Synthesis and biological evaluation of 14-alkoxymorphinans 21. Novel 4-alkoxy and 14-phenylpropoxy derivatives of the μ opioid receptor antagonist cyprodime

Article abstract of DOI:10.1021/jm031126k

The synthesis, biological, and pharmacological evaluation of novel derivatives of cyprodime are described. Their binding affinities at μ, δ, and κ opioid receptors were evaluated using receptor binding assay. It was observed that the affinity of these compounds was sensitive to the character and length of the substituent in position 4. Further prolongation of the 4-alkoxy group of cyprodime (1) and its 4-butoxy analogue 2 is detrimental for the μ opioid receptor affinity. Introduction of an arylalkoxy group at C-4 does not increase μ affinity in the case of benzyloxy, while a phenylpropoxy group reduces μ affinity. The δ and κ affinities were also reduced compared to the reference compounds. A significant increase in the affinity at the μ opioid receptors was achieved by introducing a 14-phenylpropoxy group. Increases in the affinity at δ and κ receptors were also observed. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. In the [ ³⁵S]GTPγS binding assay, all tested compounds were partial agonists at μ and δ receptors. Compounds 8 and 17 showed antagonism at κ receptors, while compound 7 exhibited some partial agonist activity at this receptor. The novel derivatives of cyprodime containing a 14-phenylpropoxy group acted as potent antinociceptives. When tested in vivo, compounds 7, 8, and 17 were considerably more potent than morphine, with phenol 7 showing the highest antinociceptive potency (21-fold in the hot plate test, 38-fold in the tail flick test, and 300-fold in the paraphenylquinone writhing test) in mice. Introduction of a 14-phenylpropoxy substituent leads to a profound alteration in the pharmacological profile of this class of compounds.

Full text of DOI:10.1021/jm031126k

3242
J . Med. Chem. 2004, 47, 3242-3247
Syn th esis a n d Biologica l Eva lu a tion of 14-Alk oxym or p h in a n s. 21.1 Novel
4-Alk oxy a n d 14-P h en ylp r op oxy Der iva tives of th e µ Op ioid Recep tor
An ta gon ist Cyp r od im e
Mariana Spetea,# Falko Schu¨llner,# Radu C. Moisa,‡ Ilona P. Berzetei-Gurske,‡ Barbara Schraml,#
Cynthia Do¨rfler,# Mario D. Aceto,† Louis S. Harris,† Andrew Coop,§ and Helmut Schmidhammer*,#
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52a,
A-6020 Innsbruck, Austria, Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck,
Peter-Mayr-Strasse 1, A-6020 Innsbruck, Austria, SRI International, Biosciences Division, 333 Ravenswood Avenue,
Menlo Park, California 94025, Department of Pharmacology and Toxicology, Medical College of Virginia,
Virginia Commonwealth University, Richmond, Virginia 23298-0613, and Department of Pharmaceutical Sciences,
School of Pharmacy, University of Maryland, Baltimore, Maryland 21201
Received December 4, 2003
The synthesis, biological, and pharmacological evaluation of novel derivatives of cyprodime
are described. Their binding affinities at µ, δ, and κ opioid receptors were evaluated using
receptor binding assay. It was observed that the affinity of these compounds was sensitive to
the character and length of the substituent in position 4. Further prolongation of the 4-alkoxy
group of cyprodime (1) and its 4-butoxy analogue 2 is detrimental for the µ opioid receptor
affinity. Introduction of an arylalkoxy group at C-4 does not increase µ affinity in the case of
benzyloxy, while a phenylpropoxy group reduces µ affinity. The δ and κ affinities were also
reduced compared to the reference compounds. A significant increase in the affinity at the µ
opioid receptors was achieved by introducing a 14-phenylpropoxy group. Increases in the affinity
at δ and κ receptors were also observed. These findings provide further evidence that the nature
of the substituent at position 14 has a major impact on the abilities of morphinans to interact
with opioid receptors. In the [35S]GTPγS binding assay, all tested compounds were partial
agonists at µ and δ receptors. Compounds 8 and 17 showed antagonism at κ receptors, while
compound 7 exhibited some partial agonist activity at this receptor. The novel derivatives of
cyprodime containing a 14-phenylpropoxy group acted as potent antinociceptives. When tested
in vivo, compounds 7, 8, and 17 were considerably more potent than morphine, with phenol 7
showing the highest antinociceptive potency (21-fold in the hot plate test, 38-fold in the tail
flick test, and 300-fold in the paraphenylquinone writhing test) in mice. Introduction of a 14-
phenylpropoxy substituent leads to a profound alteration in the pharmacological profile of this
class of compounds.
In tr od u ction
Removing the 6-keto function in cyprodime produced
only a small reduction in µ antagonist potency but was
accompanied by an increase in κ and δ antagonist
potency, resulting in a decrease of µ selectivity.13 An
extensive study on cyprodime-related compounds re-
vealed that several modifications to the cyprodime
molecule (e.g., an additional methoxy group at C-3,
different substituents at C-4, a 14-ethoxy group, an
N-allyl group) yielded compounds with either less µ
selectivity or partial agonist activity.14 Increasing the
chain length at C-4 by introduction of a butoxy group
(compound 2, Figure 1) resulted in increased affinity
at µ receptors (ca. 2-fold) but very little change in either
selectivity or intrinsic activity. Introduction of a hydroxy
group at C-3 of cyprodime and analogues markedly
enhanced affinity at all three opioid receptor types and
retained pure antagonism, while selectivity for the µ
opioid receptor was reduced.15
Cyprodime (1) was reported as the first nonpeptidic,
competitively pure and specific µ opioid receptor an-
tagonist.2 Although cyprodime shows lower affinity at
the µ opioid receptor than naloxone, its significantly
increased µ selectivity makes it a very valuable tool in
opioid research.3-9 Cyprodime has been prepared in
tritium-labeled form and has become a useful tool for
radioligand binding assays especially because it is
commercially available.10 Cyprodime was shown to
antagonize sufentanil-induced respiratory depression in
the dog.11 Coadministration of cyprodime with levodopa
decreased dyskinesia in a primate model of Parkinson’s
disease without attenuation of the anti-Parkinsonian
actions of levodopa.12
This paper is dedicated to Dr. Arnold Brossi on the occasion of
his 80th birthday and to Prof. Dr. Leendert Maat on the occasion of
his 70th birthday.
In an effort to investigate the effect of a further
increase of the chain length at C-4 on opioid binding
properties, we have synthesized 4-phenylpropoxy-, 4-ben-
zyloxy-, and 4-hexyloxy-substituted cyprodime deriva-
tives (compounds 4-6; Figure 1). A 14-phenylpropoxy
group was very recently found to significantly increase
* To whom correspondence should be addressed. Phone: (43) 512-
507-5248. Fax: (43) 512-507-2940. E-mail: Helmut.Schmidhammer@
uibk.ac.at.
#
University of Innsbruck.
‡ SRI International.
† Virginia Commonwealth University.
§ University of Maryland.
10.1021/jm031126k CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/08/2004

14-Alkoxymorphinans
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3243
Sch em e 1
F igu r e 1.
binding affinities of morphinan-6-ones at all three opioid
receptor types.16,17 In addition, it became apparent that
a 14-phenylpropoxy group gives rise to highly potent
analgesics also in morphinan-6-ones having a cyclopro-
pylmethyl or allyl group at the morphinan nitrogen.16
Another aim of the study was to investigate whether a
14-phenylpropoxy group would also convert cyprodime
and analogues into opioid agonists with high affinity to
all three receptor types. The 14-phenylpropoxy deriva-
tives 7 and 8 were prepared and biologically and
pharmacologically characterized.
hydrogenation of 14 over Pd/C gave compound 15, which
was N-demethylated using 1-chloroethyl chlorofor-
mate.19 The corresponding carbamate was cleaved by
refluxing in MeOH/HCl to yield the N-normorphinan
16, which was cyclopropylmethylated to afford 17. The
4,5-ring opening of compound 17 with activated zinc in
the presence of NH4Cl in MeOH14 gave phenol 7, which
was 4-O-alkylated with phenyltrimethylammonium chlo-
ride and butyl iodide, respectively, to afford compounds
8 and 9.
Ch em istr y
To obtain the 4-phenylpropoxy analogue of cyprodime
(compound 4, Figure 1), 17-(cyclopropylmethyl)-4-hy-
droxy-14â-methoxymorphinan-6-one14 was first 14-O-
alkylated with cinnamyl bromide (3-bromo-1-phenyl-1-
propene) in DMF in the presence of K2CO3 to afford
compound 3, which was subsequently hydrogenated
over Pd/C to yield compound 4. Compounds 5 and 6 were
prepared analogously to the synthesis of compound 3
using benzyl chloride and hexyl iodide, respectively
(Figure 1).
The synthesis of the 14-phenylpropoxy analogues of
cyprodime (compounds 7-9, 17) started from 14-hy-
droxycodeinone (10, Scheme 1). 10 was 14-O-alkylated
with cinnamyl bromide in DMF in the presence of NaH
to give compound 11, which was hydrogenated over
Pd/C to afford 14-phenylpropoxy-substituted 12. The
3-O-methyl ether of compound 12 was cleaved by
refluxing in 48% HBr to obtain phenol 13, which was
converted into the phenyltetrazolyl ether 14 by reaction
with 5-chloro-1-phenyl-1H-tetrazole18 in DMF. Catalytic
Resu lts a n d Discu ssion
Op ioid Recep tor Bin d in g. The new compounds
were evaluated in receptor binding assays in rat brain
membranes by displacement of [3H]DAMGO (µ), [3H]-
[Ile5,6]deltorphin II (δ), and [3H]U69,593 (κ).20 Com-
pounds 3, 4, and 6 exhibited lower affinity at the µ
opioid receptor and decreased binding to δ and κ
receptors compared to cyprodime and its analogue 2
(Table 1). Compounds 5 and 9 had affinities at the µ
binding sites comparable to those of the reference
compounds, but some increase in the affinities at δ and
κ receptors was observed. The 14-phenylpropoxy-
substituted compounds 7, 8, and 17 showed affinities
in the subnanomolar range at the µ opioid receptor.
Their interaction with the µ receptor was remarkably
improved, being 2 orders of magnitude higher than that
of the reference compounds. Among the tested com-
pounds, the 14-phenylpropoxy derivative 8 and its
Ta ble 1. Opioid Receptor Binding Affinities and Selectivities of Compounds 3-9 and 17 and Reference Compounds in Rat Brain
Membranes
Ki ( SEM (nM)
[3H][Ile5,6]deltorphin II (δ)
selectivity ratio
δ/µ κ/µ
13
4.8
compd
[3H]DAMGO (µ)
[3H]U69,593 (κ)
3
4
5
6
7
8
9
17
2
27.9 ( 0.8
43.3 ( 4.4
11.6 ( 0.7
44.9 ( 1.7
0.40 ( 0.05
0.34 ( 0.05
14.9 ( 2.2
0.84 ( 0.08
13.8 ( 0.8
10.6 ( 0.7
841 ( 113
1412 ( 134
213 ( 17
1172 ( 120
5.06 ( 0.53
16.9 ( 0.547
232 ( 20
46.2 ( 4.9
765 ( 70
414 ( 27
359 ( 16
208 ( 61
56.8 ( 9.3
441 ( 55
5.84 ( 0.69
7.36 ( 1.68
150 ( 47
22.8 ( 0.4
261 ( 38
109 ( 4
30
33
18
26
13
50
16
55
55
39
4.9
9.8
15
22
10
27
19
10
cyprodime (1)

3244 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Spetea et al.
Ta ble 2. Stimulation of [35S]GTPγS Binding by Compounds 7, 8, and 17 and Reference Compounds in Recombinant Human Opioid
Receptorsa
µ opioid receptor
δ opioid receptor
κ opioid receptor
Emax
Emax
Emax
compd
(% maximal stimulation) EC50 (nM) (% maximal stimulation) EC50 (nM) (% maximal stimulation) EC50 (nM)
7
8
17
2
35 ( 9.5
35 ( 2.5
43 ( 8.8
3.47 ( 0.86
1.97 ( 0.89
9.80 ( 1.25
>10000
49 ( 9.9
22 ( 3.3
17 ( 7.7
22 ( 6.0
18 ( 2.4
7.91 ( 0.34
20.6 ( 9.3
86.8 ( 2.4
1613 ( 130
1105 ( 163
45.8 ( 11.0
4.51 ( 0.13
>10000
>10000
>10000
117 ( 0.8
cyprodime (1)
33 ( 2.9
20.3 ( 1.8
18.8 ( 6.4
a
Membranes from CHO cells that stably expressed µ, δ, or κ opioid receptors were incubated with varying concentrations of the
compounds. EC50 values represent the concentration of compound necessary to produce 50% of the Emax value. Data represent the
mean ( SEM.
Ta ble 3. Antagonist Ke Values of Compounds 8 and 17 and
Reference Compoundsa
Ke ( SEM (nM)
compd
DAMGO (µ)
U69,593 (κ)
8
17
2
nt
nt
2.52 ( 0.32
8.54 ( 1.08
120 ( 6
11.1 ( 0.7
12.4 ( 1.7
cyprodime (1)
26.1 ( 5.0
a
Membranes from CHO cells that stably expressed either µ or
F igu r e 2.
κ opioid receptors were incubated with DAMGO or U69,593 in the
presence of varying concentrations of the compound. nt, not tested.
and analogue 2 (Table 2). The rank orders of the EC50
values substantially correlated with the Ki values
obtained for the compounds in the binding assay with
[3H]DAMGO and [3H][Ile5,6]deltorphin II. All new de-
rivatives were partial agonists at µ and δ receptors.
Among the most potent compounds, 8 had the lowest
EC50 value at the µ receptor and compound 7 had the
lowest at the δ receptor. Only compound 7 exhibited
some partial agonist activity at κ receptors (EC50 ) 4.51
nM). Compounds 8 and 17 were tested for antagonism
at κ receptors (Table 3), and they showed Ke values of
2.52 and 8.54 nM, respectively. Cyprodime and its
analogue 2 were a low-efficacy partial agonist and
antagonist, respectively, at all receptors in this func-
tional assay (Table 2).
4-hydroxy analogue 7 displayed the highest µ affinities
(Ki of 0.34 and 0.40 nM, respectively). Compared to
cyprodime and analogue 2, the affinities of compounds
7 and 8 were increased 30- to 40-fold at µ, 25- to 150-
fold at δ, and 15- to 45-fold at κ receptors. Of the new
derivatives, compounds 8 and 17 were the most selective
for the µ opioid receptor with δ/µ selectivity ratios of 50
and 55, respectively, and κ/µ selectivity ratios of 22 and
27, respectively, which are equivalent to or higher than
those of the reference compounds (Table 1).
Introduction of a phenylpropoxy and hexyloxy sub-
stituent at C-4 was detrimental to µ receptor affinity,
while a benzyloxy group retained µ affinity but in-
creased δ and κ affinity, thus resulting in less µ
selectivity compared to cyprodime and analogue 2. A
phenylpropoxy substituent at C-14 was able to consider-
ably increase the binding to the µ, δ, and κ receptors in
the presence of a hydroxyl and methoxy group at C-4
(compounds 7 and 8, respectively) and a 4,5-ether bridge
(compound 17). Enlarging the substituent at C-4 (butoxy
group) in the presence of a phenylpropoxy substituent
(compound 9) resulted in reduction of affinity at µ, δ,
and κ receptors.
An tin ocicep tive Assa ys. Compounds 7, 8, and 17
of this series were tested for their antinociceptive
potencies in vivo in the hot-plate (HP), the tail-flick (TF),
and the paraphenylquinone writhing (PPQ) tests in mice
(Table 4). All compounds were considerably more potent
than morphine in all three in vivo assays. Derivative 7,
a partial agonist exhibiting the best affinity at the µ
opioid receptor (Ki ) 0.40 nM) and also good affinity at
the δ and κ receptors, had the highest antinociceptive
potency, with a potency 21-fold higher in the HP, 38-
fold higher in the TF, and ca. 300-fold higher in the PPQ
compared to morphine. When compared to the highly
potent µ opioid agonist 14-methoxymetopon16,20-25 (Fig-
ure 2), it became apparent that compound 7 exhibits
similar potencies in all three assays. The antinociceptive
[
35S]GTP γS Bin d in g Assa y. The three compounds
(7, 8, and 17) with subnanomolar affinity values at the
µ opioid receptor as determined in binding assays were
tested in the [35S]GTPγS binding assay.20 They produced
similar maximal stimulation of [35S]GTPγS binding
(Emax) to µ and δ receptors in comparison to cyprodime
Ta ble 4. Results of the in Vivo Activities of Compounds 7, 8, and 17 in Comparison to Morphine and 14-Methoxymetopon (HS 198)
ED50 (sc, mg/kg)a
compd
HPb
TFc
PPQd
7
8
17
0.04 (0.013-0.143)
0.3 (0.094-0.96)
0.68 (0.29-1.6)
0.03 (0.010-0.050)
0.85 (0.39-1.86)
0.05 (0.015-0.17)
0.28 (0.15-0.5)
0.187 (0.054-0.640)
0.03 (0.010-0.60)
1.9 (0.89-4.14)
0.0014 (0.0004-0.005)
0.06 (0.019-0.197)
0.0094 (0.003-0.028)
0.009 (0.003-0.023)
0.40 (0.20-0.80)
HS 198e
morphinee
a
b
d
Effective dose 50% (95% confidence limits). HP ) hot plate test. c TF ) tail flick test. PPQ ) paraphenylquinone writhing test.
e Taken from ref 16.

14-Alkoxymorphinans
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3245
17-(Cyclop r op ylm eth yl)-14â-m eth oxy-4-[3-(p h en ylp r o-
p yl)oxy]m or p h in a n -6-on e Hyd r och lor id e (4‚HCl). A mix-
ture of 3 (oil, 480 mg, 1.05 mmol), 10% Pd/C (60 mg), and
MeOH (20 mL) was hydrogenated at room temperature and
35 psi for 45 min. The catalyst was filtered off, and the filtrate
was evaporated. The residue (475 mg of brownish oil) was
purified by column chromatography (silica gel, elution with
CH2Cl2/MeOH/concentrated NH4OH solution, 250:2.5:0.5) to
afford a slightly yellow oil (190 mg of 4, 62%). The hydrochlo-
ride salt was obtained in the usual way (Et2O/HCl) to yield
191 mg (37%) of 4‚HCl: mp 185-192 °C; IR (KBr) 1710 (CdO)
activities of the 4-methoxy derivative 8 and compound
17, which display also high µ affinity and µ selectivity,
were slightly lower compared to analogue 7, which has
a 4-hydroxy group. All of the compounds (7, 8, and 17)
were essentially inactive as antagonists in the TF test
versus morphine. None of the compounds exhibited
sufficient antagonist activity to enable the determina-
tion of its AD50. The novel derivatives of cyprodime
containing a 14-phenylpropoxy group acted as potent
antinociceptives. This is in agreement with our recent
observations in other morphinan series.16,17
1
cm-1; H NMR (DMSO-d6) δ 8.91 (s, br, +NH), 7.34-7.16 (m,
12 arom H), 6.83-6.81 (m, 2 arom H), 3.43 (s, CH3O); CI-MS
m/z 460 (M+ + 1). Anal. (C30H37NO3‚HCl‚0.4H2O) C, H, N.
Con clu sion s
4-Ben zyloxy-17-(cyclop r op ylm eth yl)-14â-m eth oxym or -
p h in a n -6-on e Hyd r och lor id e (5‚HCl). A mixture of 17-
(cyclopropylmethyl)-4-hydroxy-14 â-methoxymorphinan-6-one14
(700 mg, 2.05 mmol), benzyl chloride (0.32 mL, 2.78 mmol),
K2CO3 (770 mg, 5.59 mmol), and anhydrous DMF (5 mL) was
stirred under N2 at room temperature for 24 h. After addition
of H2O (15 mL), the mixture was extracted with CH2Cl2 (5 ×
20 mL), and the combined organic layers were washed with
H2O (2 × 100 mL) and brine (4 × 100 mL), dried (Na2SO4),
and evaporated. The residue (830 mg of yellow-brown oil) was
purified by column chromatography (silica gel, elution with
CH2Cl2/MeOH/concentrated NH4OH solution, 250:4.5:0.5) to
afford a yellowish oil (542 mg of 5, 61%). A part of this oil
(169 mg) was dissolved in Et2O, and 5‚HCl was precipitated
with Et2O/HCl: colorless crystals (120 mg); mp 224-229 °C;
IR (KBr) 1708 (CdO) cm-1; 1H NMR (DMSO-d6) δ 8.93 (s, br,
+NH), 7.59-7.35 (m, 5 arom H), 7.22 (t, J ) 8.0, 1 arom H),
6.97 (d, J ) 8.0, 1 arom H), 6.85 (d, J ) 8.0, 1 arom H), 3.42
(s, CH3O); CI-MS m/z 432 (M+ + 1). Anal. (C28H33NO3‚HCl‚
0.2H2O) C, H, N.
It was found that further prolongation of the 4-alkoxy
group of cyprodime and its 4-butoxy analogue 2 is
detrimental for µ opioid receptor affinity. Introduction
of an arylalkoxy group at C-4 does not increase µ affinity
in the case of benzyloxy, while a phenylpropoxy group
at C-4 reduces µ affinity. The present study on different
cyprodime derivatives provides further evidence that the
nature of the substituent at position 14 has a major
impact on the ability of morphinans to interact with
opioid receptors. Introduction of a 14-phenylpropoxy
group markedly increases binding affinities to µ and also
to δ and κ receptors and gives rise to a significant
increase in the agonist potency. The new derivatives
containing a 14-phenylpropoxy group acted as potent
antinociceptives. Thus, the presence of this substituent
leads to a profound alteration in the pharmacological
profile in this class of compounds.
17-(Cyclop r op ylm eth yl)-4-h exyloxy-14â-m eth oxym or -
p h in a n -6-on e Hyd r och lor id e (6‚HCl). A mixture of 17-(cy-
clopropylmethyl)-4-hydroxy-14â-methoxymorphinan-6-one14 (400
mg, 1.17 mmol), n-hexyl iodide (0.35 mL, 2.36 mmol), K2CO3
(490 mg, 3.56 mmol), and anhydrous DMF (5 mL) was stirred
under N2 at 50 °C (bath temperature) for 2 h. The inorganic
material was filtered off, and the filtrate was evaporated. The
residue was dissolved in CH2Cl2 (50 mL), washed with H2O
(3 × 30 mL) and brine (1 × 30 mL), dried (Na2SO4), and
evaporated. The remaining yellow oil (470 mg) was purified
by column chromatography (silica gel, elution with CH2Cl2/
MeOH/concentrated NH4OH solution, 250:4:0.5) to afford a
yellowish oil (389 mg of 6, 78%). The hydrochloride salt was
obtained in the usual way (Et2O/HCl) to yield 417 mg (77%)
of 6‚HCl: mp 134-142 °C; IR (KBr) 1724 (CdO) cm-1; 1H NMR
(DMSO-d6) δ 9.11 (s, br, +NH), 7.20 (t, J ) 8.0, 1 arom H),
6.86 and 6.81 (2 d, J ) 8.0, 8.0, 2 arom H), 3.43 (s, CH3O);
CI-MS m/z 426 (M+ + 1). Anal. (C27H39NO3‚HCl‚0.9H2O) C,
H, N.
Exp er im en ta l Section
The required reagents as well as anhydrous DMF were
purchased from Fluka, Switzerland, in the highest purities
available. The solvents were distilled before usage. Melting
points were determined on a Kofler melting point microscope
and are uncorrected. IR spectra were recorded with a Mattson
Galaxy series FTIR 3000 spectrometer (in cm-1). 1H NMR
spectra were recorded on a Varian Gemini 200 (200 MHz)
spectrometer. Chemical shifts (δ) are reported in ppm (relative
to SiMe4 as internal standard), and coupling constants (J ) are
in Hz. Mass spectra were recorded on a Finnigan Mat SSQ
7000 apparatus. Elemental analyses were performed at the
Institute of Physical Chemistry at the University of Vienna,
Austria. For TLC, POLYGRAM SIL G/UV254 precoated plastic
sheets (Macherey-Nagel, Germany) were used (eluent: CH2-
Cl2/MeOH/concentrated NH4OH solution, 90:9:1), and for
column chromatography, silica gel 60 (230-400 mesh ASTM,
Fluka, Switzerland) was used.
7,8-Did eh yd r o-4,5R-ep oxy-3-m et h oxy-17-m et h yl-14â-
{[(E)-3-ph en ylpr op-2-en yl]oxy}m or ph in an -6-on e (11). NaH
(0.92 g, 38.30 mmol, obtained from 1.53 g of 60% NaH
dispersion in oil after washings with petroleum ether) was
added to a stirred solution of 10 (4.00 g, 12.77 mmol) in
anhydrous DMF (100 mL) at 0 °C under N2. After 30 min, a
solution of cinnamyl bromide (3.27 g, 16.59 mmol) in anhy-
drous DMF (20 mL) was added slowly within 10 min, and the
resulting mixture was stirred for another 30 min at 0 °C and
1.5 h at room temperature. Excess NaH was destroyed
carefully by addition of small pieces of ice. Then the mixture
was diluted with H2O (100 mL) and extracted with CH2Cl2
(4 × 100 mL), and the combined organic layers were washed
with H2O (5 × 150 mL) and brine (150 mL), dried (Na2SO4),
and evaporated. The residue (4.22 g, orange oil) crystallized
spontaneously and was treated with boiling MeOH (10 mL)
to yield 3.23 g (59%) of 11 (mp 210-215 °C). A small portion
was recrystallized from MeOH to afford an analytical sample
17-(Cyclop r op ylm eth yl)-14â-m eth oxy-4-{[(E)-3-p h en yl-
p r op -2-en yl]oxy}m or p h in a n -6-on e H yd r och lor id e (3‚
HCl). A mixture of 17-(cyclopropylmethyl)-4-hydroxy-14â-
methoxymorphinan-6-one14 (1.00 g, 2.93 mmol), cinnamyl
bromide (0.75 g, 3.81 mmol), K2CO3 (1.09 g, 7.91 mmol), and
anhydrous DMF (5 mL) was stirred at room temperature for
24 h. After addition of H2O (15 mL), the mixture was extracted
with CH2Cl2 (5 × 20 mL), and the combined organic layers
were washed with H2O (2 × 100 mL) and brine (4 × 100 mL),
dried (Na2SO4), and evaporated. The residue (920 mg of yellow-
brown oil) was purified by column chromatography (silica gel,
elution with CH2Cl2/MeOH/concentrated NH4OH solution, 250:
2.5:0.5) to afford a yellowish oil (833 mg of 3, 62%). To obtain
an analytical sample, a small portion of this oil was dissolved
in Et2O and 3‚HCl was precipitated with Et2O/HCl: slightly
yellow powder; mp 132-137 °C; IR (KBr) 1710 (CdO) cm-1
;
1H NMR (DMSO-d6) δ 8.83 (s, br, +NH), 7.50-7.18 (m, 6 arom
H), 6.96-6.53 (m, 2 arom H, 2 olef H), 4.79-4.74 (m, PhCH-
CHCH2), 3.43 (s, CH3O); CI-MS m/z 458 (M+ + 1). Anal.
(C30H35NO3‚HCl‚1.8H2O) C, H, N.
1
of 11: mp 216-219 °C; H NMR (CDCl3) δ 7.38-7.22 (m, 5
arom H), 6.76 (d, J ) 10.2, 1 olef H, H-C(8)), 6.69 (d, J ) 8.3,

3246 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Spetea et al.
1 arom H), 6.61 (d, J ) 8.3, 1 arom H), 6.55 (d, J ) 16.2, 1 olef
H), 6.32 (dt, J ) 16.2, J ) 5.9, 1 olef H), 6.23 (d, J ) 10.2, 1
olef H, H-C(7)), 4.78 (s, H-C(5)), 3.84 (s, CH3O), 2.51 (s, CH3N).
Anal. (C27H27NO4) C, H, N.
4,5R-E p oxy-14â-[(3-p h en ylp r op yl)oxy]m or p h in a n -6-
on e Hyd r och lor id e (16‚HCl). A mixture of 15 (3.20 g, 7.93
mmol), NaHCO3 (3.33 g, 39.65 mmol), 1-chloroethyl chloro-
formate (4.32 mL, 39.65 mmol), and 1,2-dichloroethane (40 mL)
was stirred at 60 °C (bath temperature) under N2 for 13.5 h.
The inorganic material was filtered off, and the filtrate was
evaporated. The residue (3.7 g of yellow-brown oil, pure by
TLC) was refluxed in a mixture of concentrated HCl (15 mL)
and MeOH (35 mL) without further purification and charac-
terization. Then the solution was evaporated and the residue
was crystallized from MeOH/Et2O to afford 2.77 g (82%) of 16‚
HCl: mp >225 °C (dec); IR (KBr): 1729 (CdO) cm-1; 1H NMR
(DMSO-d6) δ 9.25 (s, br, +HN), 8.11 (s, br, +HN), 7.34-7.12
(m, 5 arom H), 7.16 (t, J ) 8.0, 1 arom H), 6.85 (d, J ) 8.0, 1
arom H), 6.77 (d, J ) 8.0 Hz, 1 arom H), 4.96 (s, H-C(5)); CI-
MS m/z 390 (M+ + 1). Anal. (C25H27NO3‚HCl‚0.3H2O) C, H,
N.
4,5R-Ep oxy-3-m eth oxy-17-m eth yl-14b-(3-p h en ylp r op yl-
oxy)m or p h in a n -6-on e ()14-O-(3-P h en ylp r op yl)oxyco-
d on e) (12). A mixture of 11 (12.70 g, 29.57 mmol) and 1.27 g
Pd/C (10%) in glacial acetic acid (160 mL) was hydrogenated
at room temperature and 40 psi for 1 h. The catalyst was
filtered off, the filtrate was evaporated, the residue was
alkalinized with concentrated NH4OH solution and extracted
with CH2Cl2 (4 × 70 mL). The combined organic layers were
washed with H2O (3 × 150 mL) and brine (3 × 150 mL), dried
(Na2SO4), and evaporated. The residue (14 g of yellow-brown
oil) was crystallized from MeOH to yield 10.14 g (79%) colorless
needles of 12 (mp 116-118 °C). A small portion was recrystal-
lized from MeOH to afford an analytical sample of 12: mp
119-121 °C; 1H NMR (CDCl3) δ 7.35-7.15 (m, 5 arom H), 6.68
(d, J ) 8.2, 1 arom H,), 6.60 (d, J ) 8.2, 1 arom H,), 4.63 (s,
H-C(5)), 3.89 (s, CH3O), 2.34 (s, CH3N). Anal. (C27H31NO4) C,
H, N.
4,5R-E p oxy-3-h yd r oxy-17-m et h yl-14â-[(3-p h en ylp r o-
p yl)oxy]m or p h in a n -6-on e H yd r och lor id e (13‚H Cl). A
solution of 12 (10.1 g, 23.30 mmol) in 48% HBr (140 mL) was
refluxed for 25 min. After cooling, the solution was poured on
ice-water (100 mL), alkalinized with concentrated NH4OH
solution, and extracted with CH2Cl2 (5 × 120 mL). The
combined organic layers were washed with H2O (150 mL) and
brine (4 × 100 mL), dried (Na2SO4), and evaporated. The
residue (13.85 g of yellow-brown oil) was purified by column
chromatography (silica gel, elution with CH2Cl2/MeOH/
concentrated NH4OH solution, 250/2.5/0.5) to afford a yellow-
ish oil (6.48 g of 13, 66%) which was used as such for the next
step. For analysis, a small portion was converted into the
hydrochloride salt in the usual way (Et2O/HCl) to yield
analytically pure 13‚HCl: mp 181-188 °C (dec); 1H NMR
(DMSO-d6) δ 9.50 (s, OH), 8.68 (s, br, +NH), 7.34-7.16 (m, 5
arom H), 6.70 (d, J ) 8.0, 1 arom H), 6.65 (d, J ) 8.0, 1 arom
H), 4.87 (s, H-C(5)), 2.92 (d, +NCH3). Anal. (C26H29NO4‚HCl‚
1.5H2O) C, H, N.
4,5R-Ep oxy-17-m eth yl-14â-[(3-p h en ylp r op yl)oxy]-3-[(1-
p h en yl-1H-tetr a zole-5-yl)oxy]m or p h in a n -6-on e (14). A
mixture of 13 (6.38 g, 15.20 mmol), K2CO3 (5.67 g, 41.06 mmol),
5-chloro-1-phenyl-1H-tetrazole (3.02 g, 16.73 mmol), and an-
hydrous DMF (40 mL) was stirred at room temperature for
23 h. After addition of H2O (300 mL), the mixture was
extracted with CH2Cl2 (3 × 75 mL). The combined organic
layers were washed with H2O (2 × 200 mL) and brine (3 ×
250 mL), dried (Na2SO4), and evaporated. The residue (7.48 g
yellowish oil) was purified by column chromatography (silica
gel, elution with CH2Cl2/MeOH/concentrated NH4OH solution,
250:2:0.5) to afford a yellow oil (6.41 g of 14, 75%) which was
used as such for the next step. A small portion was crystallized
from Et2O to give an analytical sample of 14: mp 117-119
°C; IR (KBr): 1723 (CdO) cm-1; 1H NMR (DMSO-d6) δ 7.88-
7.83 (m, 2 arom H), 7.73-7.62 (m, 3 arom H), 7.30-7.16 (m, 6
arom H), 6.85 (d, J ) 8, 1 arom H), 4.93 (s, H-C(5)), 2.29 (s,
CH3N); CI-MS m/z 564 (M+ + 1). Anal. (C33H33N5O4) C, H, N.
4,5R-Ep oxy-17-m eth yl-14â-[(3-p h en ylp r op yl)oxy]m or -
p h in a n -6-on e (15). A mixture of 14 (6.20 g, 11.00 mmol) and
2.48 g of Pd/C (10%) in glacial acetic acid (100 mL) was
hydrogenated at 40 °C and 50 psi for 17 h. The catalyst was
filtered off, the filtrate was reduced to 30 mL by evaporation,
and ice-water (100 mL) was added. The solution was alka-
linized with concentrated NH4OH solution and extracted with
CH2Cl2 (1 × 100 mL, 3 × 75 mL). The combined organic layers
were washed with brine (4 × 200 mL), dried (Na2SO4), and
evaporated. The residue (4.15 g of yellowish oil) was crystal-
lized from little MeOH to yield 3.20 g (72%) of 15 as colorless
crystals: mp 105-109 °C; IR (KBr) 1721 (CdO) cm-1; 1H NMR
(DMSO-d6) δ 7.29-7.16 (m, 5 arom H), 7.04 (t, J ) 8.0, 1 arom
H), 6.73 (d, J ) 8.0, 1 arom H), 6.64 (d, J ) 8.0, 1 arom H),
4.75 (s, H-C(5)), 2.28 (s, CH3N); CI-MS m/z 404 (M+ + 1). Anal.
(C26H29NO3) C, H, N.
17-(Cyclop r op ylm eth yl)-4,5R-ep oxy-14â-[(3-p h en ylp r o-
pyl)oxy]m or ph in an -6-on e Hydr och lor ide (17‚HCl). A mix-
ture of 16‚HCl (2.36 g, 5.55 mmol), K2CO3 (2.13 g, 15.40 mmol),
cyclopropylmethyl bromide (0.64 mL, 6.67 mmol), and anhy-
drous DMF (20 mL) was stirred at 80 °C (bath temperature)
under N2 for 8 h. The inorganic material was filtered off, and
the filtrate was evaporated. The residue was dissolved in CH2-
Cl2 (150 mL), washed with H2O (5 × 150 mL) and brine (150
mL), dried (Na2SO4), and evaporated. The residue (2.43 g of
17 as a yellowish oil, 99%) was used for the next step without
further purification. A small portion was converted into the
hydrochloride salt in the usual way (Et2O/HCl) to yield an
analytical sample of 17‚HCl: mp 145-150 °C; IR (KBr) 1726
1
(CdO) cm-1; H NMR (DMSO-d6) δ 8.26 (s, br, +HN), 7.31-
7.14 (m, 5 arom H), 7.18 (t, J ) 8.0, 1 arom H), 6.85 (d, J )
8.0, 1 arom H), 6.78 (d, J ) 8.0, 1 arom H), 4.96 (s, H-C(5));
CI-MS m/z 444 (M+ + 1). Anal. (C29H33NO3‚HCl‚0.9H2O) C,
H, N.
17-(Cyclop r op ylm eth yl)-4-h yd r oxy-14â-[(3-p h en ylp r o-
p yl)oxy]m or p h in a n -6-on e Hyd r och lor id e (7‚HCl). To a
refluxing mixture of 17 (1.2 g, 2.71 mmol), NH4Cl (0.72 g, 13.46
mmol), and MeOH (50 mL) was added activated zinc powder
(0.88 g, 13.46 mmol) in small portions while stirring. After the
mixture was refluxed for 80 min, the inorganic material was
filtered off and the filtrate was evaporated. The residue was
dissolved in H2O (50 mL) and alkalinized with concentrated
NH4OH solution, and the mixture was extracted with CH2Cl2
(3 × 80 mL). The combined organic layers were washed with
brine (5 × 100 mL), dried (Na2SO4), and evaporated to give
1.20 g (99%) of 7 as a yellowish oil which was used as such for
the next step. A small portion was transformed into the
hydrochloride salt in the usual way (Et2O/HCl) to afford an
analytical sample of 7‚HCl: mp >170 °C (dec); IR (KBr) 1709
1
(CdO) cm-1; H NMR (DMSO-d6) δ 9.82 (s, OH), 8.43 (s, br,
+NH), 7.30-7.20 (m, 5 arom H), 7.03 (t, J ) 8.0, 1 arom H),
6.66 (m, 2 arom H); CI-MS m/z 446 (M+ + 1). Anal. (C29H35
NO3‚HCl‚0.7H2O) C, H, N.
-
17-(Cyclop r op ylm eth yl)-4-m eth oxy-14â-[(3-p h en ylp r o-
p yl)oxy]m or p h in a n -6-on e Hyd r och lor id e (8‚HCl). A mix-
ture of 7‚HCl (0.40 g, 0.90 mmol), K2CO3 (0.37 g, 2.69 mmol),
phenyltrimethylammonium chloride (0.46 g, 2.69 mmol), and
anhydrous DMF (6 mL) was stirred at 80 °C (bath tempera-
ture) under N2 for 3.5 h. After the mixture was cooled, the
inorganic material was filtered off, the filtrate was evaporated,
and the residue was dissolved in CH2Cl2 (100 mL), washed
with brine (4 × 150 mL), dried (Na2SO4), and evaporated. The
residue (0.30 g of dark oil) was purified by column chroma-
tography (silica gel, elution with CH2Cl2/MeOH/concentrated
NH4OH solution, 250:4:0.5) to afford a yellow oil (0.23 g) which
was dissolved in Et2O. Addition of Et2O/HCl yielded 0.22 g
(48%) of 8‚HCl: mp 121-126 °C; IR (KBr) (CdO) 1710 cm-1
;
1H NMR (DMSO-d6) δ 8.34 (s, br, +NH), 7.30-7.16 (m, 5 arom.
H), 7.22 (t, J ) 8.0, 1 arom H), 6.88 (d, J ) 8.0, 1 arom H),
6.82 (d, J ) 8.0, 1 arom H); CI-MS m/z 460 (M+ + 1). Anal.
(C30H37NO3‚HCl‚0.7H2O) C, H, N.

14-Alkoxymorphinans
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3247
(8) Shahbazian, A.; Heinemann, A.; Schmidhammer, H.; Beubler,
E.; Holzer-Petsche, U.; Holzer, P. Involvement of µ and κ, but
not δ Opioid Receptors in the Peristaltic Motor Depression
Caused by Endogenous and Exogenous Opioids in the Guinea-
Pig Intestine. Br. J . Pharmacol. 2002, 135, 741-750.
(9) Starowicz, K.; Przewlocki, R.; Gispen, W. H.; Przewlocka, B.
Modulation of Melanocortin-Induced Changes in Spinal Noci-
ception by µ Opioid Receptor Agonist and Antagonist in Neu-
ropathic Rats. NeuroReport 2002, 13, 2447-2452.
(10) O¨ tvo¨s, F.; To´th, G.; Schmidhammer, H. Tritium Labelling of
Cyprodime ()(-)-17-(Cyclopropylmethyl)-4,14-Dimethoxymor-
phinan-6-one), a µ Receptor Selective Opioid Antagonist. Helv.
Chim. Acta 1992, 75, 1718-1720.
(11) Schmidhammer, H. Opioid Receptor Antagonists. In Progress
in Medicinal Chemistry, 35; Ellis, G. P., Luscombe, D. K., Oxford,
A. W., Eds.; Elsevier: Amsterdam, 1998; pp 83-132.
(12) Henry, B.; Fox, S. H.; Crossman, A. R.; Brotchie, J . M. µ and δ
Opioid Receptor Antagonists Reduce Levodopa-Induced Dyski-
nesia in the MPTP-Lesioned Primate Model of Parkinson’s
Disease. Exp. Neurol. 2001, 171, 139-146.
(13) Schmidhammer, H.; J ennewein, H. K.; Smith, C. F. C. Synthesis
and Biological Evaluation of 14-Alkoxymorphinans. 5. 6-Deoxy-
cyprodime, an Opioid Antagonist with Decreased µ Receptor
Selectivity in Comparison to Cyprodime. Arch. Pharm. (Wein-
heim, Ger.) 1991, 324, 209-211.
(14) Schmidhammer, H.; Smith, C. F. C.; Erlach, D.; Koch, M.;
Krassnig, R.; Schwetz, W.; Wechner, C. Synthesis and Biological
Evaluation of 14-Alkoxymorphinans. 3. Extensive Study on
Cyprodime Related Compounds. J . Med. Chem. 1990, 33, 1200-
1206.
(15) Schmidhammer, H.; J ennewein, H. K.; Krassnig, R.; Traynor,
J . R.; Patel, D.; Bell, K.; Froschauer, G.; Mattersberger, K.;
J achs-Ewinger, C.; J ura, P.; Fraser, G. L.; Kalinin, V. N.
Synthesis and Biological Evaluation of 14-Alkoxymorphinans.
11. 3-Hydroxycyprodime and Analogues: Opioid Antagonist
Profile in Comparison to Cyprodime. J . Med. Chem 1995, 38,
3071-3077.
(16) Greiner, E.; Spetea, M.; Krassnig, R.; Schu¨llner, F.; Aceto, M.;
Harris, L. S.; Traynor, J . R.; Woods, J . H.; Coop, A.; Schmidham-
mer, H. Synthesis and Biological Evaluation of 14-Alkoxymor-
phinans. 18. N-Substituted 14-Phenylpropyloxymorphinan-6-
ones with Unanticipated Agonist Properties: Extending the
Scope of Common Structure-Activity Relationships. J . Med.
Chem. 2003, 46, 1758-1763.
(17) Schu¨tz, J .; Spetea, M.; Koch, M.; Aceto, M. D.; Harris, L. S.; Coop,
A.; Schmidhammer, H. Synthesis and Biological Evaluation of
14-Alkoxymorphinans. 20. 14-Phenylpropoxymetopon, an Ex-
tremely Powerful Analgesic. J . Med. Chem. 2003, 46, 4182-
4187.
4-(n -Bu t oxy)-17-(cyclop r op ylm et h yl)-14â-[(3-p h en yl-
p r op yl)oxy]m or p h in a n -6-on e Hyd r och lor id e (9‚HCl). A
mixture of 7‚HCl (0.60 g, 1.34 mmol), K2CO3 (0.55 g, 4.01
mmol), n-butyl iodide (0.31 mL, 2.67 mmol), and anhydrous
DMF (5 mL) was stirred at 90 °C (bath temperature) under
N2 for 7 h. After the mixture cooled, the inorganic material
was filtered off, the filtrate was evaporated, and the residue
was dissolved in CH2Cl2 (100 mL), washed with brine (3 ×
150 mL), dried (Na2SO4), and evaporated. The residue (0.43 g
of brown oil) was purified by column chromatography (silica
gel, elution with CH2Cl2/MeOH/concentrated NH4OH solution,
250:4:0.5) to afford a yellow oil (0.26 g) which was dissolved
in Et2O. Addition of Et2O/HCl yielded 0.19 g (26%) of 9‚HCl:
mp 172-177 °C; IR (KBr) (CdO) 1711 cm-1; 1H NMR (DMSO-
d6) δ 8.52 (s, br, +NH), 7.30-7.15 (m, 6 arom H), 6.86 (d, J )
8.0, 1 arom H), 6.80 (d, J ) 8.0, 1 arom H), 3.95 (t, J ) 6.4,
(C4)OCH2(CH2)2CH3); CI-MS m/z 502 (M+ + 1). Anal. (C33H43
NO3‚HCl‚0.5H2O) C, H, N.
-
Op ioid Recep tor Bin d in g Assa ys. Rat brain membrane
preparations and binding assays were performed as de-
scribed.20
[
35S]GTP γS Bin d in g Assa y. Membrane preparation from
Chinese hamster ovary (CHO) cells transfected with human
opioid receptors and binding assays were performed as de-
scribed.20
In Vivo An tin ociciep tive Tests have been performed as
earlier described.16,17
Ack n ow led gm en t. We thank Tasmanian Alkaloids
Pty. Ltd., Westbury, Tasmania, Australia, for the gener-
ous gift of thebaine. We further thank Dr. D. Rakowitz
for performing the mass spectra and Andrea Kaletsch
for the technical assistance. The in vivo pharmacological
evaluation was carried out under the auspices of the
Drug Evaluation Committee of the College on Problems
of Drug Dependence of the USA, while the in vitro
functional assays were performed on a contract from the
National Institute on Drug Abuse (Grant N01DA-1-
8816).
(18) Beyerman, H. C.; Buurmann, E.; Lie, T. S.; Maat, L. Selective
Removal of Phenolic Hydroxyl Groups of Morphinan Derivatives.
Synthesis of rac. N-Formyl-3-Methoxy-6-Oxomorphinan. Recl.
Trav. Chim. Pays-Bas 1976, 95, 43-44.
(19) Olofson, R. A.; Martz, J . T.; Senet, J .-P.; Piteau, M.; Malfroot,
Th. A New Reagent for the Selective, High-Yield N-Dealkylation
of Tertiary Amines: Improved Synthesis of Naltrexone and
Nalbuphine. J . Org. Chem. 1984, 49, 2081-282.
(20) Spetea, M.; Erlandsson Harris, H.; Berzetei-Gurske, I.; Klareskog,
L.; Schmidhammer, H. Binding, Pharmacological and Immuno-
logical Profiles of the δ Selective Opioid Receptor Antagonist HS
378. Life Sci. 2001, 69, 1775-1782.
(21) Schmidhammer, H.; Schratz, A.; Mitterdorfer, J . Synthesis and
Biological Evaluation of 14-Alkoxymorphinans. 8. 14-Meth-
oxymetopon, an Extremely Potent Opioid Agonist. Helv. Chim.
Acta 1990, 73, 1784-1787.
(22) Zernig, G.; Saria, A.; Krassnig, R.; Schmidhammer, H. Signal
Transduction Efficacy of the Highly Potent µ Opioid Agonist 14-
Methoxymetopon. Life Sci. 2000, 66, 1871-1877.
(23) Urigu¨en, L.; Fernandez, B.; Romero, E. M.; De Pedro, N.;
Delgado, M. J .; Guaza, C.; Schmidhammer, H.; Viveros, M. P.
Effects of 14-Methoxymetopon, a Potent Opioid Agonist, on the
Responses to the Tail Electric Stimulation Test and Plus-Maze
Activity in Male Rats: Neuroendocrine Correlates. Brain Res.
Bull. 2002, 57, 661-666.
Refer en ces
(1) Part 20 of this series: Schu¨tz, J .; Spetea, M.; Koch, M.; Aceto,
M. D.; Harris, L. S.; Coop, A.; Schmidhammer, H. Synthesis and
Biological Evaluation of 14-Alkoxymorphinans. 20. 14-Phenyl-
propoxymetopon: An Extremely Potent Analgesic. J . Med.
Chem. 2003, 46, 4182-4187.
(2) Schmidhammer, H.; Burkard, W. P.; Eggstein-Aeppli, L.; Smith,
C. F. C. Synthesis and Biological Evaluation of 14-Alkoxymor-
phinans. 2. (-)-N-(Cyclopropylmethyl)-4,14-Dimethoxymorphi-
nan-6-one, a Selective µ Opioid Receptor Antagonist. J . Med.
Chem. 1989, 32, 418-421.
(3) Freye, E.; Latasch, L.; Schmidhammer, H. Pharmacodynamic
Effects of S-(+)-Ketamine on EEG, Evoked Potentials and
Respiration. A Study in the Awake Dog. Anaesthesist 1992, 41,
527-533.
(4) Spetea, M.; O¨ tvo¨s, F.; To´th, G.; Nguyen, T. M.-D.; Schiller, P.
W.; Vogel, Z.; Borsodi, A. Interaction of Agonist Peptide [3H]-
Tyr-D-Ala-Phe-Phe-NH2 with µ Opioid Receptor in Rat Brain and
CHO-µ/1 Cell Line. Peptides 1998, 19, 1091-1098.
(5) Ni, Q.; Xu, H.; Partilla, J . S.; Rice, K. C.; Matecka, D.; Calderon,
S. N.; Porreca, F.; Lai, J .; Schmidhammer, H.; Krassnig, R.;
Rothman, R. B. Opioid Peptide Receptor Studies. 9. Identifica-
tion of a Novel Non µ Non δ like Opioid Peptide Binding Site in
Rat Brain. Peptides 1998, 19, 1079-1090.
(6) Hutcheson, D. M.; Sa´nchez-Blazquez, P.; Rodriguez-Diaz, M.;
Garzon, J .; Schmidhammer, H.; Borsodi, A.; Roques, B. P.;
Maldonado, R. Use of Selective Antagonists and Antisense
Oligonucleotides To Evaluate the Mechanisms of BUBU Anti-
nociception. Eur. J . Pharmacol. 1999, 383, 29-37.
(24) King, M. A.; Su, W.; Nielan, C. L.; Chang, A. H.; Schu¨tz, J .;
Schmidhammer, H.; Pasternak, G. W. 14-Methoxymetopon, a
Very Potent µ Opioid Analgesic with an Unusual Pharmacologi-
cal Profile. Eur. J . Pharmacol. 2003, 459, 203-209.
(25) Freye, E.; Schmidhammer, H.; Latasch, L. 14-Methoxymetopon,
(7) Ma´rki, AÄ .; Monory, K.; O¨ tvo¨s, F.; To´th, G.; Krassnig, R.;
Schmidhammer, H.; Traynor, J . R.; Roques, B. P.; Maldonado,
R.; Borsodi, A. µ Opioid Receptor Specific Antagonist Cypro-
dime: Characterization by in Vitro Radioligand and [35S]GTPγS
Binding Assays. Eur. J . Pharmacol. 1999, 383, 209-214.
a
Potent Opioid, Induces No Respiratory Depression, Less
Sedation, and Less Bradycardia than Sufentanil in the Dog.
Anesth. Analg. 2000, 90, 1359-1364.
J M031126K