gm en t. This research was supported by
the National Institute on Drug Abuse. We thank
Michael Powers and Veronika Phillips for their capable
technical assistance in biological testing.
17-(Cyclop r op ylm eth yl)-6,7-d eh yd r o-4,5r-ep oxy-3,14-
d ih yd r oxy-2′-isobu tyl-3′-m eth ylp yr r olo[6,7:4′,5′]m or p h i-
n a n (5f). Compound 8f (275 mg, 1.7 mmol) and naltrexone
hydrochloride (629 mg) were dissolved in 45 mL of benzene/
DMF (1:1) in the presence of methanesulfonic acid (1.0 equiv,
107 µL) and treated as described for 5a to afford pyrrole 5f
Refer en ces
(1) Portoghese, P. S.; Sultana, M.; Nagase, H.; Takemori, A. E.
Application of the Message-Address Concept in the Design of
Highly Potent and Selective non-Peptide δ-Opioid Receptor
Antagonists. J . Med. Chem. 1988, 31, 281-282.
(2) Portoghese, P. S.; Sultana, M.; Takemori, A. E. Design of
Peptidomimetic δ Opioid Receptor Antagonists Using the Mes-
sage-Address Concept. J . Med. Chem. 1990, 33, 1714-1720.
(3) Portoghese, P. S.; Nagase, H.; MaloneyHuss, K. E.; Lin, C.-E.;
Takemori, A. E. Role of Spacer and Address Components in
Peptidomimetic δ Opioid Receptor Antagonists Related to Nal-
trindole. J . Med. Chem. 1991, 34, 1715-1720.
(4) Portoghese, P. S.; Nagase, H.; Lipkowski, A.; Larson, D. L.;
Takemori, A. E. Binaltorphimine-Related Ligands and Their κ
Opioid Receptor Antagonist Selectivity. J . Med. Chem. 1988, 31,
836-841.
(5) Portoghese, P. S., Sultana, M.; Nagase, H.; Takemori, A. E. A
Highly Selective δ1-Opioid Receptor Antagonist: 7-benzylidenen-
altrexone. Eur. J . Pharmacol. 1992, 218, 195-196.
(6) Gilchrist, T. L. Heterocyclic Chemistry, 2nd ed.; J ohn Wiley &
Sons: New York, 1992.
(7) Rapoport, H.; Knudsen, C. G. R-Amino Acids as Chiral Educts
for Asymmetric Products. J . Org. Chem. 1983, 48, 2260-2266.
(8) Rang, H. P. Stimulant Actions of Volatile Anaesthetics on
Smooth Muscle. J . Pharmacol. Chemother. 1965, 22, 356-365.
(9) Henderson, G.; Hughes, J .; Kosterlitz, H. W. A New Example of
a Morphine-Sensitive Neuro-Effector Junction: Adrenergic Trans-
mission in the Mouse Vas Deferens. Br. J . Pharmacol. 1972, 46,
746-766.
(10) Fournie-Zaluski, M.-C.; Gacel, G.; Maigret, B.; Premilat, S.;
Roques, B. P. Structural Requirements for Specific Recognition
of Mu or Delta Opiate Receptors. Mol. Pharmacol. 1981, 20,
484-491.
1
(210 mg, 30%): mp 114-116 °C; H NMR (300 MHz, CDCl3)
δ 8.06 (s, 1H, PhOH), 6.63 (d, 1H, J ) 7.50 Hz, H2), 6.53 (d,
1H, J ) 7.50 Hz, H1), 5.59 (s, 1H, H5), 3.26 (d, 1H, J ) 6.30
Hz, H9), 3.06 (d, 1H, J ) 18.30 Hz, H10), 2.70 (m, 2H), 2.50-
2.24 (m, 8H), 1.79 (s, 3H, Me), 1.69 (m, 4H, CH H15 CH2), 0.88
(m, 1H, H19), 0.83 (d, 3H, J ) 2.40 Hz, Me), 0.81 (d, 3H, J )
2.40 Hz, Me), 0.53 (m, 2H, H20 H21), 0.13 (m, 2H, H20 H21); 13
C
NMR (75 MHz, CDCl3) δ 143.24, 139.48, 131.79, 131.06,
126.09, 120.14, 119.35, 119.24, 117.39, 113.03, 87.59, 73.73,
62.90, 60.08, 48.48, 44.37, 36.04, 32.18, 30.05, 29.96, 23.76,
23.29, 23.16, 10.01, 9.51, 4.76, 4.39; HRMS (FAB) 435 (M +
H+), calcd 435.2647, obsvd 435.2652. Anal. (C27H34O3N2‚H2O)
C, H, N.
17-(Cyclop r op ylm eth yl)-6,7-d eh yd r o-4,5r-ep oxy-3,14-
d ih yd r oxy-2′,3′-d ip h en ylp yr r olo[6,7:4′,5′]m or p h in a n (5g).
Compound 8g (180 mg, 0.7 mmol) and naltrexone hydrochlo-
ride (137 mg) were dissolved in 40 mL of benzene/DMF (1:1)
in the presence of methanesulfonic acid (59 µL) and treated
as described for 5a to afford pyrrole 5g (72 mg, 30%): mp dec
1
185 °C; NMR (300 MHz, CDCl3) δ 8.79 (s, 1H, PhOH), 7.15
(m, 10H), 6.71 (d, 1H, J ) 8.40 Hz, H2), 6.58 (d, 1H, J ) 8.40
Hz, H1), 5.72 (s, 1H, H5), 3.27 (d, 1H, J ) 6.30 Hz, H9), 3.10
(d, 1H, J ) 18.33 Hz, H10), 2.74-2.26 (m, 10H), 1.75 (d, 1H, J
) 10.80 Hz, H15), 0.86 (m, 1H, H19), 0.56 (m, 2H, H21 H20), 0.15
(m, 2H, H20 H21); 13C NMR (75 MHz, CDCl3) δ 143.26, 139.40,
136.17, 133.53, 131.50, 131.47, 130.79, 129.04, 128.78, 127.68,
127.09, 126.49, 126.13, 123.42, 121.06, 120.37, 119.88, 117.64,
87.04, 73.73, 62.53, 60.01, 48.56, 44.44, 32.16, 30.32, 23.65,
9.93, 4.91, 4.26; HRMS (FAB) 517 (M + H+), calcd 517.2491,
obsvd 517.2473. Anal. (C34H32O3N2).
(11) Werling, L. L.; Zarr, G. D.; Brown, S. R.; Cox, B. M. Opioid
Binding to Rat and Guinea Pig Neural Membranes in the
Presence of Physiological Cations at 37 °C. J . Pharmacol. Exp.
Ther. 1986, 233, 722-728.
(12) Yamamura, M. S.; Horvath, R.; Toth, G.; Otvos, F.; Malatynska,
E.; Knapp, R. J .; Porreca, F.; Hruby, V. J .; Yamamura, H. I.
Characterization of [3H]Naltrindole Binding to Delta Opioid
Receptors in Rat Brain. Life Sci. 1992, 50, 119-124.
(13) Handa, B. K.; Lane, A. C.; Lord, J . A. H.; Morgan, B. A.; Rance,
M. J .; Smith, C. F. C. Analogs of â-LPH61-64 Possessing
Selective Agonist Activity at Mu-Opiate Receptors. Eur. J .
Pharmacol. 1981, 70, 531-540.
17-(Cyclop r op ylm eth yl)-6,7-d eh yd r o-4,5r-ep oxy-3,14-
d ih yd r oxy-2′-isobu tyl-3′-p h en ylp yr r olo[6,7:4′,5′]m or p h i-
n a n (5h ). Compound 8h (80 mg, 0.4 mmol) and naltrexone
hydrochloride (67 mg) were dissolved in 30 mL of benzene/
DMF (1:1) in the presence of methanesulfonic acid (29 µL) and
treated as described for 5a to afford pyrrole 5h (30 mg, 20%):
mp 150-152 °C; 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H,
PhOH), 7.27 (m, 3H, Ph), 7.17 (m, 2H, Ph), 6.70 (d, 1H, J )
(14) Lahti, R. A.; Mickleson, M. M.; McCall, J . M.; von Voigtlander,
P. F. [3H]U69593, A Highly Selective Ligand for the Opioid κ
Receptor. Eur. J . Pharmacol. 1985, 109, 281-284.
J M970189Y