Synthesis and opioid activity of novel 6-ketolevorphanol derivatives

Article abstract of DOI:10.2174/157340613804488323

Novel 6-ketolevorphanol analogs with diverse substitution patterns at ring C were synthesized and their binding affinities at the μ, δ and κ opioid receptors were investigated. The in vitro activity of the new analogs was then evaluated in the functional

Full text of DOI:10.2174/157340613804488323

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Medicinal Chemistry, 2013, 9, 1-10
1
Synthesis and Opioid Activity of Novel 6-ketolevorphanol Derivatives
Zsuzsanna Gyulai,a Antal Udvardy,b Attila Cs. Bényei,b Jakub Fichna,c,d Katarzyna Gach,c Martin
Storr,d Géza Tóth,e Sándor Antus,a,f Sándor Berényi,a Anna Janecka,c and Attila Siposa*
aDepartment of Organic Chemistry, University of Debrecen, Debrecen, Hungary
bDepartment of Physical Chemistry, University of Debrecen, Debrecen, Hungary
cDepartment of Medicinal Chemistry, Medical University of Lodz, Lodz, Poland
dDivision of Gastroenterology, Department of Medicine, Snyder Institute of Infection, Immunity and Inflammation (III),
University of Calgary, Alberta, Canada
eInstitute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
fResearch Group for Carbohydrates of the Hungarian Academy of Sciences, Debrecen, Hungary
Abstract: Novel 6-ketolevorphanol analogs with diverse substitution patterns at ring C were synthesized and their binding
affinities at the ꢀ, ꢁ and ꢀ opioid receptors were investigated. The in vitro activity of the new analogs was then evaluated
in the functional assay based on the electrically-stimulated contractions of the mouse ileum. It was shown that analogs
with ꢁ7,8 bond had no significant potency at any of the opioid receptor types. In contrast, analogs with the saturated ring C
were either potent ꢀ agonist or antagonist depending on the absence or presence of the hydroxyl group in position 14.
Keywords: Analgesics, Opioid receptors, Binding Assay, Agonist, Antagonist.
7
INTRODUCTION
O
8
6
H3CO
H
9
Current treatment of pain is based on the concept elabo-
rated by the World Health Organization, according to which
pain medications are categorized into three groups depending
on their potency [1]. In the first group there are non-opioid
drugs such as aspirin and other non-steroidal anti-
inflammatory agents. The second group consists of weak
opioids (e.g. codeine) and their combinations with non-
opioid pain-killers. The most powerful analgesics, strong
opioids, are in the third group and are represented by natural
and semi-synthetic morphinans (e.g. morphine, hydromor-
phone, oxymorphone, oxycodone, levorphanol) and synthetic
opioids (e.g. fentanyl and methadone). Levorphanol (1) was
originally synthesized by Grewe and co-workers in the
course of investigations aimed at the total synthesis of mor-
phine [2]. This work was extended by Schnider and Heller-
bach [3] who developed a synthetic route for the efficient
production of levorphanol (1) which is a highly potent and
clinically valuable analgesic. Levorphanol (1) has twice the
activity of morphine, greater duration of effect and less fre-
quent or severe side-effects [4] and is a full ꢀ agonist [5].
Recently, compound 1 is considered an underestimated and
neglected opioid both, in medicinal practice (due to its
higher price compared with morphine) and in pharmaceutical
research, despite its remarkable and unusual pharmacological
profile (Fig. 1) [6].
C
14
CH3
N
N
5
H3C
H3C
15
O
B
10
4
A
3
1
OH
OH
2
1
2
Fig. (1). Structure of strong opioids.
The high ꢂ, ꢁ and ꢀ opioid receptor affinity of levorpha-
nol (with Ki values 0.21, 4.2 and 2.3 nM, respectively [4])
and the development of synthetic methods of functionaliza-
tion, encouraged us for extending structure-activity relation-
ship data of this compound. In general for morphinans, sig-
nificantly increased opioid receptor affinity was observed for
derivatives with substituents at C14 and with short-chain
alkyl groups at the 5ꢂ-position [7]. Also catalytic hydrogena-
tion of the ꢁ7,8 bond in morphinans afforded analogs with
increased analgesic activity [8]. For example, 14ꢂ-
methoxymetopon (2) is a very potent ꢂ-opioid receptor-
selective analgesic with an unusual pharmacological profile
and remarkable intrinsic activity [7]. Considering strictly the
ketomorphinan structure, several important approaches were
reported in the past for successful derivatizations [9].
In Fig. (2) six representative structures are presented for
this backbone. Compounds 3a and 3b without the 3-
hydroxyl function were found to be equipotent and six times
more potent in in vivo hot plate tests (HPT) as morphine,
respectively [10]. Derivatives 3c and 3d having only the keto
*Address correspondence to this author at the Department of Pharmaceuti-
cal Chemistry, University of Debrecen, P. O. Box 55, 4010 Debrecen,
Hungary; Tel: +36 52512900; Fax: +36 52512836;
E-mail: sipos.attila@pharm.unideb.hu
1875-6638/13 $58.00+.00
© 2013 Bentham Science Publishers

2
Medicinal Chemistry, 2013, Vol. 9, No. 1
R1
Gyulai et al.
R2
R3
R4
formation of the dienyl enolether of ring C into the ꢁ,ꢀ-
unsaturated ketone. Compounds 5a and 5b were obtained in
67% and 60% yields, respectively.
3a
3b
3c
H
H
H
OH
H
OH
O
R4
OMe
OMe
H
H
H
OH
H
Fully stereoselective hydroxylation of 5a,b at position 14
was accomplished applying the procedure elaborated by
Coop and Rice [16]. Treatment of 5a,b with cobalt(III)-
acetate in acetic acid, followed by the purification of the
crude product by column chromatography furnished pure
14ꢀ-hydroxyl congeners 6a and 6b in 44% and 47% yields,
respectively. In the next step, the ꢁ7,8 bonds in both 5-alkyl
codeinones 5a,b and 5-alkyl-14-hydroxycodeinones 6a,b
were hydrogenated using 10 % palladium on charcoal as a
catalyst to give dihydrocodeinones 7a,b and 8a,b, respec-
tively, in very good yields.
R3
R2
N
H3C
3d OMe OMe
H
3e OMe OMe Me
H
R1
Fig. (2). Structures of representative ketomorphinans.
function in ring C were proven to be three times as potent in
the HPT as morphine [11], while 3e with the 5ꢀ-methyl sub-
stituent had a 1.5 times increased potency comparing with
morphine [12]. These results also prompted us to further
extend the available structure-activity data on this field al-
lowing more accurate assumptions on future drug design. In
agreement with this, we report here the synthesis and in vitro
characterization of 5ꢀ- and 14ꢀ-substituted ketolevorphanol
congeners.
These transformations allowed us to prepare several pen-
tacyclic 4,5-epoxymorphinans 5a,b-8a,b with diversely
functionalized ring C. Finally, all obtained pentacyclic mor-
phinans 5a,b-8a,b were transformed into target tetracyclic 5-
alkylmorphinans 17a,b-20a,b using the strategy described by
Hupp and Neumeyer [13] (Scheme 2).
RESULTS AND DISCUSSION
Opening of O-C5 ether bond was performed using zinc
under acidic conditions. Treatment of the obtained phenols
9a,b-12a,b with N-phenyl-bis(trifluoromethanesulfonate)
amide in the presence of cesium carbonate gave triflates
which were used without further purification in the next step.
These triflates were cleaved to morphinones 13a,b-16a,b
using palladium acetate, diphenylphosphinopropane (dppp),
and 5 equivalents of triethylsilane at 60 oC for 4 h under inert
atmosphere. In the last step, the targeted 3-hydroxy-
morphinones 17a,b-20a,b were obtained by standard O-
demethylation of morphinones 13a,b-16a,b using a di-
chloromethane solution of BBr3.
The synthetic route to new 5ꢀ-alkylmorphinans 17a,b-
20a,b was based on a recently published strategy [13], which
allows the preparation of diversely functionalized morphi-
nans without the 4,5-epoxy moiety. Our present work con-
firmed that this procedure could be extended for compounds
with diverse substitution patterns at ring C.
Starting 5ꢀ-alkyl congeners of thebaine 4a,b were syn-
thesized as described by Boden et al. [14]. Preparation of
these compounds involved formation of thebaine anion at
low temperature (-78oC) and subsequent reaction of this nu-
cleophile with alkyl halides.
Yields of the three main steps of the conversion of 4,5-
epoxymorphinans 5a,b-8a,b into tetracyclic 5-alkylmor-
phinans 17a,b-20a,b were summarized in Table 1. Generally
compounds with of ꢁ7,8 bond were obtained in somewhat
lower overall yields than their saturated counterparts.
5ꢀ-Alkylthebaines 4a,b were then converted into the cor-
responding 5-substituted codeinones 5a,b using the method-
ology first reported by Dauben et al. [15] and adapted for 5-
methylthebaine by Boden et al. [14] (Scheme 1). The proce-
dure utilizes mercury(II)-acetate in formic acid for the trans-
OCH3
O
O
O
HO
HO
HCOOH/
R
Pd/C
H2
R
R
R
N
N
N
N
Co(OAc)3
AcOH
Hg(OAc)2
H3C
H3C
H3C
H3C
O
O
O
O
N2
OCH3
OCH3
OCH3
OCH3
5a,b
Pd/C
H2
7a,b
6a,b
4a,b
O
R
4-8a Me
4-8b Et
R
O
N
H3C
OCH3
8a,b
Scheme 1. Synthesis route to 5ꢀ-alkyl-codeinones with diverse ring C pattern.

Synthesis and Opioid Activity of Novel 6-ketolevorphanol Derivatives
Medicinal Chemistry, 2013, Vol. 9, No. 1
3
X
O
X
O
X
O
X
O
Y
Y
Y
Y
R'
R'
R'
R'
R
R
R
R
1. PhN(Tf)2/Cs2CO3
H3C
N
N
N
N
Zn/NH4Cl
BBr3
H3C
H3C
H3C
O
OH
2. Pd(OAc)2,dppp
Et3SiH
OCH3
OCH3
OCH3
OH
17-20 a&b
5-8 a&b
9-12 a&b
13-16 a&b
R
R'
H
X- -Y
C=C
C=C
C=C
C=C
C-C
C-C
C-C
C-C
5,9,13,17a Me
5,9,13,17b Et
6,10,14,18a Me
6,10,14,18b Et
7,11,15,19a Me
7,11,15,19b Et
8,12,16,20a Me
8,12,16,20b Et
H
OH
OH
OH
OH
H
H
Scheme 2. General synthesis of 5ꢁ-alkylmorphinans 17-20 a,b.
Table 1. Comparison of Isolated Yields for the 3 Main Steps of the Conversion of 4,5-epoxymorphinans 5-8a,b into Tetracyclic 5-
alkylmorphinans 17-20a,b
Isolated YIELDS* (%) for
Transformations
Reductive Opening
of the Ether Bridge
Triflation and Removal
of 4-OH Function
O-demethylation
5a ꢀ 9a ꢀ 13a
5b ꢀ 9b ꢀ 13b
6a ꢀ 10a ꢀ 14a
6b ꢀ 10b ꢀ 14b
7a ꢀ 11a ꢀ 15a
7b ꢀ 11b ꢀ 15b
8a ꢀ 12a ꢀ 16a
47
51
44
59
69
64
61
67
53
57
61
60
59
71
54
54
74
65
63
59
78
74
75
80
8b ꢀ 12b ꢀ 16b
*Reported yields are averages of 3 runs
The synthesis of phenol 12a gave rise to fine crystals
which were found to be suitable for X-ray analysis (Fig. 3,
deposited in the Cambridge Crystallographic Data Centre
under deposition number CCDC 820388). This study al-
lowed us to confirm the orientation of 5ꢀ-substituent and the
relative position of 5ꢀ-methyl and 6-keto functions.
Potency and selectivity of new analogs 17a,b-20a,b to-
wards ꢀ, ꢀ, and ꢂ opioid receptors were evaluated by radio-
ligand binding assays according to the known procedures
[17]. Rat brain membranes were used as a source of ꢀ and ꢀ
receptors, and guinea pig brain membranes as a source of ꢂ
receptors. IC50 values at ꢀ, ꢁ and ꢂ opioid receptors, deter-
mined against [3H]DAMGO, [3H][Ile5,6]deltorphin-2 and
[3H]U69,593, respectively, were collected in Table 2.
Fig. (3). ORTEP view of compound 12a at 50% probability level.

4
Medicinal Chemistry, 2013, Vol. 9, No. 1
Gyulai et al.
Table 2. Opioid Receptor Binding Affinities of 5ꢀ-alkylmorphinans 17a,b-20 a,b
IC50
[nM]
Selectivity
Compound
ꢀa
ꢁb
ꢂc
ꢂ/ꢂ
ꢂ/ꢁ
17a
435 39
351 28
>1000
>1000
>1000
>1000
>1000
>1000
>1000
162 14
16.8 1.4
>1000
>1000
>2.30
>2.85
-
-
17b
-
18a
>1000
>1000
-
18b
>1000
730 58
15.2 1.6
21.1 2.2
11.5 1.3
24.9 2.2
9.27 1.0
<0.73
11.3
1.26
0.69
0.65
7.24
<0.73
<0.02
<0.02
<0.01
0.15
0.55
19a
1.34 0.12
16.8 1.1
16.7 1.5
38.1 0.4
1.28 0.11
19b
20a
20b
Levorphanol (1)
All values are expressed as mean S.E.M. of three determinations performed in duplicate.
aDetermined against [3H]DAMGO.
bDetermined against [3H][Ile5,6]deltorphin-2.
cDetermined against [3H]U69,593
120
100
80
120
100
80
60
40
20
0
60
40
20
0
20a
20b
+ naloxone
+ naloxone
-10
-9
-8
-7
-6
-10
-9
-8
-7
-6
logC
logC
A
B
120
100
80
60
40
20
0
levorphanol
+ naloxone
-10
-9
-8
-7
-6
logC
C
Fig. (4). Concentration–response curves showing the longitudinal smooth muscle contraction in mouse ileum induced by compounds 1,
20a,b (10ꢀ10–10ꢀ6 M) alone or in the presence of non-selective opioid receptor antagonist naloxone (10ꢀ6 M). Data represent mean SEM for
n=6–10 experiments.
For comparison, opioid binding data for levorphanol (1)
were also included. Structurally, new analogs differed by the
presence of the ꢁ7,8 bond and OH group at the C14. Addi-
tionally, there was either a methyl or ethyl group at the 5ꢀ
position, however none of these alkyl groups influenced the
binding more than the other.
Compounds 17a,b and 18a,b with ꢁ7,8 bond all displayed
a very poor binding at opioid receptors, whether they had the
OH group at C14 or not. It seems that ꢁ,ꢀ-unsaturated ketone
function in the ring C represents a more rigid structure that
cannot fit into the binding pocket of the receptor. On the
contrary, analogs 19a,b and 20a,b with saturated ring C
showed significant potency at the ꢂ and ꢂ opioid receptors,
but did not bind to the ꢃ receptor.
Then, we examined the effect of compounds which had
high potency at the ꢂ and ꢂ opioid receptors (19a,b and 20
a,b), on electrically-stimulated contractions of the mouse
ileum, to test the in vitro activity of these drugs in a tissue

Synthesis and Opioid Activity of Novel 6-ketolevorphanol Derivatives
Medicinal Chemistry, 2013, Vol. 9, No. 1
5
A
B
120
100
80
120
100
80
60
40
20
0
60
40
20
(-)-U50488
+ 19a
(-)-U50488
+ 19b
0
-10
-9
-8
-7
-6
-10
-9
-8
-7
-6
logC
logC
C
120
100
80
60
40
20
0
(-)-U50488
+ nor-BNI
-10
-9
-8
-7
-6
logC
Fig. (5). Concentration–response curves showing the longitudinal smooth muscle contraction in mouse ileum induced by (-)-U50488 ꢀ ago-
nist (10ꢁ10–10ꢁ6 M) alone or in the presence of compounds 19a,b and the potent ꢀ antagonist nor-BNI (10ꢁ6 M). Data represent mean SEM
for n=6–10 experiments.
where opioid effects are well characterized. Electrical stimu-
lation of ileal preparations results in activation of cholinergic
neurons, which leads to twitch contractions of the smooth
muscular tissue [18]. The opioid-induced inhibition of elec-
trically-stimulated twitch contractions provides a good func-
tional assay for opioid activity.
Compounds 19a,b did not influence the smooth muscle
contractions in mouse ileum tissue but blocked the effect
exerted by the ꢂ agonist (-)-U50,488 (Fig. 5A,B). These data
suggest that 19a,b acted as antagonist at the ꢂ opioid recep-
tors in the mouse ileum. A well known ꢂ antagonist, nor-
binaltorphimine (nor-BNI), was used for comparison (Fig.
5C). The pA2 values for analogs 19a,b and nor-BNI are
shown in Table 4. Compound 19b exerted the same, concen-
tration-dependent, antagonist effect at the ꢂ opioid receptor
as nor-BNI (Fig. 6), while 19a was only a weak antagonist.
Analogs 20a,b, similarly to levorphanol (1), concentra-
tion-dependently reduced the amplitude of electrically-
induced twitch contractions (Fig. 3A-C) and the EC50 values
were in the nanomolar range (Table 3). The inhibitory effect
of 1 and agonists 20a,b on smooth muscle contractility was
blocked by the opioid receptor antagonist naloxone (10-6 M),
indicating that the effects of these compounds were mediated
by the opioid receptors (Fig. 4A-C).
CONCLUSIONS
In conclusion we have studied the structure-activity rela-
tionship of several new congeners of levorphanol (1). Ke-
tolevorphanols 17a,b-20a,b modified in ring C were pre-
pared by extending a previously published procedure for 5ꢀ-
substituted 4,5-epoxymorphinans. The pharmacological
properties of the novel derivatives at the opioid receptors
were evaluated by both binding studies and in vitro func-
tional measurements based on the electrically-stimulated
contractions of the mouse ileum. Analogs 17a,b and 18a,b
with ꢁ7,8 bond had no significant potency at any of the opioid
receptor types. In contrast, analogs 19a,b-20a,b, with the
saturated ring C, showed interesting pharmacological proper-
ties. Depending on the absence or presence of the hydroxyl
group at position 14, they were either potent ꢂ agonist
(20a,b) or antagonist (19a,b), respectively. The potency of
Table 3. Agonist Potency of Levorphanol (1) and Analogs 20a
and 20b
EC50
Compound
[nM]
20a
20b
64.7 5.8
27.8 3.1
16.1 2.5
Levorphanol (1)

6
Medicinal Chemistry, 2013, Vol. 9, No. 1
Gyulai et al.
General Procedure for the Conversion of 5ꢀ-
A
alkylthebaines 4a,b into 5-substituted Codeines 5a,b
120
100
80
60
40
20
0
(-)-U50488
+ 19b 10-9
+ 19b 10-8
+ 19b 10-7
+ 19b 10-6
To a stirred solution of 5-alkylthebaine (1.7 mmol) in 3
M formic acid (500 mL) mercuric acetate (1.7 mmol, 550
mg) was added and the mixture was stirred under nitrogen at
room temperature for 12 h. After this period of time satu-
rated K2CO3 solution (600 mL) was added carefully, and the
mixture was extracted with CH2Cl2 (4 x 60 mL). The com-
bined extracts were washed with water and brine, and sol-
vent was evaporated to yield red residue which was passed
through a silica gel column (eluent CH2Cl2/CH3OH = 8/2) to
give pure 5a or 5b.
M
M
M
M
-10
-9
-8
-7
-6
5ꢀ-Methylcodeinone (5a)
logC
This compound was obtained in 67% yield. The physical
and spectral data were found to be in accordance with previ-
ously published ones [19].
B
120
100
80
60
40
20
0
(-)-U50488
+ norBNI 10-9
+ norBNI 10-8
+ norBNI 10-7
+ norBNI 10-6
M
5ꢀ-Ethylcodeinone (5b)
Yield: 60%. M.p.: 167-169oC; IR (KBr) 1686 cm-1
(C=O); 1H-NMR (CDCl3) ꢀ=6.64-6.57 (3H, m, H1, H2, H8);
6.09 (1H, d, H7, J7-8=10.2); 3.85 (3H, s, C3-OCH3); 2.43
(3H, s, N-CH3); 1.97 (2H, q, C5-CH2, J=4.4); 0.99 (3H, t,
CH2-CH3, J=4.5); MS (ESI) m/z 326 [M+1]+.
M
M
M
General Procedure for the Oxidation of 5ꢀ-
alkylcodeinones
codeinones 6a,b
5a,b
to
5ꢀ-alkyl-14ꢀ-hydroxy-
-10
-9
-8
logC
-7
-6
Fig. (6). Concentration–response curves showing the longitudinal
smooth muscle contraction in mouse ileum induced by (-)-U50488
ꢂ agonist (10ꢁ10–10ꢁ6 M) alone or in the presence of compound 19b
and the potent ꢂ agonist nor-BNI in the given concentrations.
Co(OAc)3 (1.35 mmol, 319 mg), prepared as previously
reported [22] was added to a solution of 5ꢀ-alkylcodeinone
(1.35 mmol) in acetic acid (4 mL). After stirring for 24h at
r.t. additional Co(OAc)3 (1.35 mmol, 319 mg) was added and
the solution was stirred for 4h. The mixture was diluted with
water (30 mL), excess of the oxidant was destroyed with
saturated NaHSO3 solution. Then the pH of the reaction mix-
ture was adjusted to 8 by addition of saturated solution of
NaHCO3. The products were extracted with dichloromethane
(3 x 50 mL), washed with brine (100 mL), and dried. After
removal of the solvent, crude product was purified by col-
umn chromatography (eluent CH2Cl2/CH3OH = 9/1) to give
pure 6a or 6b.
Table 4. Antagonist Potency of nor-BNI and Analogs 19a and
19b at the ꢂ Opioid Receptor
*
Compound
pA2
19a
19b
8.70
10.99
10.91
nor-BNI
14ꢀ-Hydroxy- 5ꢀ-methylcodeinone (6a)
*Determined against (-)-U50488
This compound was obtained in 44% yield. The physical
and spectral data were found to be in accordance with previ-
ously published ones [20].
19b was comparable to the potency of nor-BNI, a well-
known, selective ꢂ opioid receptor antagonist.
5ꢀ-Ethyl-14ꢀ-hydroxycodeinone (6b)
Experimental Part
Yield: 47%. M.p.: 212-214oC; IR (KBr) 1687 cm-1
Melting points were determined with a Kofler hot-stage
apparatus and are uncorrected. Thin layer chromatography
was performed on precoated Merck 5554 Kieselgel 60 F254
foils using 80% CH2Cl2/20% CH3OH mobile phase. The
1
(C=O); H-NMR (CDCl3) ꢀ=6.87 (1H, d, H8, J7-8=10.2),
6.64 (2H, dd, H1, H2, J1-2=8.1); 6.11 (1H, d, H7, J7-8=10.2);
3.83 (3H, s, C3-OCH3); 2.41 (3H, s, N-CH3); 2.01 (2H, q,
C5-CH2, J=4.2); 1.07 (3H, t, CH2-CH3, J=4.3); MS (ESI)
m/z 342 [M+1]+.
1
spots were visualized with Dragendorff’s reagent. H NMR
spectra were recorded at 400 MHz using a Bruker Avance
DRX400 spectrometer; chemical shifts were reported in ppm
(ꢄ) from internal TMS for all the undoubtedly identifiable
signs. Coupling constants (J) were measured in Hz. Mass
spectra were recorded on a Varian MAT 44 S apparatus. IR
spectra were recorded with a Mattson Galaxy Series FTIR
3000 spectrometer (in cm-1). Elemental analyses (C, H) were
obtained on a Carlo Erba 1108 analyzer.
Hydrogenation of ꢁ7,8 of Substituted Codeinones 5a,b and
14-hydroxy-codeinones 6a,b
A mixture of 1 mmol of the unsaturated codeinone, 90
mg of Pd/C (10%) and 200 mL of ethanol (96%) was hydro-
genated at 35 psi (r.t.) for 10 h. The obtained mixture was
filtered through a short pad of Celite and washed with 3x10

Synthesis and Opioid Activity of Novel 6-ketolevorphanol Derivatives
Medicinal Chemistry, 2013, Vol. 9, No. 1
7
mL of dichloromethane:methanol=8:2. The resulting organic
solution was concentrated to dryness under vacuum. The
crude compound was found in every case pure enough to
step forward without purification.
J7-8=10.3); 3.81 (3H, s, C3-OCH3); 2.45 (3H, s, N-CH3); 1.20
(3H, d, C5-CH3, J=7.1); MS (ESI) m/z 330 [M+1]+.
(-)-4,14ꢀ-Dihydroxy-5ꢀ-ethyl-3-methoxy-17-methyl-7,8-
didehydromorphinan-6-one (10b)
5ꢀ-Methyl-dihydrocodeinone (7a)
1
M.p.: 184-186oC; IR (KBr) 1691 cm-1 (C=O); H-NMR
This compound was obtained in 87% yield. The physical
and spectral data were found to be in accordance with previ-
ously published ones [14].
(CDCl3) ꢀ=6.59-6.52 (3H, m, H1, H2, H8); 6.05 (1H, d, H7,
J7-8=9.8); 3.87 (3H, s, C3-OCH3); 2.47 (3H, s, N-CH3); 1.85
(2H, q, C5-CH2, J=4.4); 1.06 (3H, t, CH2-CH3, J=4.3); MS
(ESI) m/z 344 [M+1]+.
5ꢀ-Ethyl-dihydrocodeinone (7b)
Yield: 90%. M.p.: 139-140.5oC; IR (KBr) 1719 cm-1
(C=O); 1H-NMR (CDCl3) ꢀ=6.61 (2H, dd, H1, H2, J1-2=8.0);
3.87 (3H, s, C3-OCH3); 2.41 (3H, s, N-CH3); 1.99 (2H, q,
C5-CH2, J=4.0); 1.07 (3H, t, CH2-CH3, J=4.2); MS (ESI)
m/z 328 [M+1]+.
(-)-5ꢀ,17-dimethyl-4-hydroxy-3-methoxy-morphinan-6-
one (11a)
1
M.p.: 201-203oC; IR (KBr) 1721 cm-1 (C=O); H-NMR
(CDCl3) ꢀ=6.61 (2H, dd, H1, H2, J1-2=8.4); 3.86 (3H, s, C3-
OCH3); 2.45 (3H, s, N-CH3); 1.20 (3H, d, C5-CH3, J=7.2);
MS (ESI) m/z 316 [M+1]+.
14ꢀ-Hydroxy-5ꢀ-methyl-dihydrocodeinone (8a)
This compound was obtained in 83% yield. The physical
and spectral data were found to be in accordance with previ-
ously published ones [21].
(-)-5ꢀ-Ethyl-4-hydroxy-3-methoxy-17-methyl-
morphinan-6-one (11b)
M.p.: 191-193.5oC; IR (KBr) 1717 cm-1 (C=O); 1H-NMR
(CDCl3) ꢀ=6.66 (2H, dd, H1, H2, J1-2=8.1); 3.82 (3H, s, C3-
OCH3); 2.39 (3H, s, N-CH3); 1.90 (2H, q, C5-CH2, J=4.1);
0.99 (3H, t, CH2-CH3, J=4.0); MS (ESI) m/z 330 [M+1]+.
5ꢀ-Ethyl-14ꢀ-hydroxy-dihydrocodeinone (8b)
Yield: 88%. M.p.: 174-175oC; IR (KBr) 1722 cm-1
(C=O); 1H-NMR (CDCl3) ꢀ=6.63 (2H, dd, H1, H2, J1-2=8.1);
3.81 (3H, s, C3-OCH3); 2.47 (3H, s, N-CH3); 2.05 (2H, q,
C5-CH2, J=4.3); 1.00 (3H, t, CH2-CH3, J=4.3); MS (ESI)
m/z 344 [M+1]+.
(-)-4,14ꢀ-Dihydroxy-5ꢀ,17-dimethyl-3-methoxy-
morphinan-6-one (12a)
M.p.: 206-208oC; IR (KBr) 1717 cm-1 (C=O); H-NMR
1
(CDCl3) ꢀ=6.59 (2H, dd, H1, H2, J1-2=8.1); 3.79 (3H, s, C3-
OCH3); 2.41 (3H, s, N-CH3); 1.18 (3H, d, C5-CH3, J=7.0);
MS (ESI) m/z 332 [M+1]+.
Ether Ring Opening Procedure
To a 100 mL round bottom flask was added 4,5-
epoxymorphinan (1 mmol) and n-PrOH:H2O=8:1 (9 mL).
Then ammonium chloride (640 mg, 11.9 mmol) was added
and the mixture was brought to reflux. Once at reflux, zinc
dust (520 mg, 8 mmol) was added over 5 min and the mix-
ture was allowed to reflux overnight. The solvent was re-
moved and water was added to the residue and basified using
NH4OH. The basic aqueous mixture was extracted with
DCM (3 x 10 mL). The organics were combined, dried using
anhydrous sodium sulphate and concentrated. Column chro-
matography was used to purify the product (eluent
CH2Cl2/CH3OH = 9/1).
(-)-4,14ꢀ-Dihydroxy-5ꢀ-ethyl-3-methoxy-17-methyl-
morphinan-6-one (12b)
M.p.: 184-185.5oC; IR (KBr) 1714 cm-1 (C=O); 1H-NMR
(CDCl3) ꢀ=6.66 (2H, dd, H1, H2, J1-2=7.9); 3.87 (3H, s, C3-
OCH3); 2.47 (3H, s, N-CH3); 1.86 (2H, q, C5-CH2, J=4.2);
0.95 (3H, t, CH2-CH3, J=4.4); MS (ESI) m/z 346 [M+1]+.
Triflation of the Phenolic 4-OH Function and Catalytic
Removal of Triflate
The phenol (1 mmol) and cesium carbonate (385 mg,
1.45 mmol) were mixed with THF (3 mL). Then N-
phenylbis(trifluoromethanesulfonate)amide (450 mg, 1.26
mmol) was added and the mixture stirred at 70°C overnight.
The THF was removed and the residue was dissolved in
DCM, washed with water, dried using anhydrous sodium
sulphate and concentrated. The crude was found pure enough
to use in the next step without further purification. The tri-
flate (0.04 mmol), 9 mg of Pd(OAc)2 (0.04 mmol) and 17 mg
of diphenylphosphinopropane (dppp) (0.04 mmol) was dis-
solved in anhydrous DMF (2.00 mL) and stirred under inert
atmosphere. Then triethylsilane (35 ꢅL, 0.20 mmol) was
added dropwise with a syringe. The mixture was heated at
60°C for 4 h. The DMF was then removed and the residue
was dissolved in DCM (10.0 mL). The organics were
washed with sat. sodium bicarbonate solution (5.00 mL) and
were dried using anhydrous sodium sulphate and concen-
trated. Column chromatography was used to purify the prod-
uct (eluent CH2Cl2/CH3OH = 95/5).
(-)-5ꢀ,17-Dimethyl-4-hydroxy-3-methoxy-7,8-
didehydromorphinan-6-one (9a)
1
M.p.: 189-191oC; IR (KBr) 1679 cm-1 (C=O); H-NMR
(CDCl3) ꢀ=6.59-6.48 (3H, m, H1, H2, H8); 6.13 (1H, d, H7,
J7-8=9.9); 3.89 (3H, s, C3-OCH3); 2.44 (3H, s, N-CH3); 1.19
(3H, d, C5-CH3, J=6.9); MS (ESI) m/z 314 [M+1]+.
(-)-5ꢀ-Ethyl-4-hydroxy-3-methoxy-17-methyl-7,8-
didehydromorphinan-6-one (9b)
M.p.: 177-178oC; IR (KBr) 1681 cm-1 (C=O); H-NMR
1
(CDCl3) ꢀ=6.66-6.57 (3H, m, H1, H2, H8); 6.09 (1H, d, H7,
J7-8=10.9); 3.82 (3H, s, C3-OCH3); 2.47 (3H, s, N-CH3); 1.91
(2H, q, C5-CH2, J=4.1); 1.10 (3H, t, CH2-CH3, J=4.2); MS
(ESI) m/z 328 [M+1]+.
(-)-4,14ꢀ-Dihydroxy-5ꢀ,17-dimethyl-3-methoxy-7,8-
didehydromorphinan-6-one (10a)
M.p.: 197-199oC; IR (KBr) 1689 cm-1 (C=O); H-NMR
1
(CDCl3) ꢀ=6.66-6.54 (3H, m, H1, H2, H8); 6.09 (1H, d, H7,

8
Medicinal Chemistry, 2013, Vol. 9, No. 1
Gyulai et al.
BBr3-mediated O-demethylation of 3-methoxymor-
phinans
(-)-5ꢀ,17-Dimethyl-3-methoxy-7,8-didehydromorphinan-
6-one (13a)
M.p.: 231-232oC; IR (KBr) 1680 cm-1 (C=O); H-NMR
(CDCl3) ꢀ=6.80-6.61 (3H, m, H1, H4, H8); 6.47 (1H, dd,
H2, J=8.3, 2.7); 6.11 (1H, d, H8, J7-8=10.0); 3.87 (3H, s, C3-
OCH3); 2.41 (3H, s, N-CH3); 1.17 (3H, d, C5-CH3, J=6.8);
MS (ESI) m/z 298 [M+1]+.
A solution of well-dried 3-methoxymorphinan (1 mmol)
1
in 10 ml of CH2Cl2 was added during 2 min to a well-stirred
1 M dichloromethane solution of BBr3 (18 mL) at 0oC. The
temperature of in the mixture then allowed rising to room
temperature and stirred for further 15 min. The reaction mix-
ture which consisted of a suspension of white solid (in
CH2Cl2) was then poured into a well-stirred mixture of 8 g of
ice and 20 ml of concentrated (28-30%) NH4OH. The two-
phase system was kept at -5 to 0oC for 0.5 h (continuous
stirring) and filtered. The resulting crystalline material was
washed thoroughly with small portions of cold CH2C12 and
H2O and dried to give the desired deprotected morphinan.
The pure base was turned into hydrochloride salt form by the
addition of HCl gas adsorbed in ether.
(-)-5ꢀ-Ethyl-3-methoxy-17-methyl-7,8-
didehydromorphinan-6-one (13b)
1
M.p.: 192-194oC; IR (KBr) 1688 cm-1 (C=O); H-NMR
(CDCl3) ꢀ=6.73-6.58 (3H, m, H1, H4, H8); 6.41 (1H, dd,
H2, J=8.1, 2.9); 6.07 (1H, d, H7, J7-8=10.4); 3.81 (3H, s, C3-
OCH3); 2.39 (3H, s, N-CH3); 1.81 (2H, q, C5-CH2, J=4.1);
1.05 (3H, t, CH2-CH3, J=4.0); MS (ESI) m/z 312 [M+1]+.
(-)-5ꢀ,17-Dimethyl-14ꢀ-hydroxy-3-methoxy-7,8-
didehydromorphinan-6-one (14a)
M.p.: 209-210.5oC; IR (KBr) 1679 cm-1 (C=O); 1H-NMR
(CDCl3) ꢀ=6.76-6.61 (3H, m, H1, H4, H8); 6.37 (1H, dd,
H2, J=7.9, 3.0); 6.05 (1H, d, H7, J7-8=10.4); 3.81 (3H, s, C3-
OCH3); 2.46 (3H, s, N-CH3); 1.23 (3H, d, C5-CH3, J=7.3);
MS (ESI) m/z 314 [M+1]+.
(-)-5ꢀ,17-Dimethyl-3-hydroxy-7,8-didehydromorphinan-
6-one.HCl (17a.HCl)
1
M.p.: 148-150oC; IR (KBr) 1676 cm-1 (C=O); H-NMR
(DMSO-d6) ꢀ=10.10-9.91 (2H, NH+, 3-OH, br s); 6.74-6.65
(2H, m, H1, H4); 6.53-6.49 (2H, m, H2, H8); 6.10 (1H, d,
H7, J7-8=10.0); 2.83 (3H, s, N-CH3); 1.15 (3H, d, C5-CH3,
J=6.9); MS (ESI) m/z 284 [M+1]+; calculated for
C18H21NO2.HCl: C, 67.60; H, 6.93; found: C, 67.54; H, 6.99.
(-)-5ꢀ-Ethyl-14ꢀ-hydroxy-3-methoxy-17-methyl-7,8-
didehydromorphinan-6-one (14b)
(-)-5ꢀ-Ethyl-3-hydroxy-17-methyl-7,8-
1
M.p.: 179-181oC; IR (KBr) 1679 cm-1 (C=O); H-NMR
didehydromorphinan-6-one.HCl (17b.HCl)
(CDCl3) ꢀ=6.73-6.61 (3H, m, H1, H4, H8); 6.43 (1H, dd,
H2, J=8.0, 2.9); 6.11 (1H, d, H7, J7-8=10.1); 3.87 (3H, s, C3-
OCH3); 2.44 (3H, s, N-CH3); 1.79 (2H, q, C5-CH2, J=4.5);
0.95 (3H, t, CH2-CH3, J=4.4); MS (ESI) m/z 328 [M+1]+.
1
M.p.: >250oC; IR (KBr) 1691 cm-1 (C=O); H-NMR
(DMSO-d6) ꢀ=10.55-9.83 (2H, NH+, 3-OH, br s); 6.77-6.71
(2H, m, H1, H4); 6.57-6.43 (2H, m, H2, H8); 6.17 (1H, d,
H7, J7-8=10.4); 2.86 (3H, s, N-CH3); 1.88 (2H, q, C5-CH2,
J=4.1); 1.01 (3H, t, CH2-CH3, J=4.3); MS (ESI) m/z 298
[M+1]+; calculated for C19H23NO2.HCl: C, 68.35; H, 7.25;
found: C, 68.24; H, 7.30.
(-)-5ꢀ,17-Dimethyl-3-methoxy-morphinan-6-one (15a)
1
M.p.: 168-170oC; IR (KBr) 1723 cm-1 (C=O); H-NMR
(CDCl3) ꢀ=6.68-6.61 (2H, m, H1, H4); 6.50 (1H, dd, H2,
J=8.1, 1.9); 3.81 (3H, s, C3-OCH3); 2.42 (3H, s, N-CH3);
1.16 (3H, d, C5-CH3, J=7.4); MS (ESI) m/z 300 [M+1]+.
(-)-3,14ꢀ-Dihydroxy-5ꢀ,17-dimethyl-7,8-
didehydromorphinan-6-one.HCl (18a.HCl)
1
M.p.: 249-251oC; IR (KBr) 1683 cm-1 (C=O); H-NMR
(-)-5ꢀ-Ethyl-3-methoxy-17-methyl-morphinan-6-one
(15b)
(DMSO-d6) ꢀ=9.90-9.73 (2H, NH+, 3-OH, br s); 6.73-6.68
(2H, m, H1, H4); 6.59-6.50 (2H, m, H2, H8); 6.35 (1H, d,
H7, J7-8=10.0); 2.79 (3H, s, N-CH3); 1.20 (3H, d, C5-CH3,
J=7.2); MS (ESI) m/z 300 [M+1]+; calculated for
C18H21NO3.HCl: C, 64.38; H, 6.60; found: C, 64.19; H, 6.69.
1
M.p.: 168-170oC; IR (KBr) 1723 cm-1 (C=O); H-NMR
(CDCl3) ꢀ=6.70-6.64 (2H, m, H1, H4); 6.48 (1H, dd, H2,
J=8.0, 2.2); 3.87 (3H, s, C3-OCH3); 2.46 (3H, s, N-CH3);
1.81 (2H, q, C5-CH2, J=4.1); 0.97 (3H, t, CH2-CH3, J=4.2);
MS (ESI) m/z 314 [M+1]+.
(-)-3,14ꢀ-Dihydroxy-5ꢀ-ethyl-17-methyl-7,8-
didehydromorphinan-6-one.HCl (18b.HCl)
(-)-5ꢀ,17-Dimethyl-4ꢀ-hydroxy-3-methoxy-morphinan-
6-one (16a)
1
M.p.: >250oC; IR (KBr) 1682 cm-1 (C=O); H-NMR
(DMSO-d6) ꢀ=9.79-9.43 (2H, NH+, 3-OH, br s); 6.72-6.54
(2H, m, H1, H4); 6.54-6.49 (2H, m, H2, H8); 6.35 (1H, d,
H7, J7-8=10.1); 2.80 (3H, s, N-CH3); 1.87 (2H, q, C5-CH2,
J=4.2); 1.06 (3H, t, CH2-CH3, J=4.3); MS (ESI) m/z 314
[M+1]+; calculated for C19H23NO3.HCl: C, 65.23; H, 6.91;
found: C, 65.37; H, 6.98.
1
M.p.: 211-213oC; IR (KBr) 1719 cm-1 (C=O); H-NMR
(CDCl3) ꢀ=6.71-6.64 (2H, m, H1, H4); 6.51 (1H, dd, H2,
J=7.8, 2.0); 3.85 (3H, s, C3-OCH3); 2.47 (3H, s, N-CH3);
1.19 (3H, d, C5-CH3, J=7.1); MS (ESI) m/z 316 [M+1]+.
(-)-5ꢀ-Ethyl-14ꢀ-hydroxy-3-methoxy-17-methyl-
morphinan-6-one (16b)
(-)-5ꢀ,17-Dimethyl-3-hydroxy-morphinan-6-one.HCl
(19a.HCl)
1
M.p.: 199oC (decomp.); IR (KBr) 1730 cm-1 (C=O); H-
1
M.p.: >250oC; IR (KBr) 1730 cm-1 (C=O); H-NMR
NMR (CDCl3) ꢀ=6.66-6.57 (2H, m, H1, H4); 6.43 (1H, dd,
H2, J=7.9, 2.1); 3.80 (3H, s, C3-OCH3); 2.41 (3H, s, N-
CH3); 1.82 (2H, q, C5-CH2, J=4.4); 1.05 (3H, t, CH2-CH3,
J=4.3); MS (ESI) m/z 330 [M+1]+.
(DMSO-d6) ꢀ=10.06-9.81 (2H, NH+, 3-OH, br s); 6.73-6.68
(2H, m, H1, H4); 6.35 (1H, dd, H2, J=8.0, 1.9); 2.76 (3H, s,
N-CH3); 1.17 (3H, d, C5-CH3, J=7.0); MS (ESI) m/z 286

Synthesis and Opioid Activity of Novel 6-ketolevorphanol Derivatives
Medicinal Chemistry, 2013, Vol. 9, No. 1
9
[M+1]+; calculated for C18H23NO2.HCl: C, 67.17; H, 7.52;
found: C, 67.31; H, 7.66.
affinities for the ꢆ, ꢇ and ꢁ opioid receptors were determined
by displacing [3H]DAMGO, [3H][Ile5,6]deltorphin-2 and
[3H]U69,593 respectively. Briefly, crude membrane prepara-
tions, isolated from Wistar rat brains or guinea pig brains,
were incubated at 25°C for 120 min. with appropriate con-
centration of a tested peptide in the presence of 0.5 nM radi-
oligand in a total volume of 0.5 ml of Tris/HCl (50 mM, pH
7.4), containing MgCl2 (5 mM), EDTA (1 mM), NaCl (100
mM), and bacitracin (20 mg/L). Non-specific binding was
determined in the presence of naloxone (1 ꢀM). Incubations
were terminated by rapid filtration through Whatman GF/B
(Brentford, UK) glass fiber strips, which had been pre-
soaked for 2 h in 0.5 % polyethylamine, using Millipore
Sampling Manifold (Billerica, USA). The filters were
washed three times with 4 ml of ice-cold Tris buffer solu-
tion. The bound radioactivity was measured in Packard Tri-
Carb 2100 TR liquid scintillation counter (Ramsey, MN,
USA) after overnight extraction of the filters in 4 ml of
Perkin Elmer Ultima Gold scintillation fluid (Wellesley,
MA, USA). Three independent experiments for each assay
were carried out in duplicate.
(-)-5ꢀ-Ethyl-3-hydroxy-17-methyl-morphinan-6-one.HCl
(19b.HCl)
1
M.p.: >250oC; IR (KBr) 1727 cm-1 (C=O); H-NMR
(DMSO-d6) ꢀ=9.86-9.65 (2H, NH+, 3-OH, br s); 6.77-6.71
(2H, m, H1, H4); 6.41 (1H, dd, H2, J=8.2, 2.1); 2.84 (3H, s,
N-CH3); 1.77 (2H, q, C5-CH2, J=4.1); 0.96 (3H, t, CH2-CH3,
J=4.3); MS (ESI) m/z 300 [M+1]+; calculated for
C19H25NO2.HCl: C, 67.94; H, 7.80; found: C, 67.82; H, 7.91.
(-)-3,14ꢀ-Dihydroxy-5ꢀ,17-dimethyl-morphinan-6-
one.HCl (20a.HCl)
M.p.: 176-178oC (Decomp.); IR (KBr) 1721 cm-1 (C=O);
1H-NMR (DMSO-d6) ꢀ=10.01-9.73 (2H, NH+, 3-OH, br s);
6.78-6.69 (2H, m, H1, H4); 6.38 (1H, dd, H2, J=8.1, 1.8);
2.81 (3H, s, N-CH3); 1.15 (3H, d, C5-CH3, J=7.1); MS (ESI)
m/z 302 [M+1]+; calculated for C18H23NO3.HCl: C, 63.99; H,
7.16; found: C, 63.89; H, 7.29.
(-)-3,14ꢀ-Dihydroxy-5ꢀ-ethyl-17-methyl-morphinan-6-
one.HCl (20b.HCl)
Animals
1
M.p.: >250oC; IR (KBr) 1727 cm-1 (C=O); H-NMR
(DMSO-d6) ꢀ=9.91-9.71 (2H, NH+, 3-OH, br s); 6.79-6.71
(2H, m, H1, H4); 6.44 (1H, dd, H2, J=8.0, 2.1); 2.80 (3H, s,
N-CH3); 1.72 (2H, q, C5-CH2, J=4.0); 1.00 (3H, t, CH2-CH3,
J=4.1);MS (ESI) m/z 316 [M+1]+; calculated for
C19H25NO3.HCl: C, 64.85; H, 7.45; found: C, 64.81; H, 7.69.
Male Swiss albino mice (CD1, Charles River, Canada),
weighing 20-26 g, were used throughout the studies. The
animals were housed at a constant temperature (22°C) and
maintained under a 12-h light/dark cycle in sawdust coated
plastic cages with access to standard laboratory chow and tap
water ad libitum. Animal use for these studies was approved
by the University of Calgary Animal Care Committee and
the experiments were performed in accordance with institu-
tional animal ethics committee guidelines that follow the
guidelines established by the Canadian Council on Animal
Care.
Crystallographic Details of Compound 12
X-ray data were collected on a Bruker-Nonius MACH3
diffractometer at 293 K, Mo Kꢃ radiation ꢂ=0.71073 Å, ꢃ
motion. The structure was solved using the SIR-92 software
[23] and refined on F2 using SHELX-97 program [24], pub-
lication material was prepared with the WINGX-97 suite
[25]. All non-hydrogen atoms were refined anisotropically.
Crystallographic data (excluding structure factors) for struc-
ture 12a have been deposited in the Cambridge Crystallo-
graphic Data Centre as supplementary publication no. CCDC
820388. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: +44 (0)1223 336033 or e-mail: de-
posit@ccdc.cam.ac.uk).
Isolated Smooth Muscle Strips
The experiments were performed as described elsewhere
[26]. Mice were sacrificed by cervical dislocation. Full-
thickness (1 cm) segments of the distal ileum were removed
and kept in ice-cold oxygenated Krebs-Ringer Solution
(mmol/L: NaCl 119, KCl 4.7, KH2PO4 1.2, NaHCO3 25,
MgSO4 1.5, CaCl2 2.5, and glucose 11). Luminal contents
were gently flushed. The preparations were mounted be-
tween two platinum electrodes and placed in separate organ
baths (25 mL; 37°C; oxygenated with 95% O2 / 5% CO2).
Using a silk thread, one end of each preparation was attached
to the bottom of the organ bath, while the other end was
connected to a FT03 force displacement transducer (Grass
Technologies, West Warwick, RI, USA). 0.5 g tension was
applied and the preparations were allowed to equilibrate for
30 min. Changes in tension were amplified by a P11T Com-
pact Transducer Amplifier (Grass Technologies, West War-
wick, RI, USA) and recorded on personal computer using the
PolyView software (Polybytes Inc., Chedar Rapids, Iowa,
USA). All experiments lasted less than 3 h and each prepara-
tion was used for a single experiment only. Electrical field
stimulation (EFS; 8 Hz, 24 V, stimulus duration 0.5 msec,
train duration 10 sec) was applied by a S88X Dual Output
Square Pulse Stimulator (Grass Technologies, West War-
wick, RI, USA). Compounds (10-10– 10-6 M) were added
cumulatively into the organ baths and effects on the EFS
Crystal Data
C19H25NO3
V = 1721.5 (3) Å3
Z = 4
Mr = 315.4
Orthorhombic, P212121
a = 8.845 (1) Å
b = 11.589 (1) Å
c = 16.794 (1) Å
Mo Kꢃ radiation, ꢂ = 0.71073 Å
ꢂ = 0.08 mmꢀ1
T = 293 K
0.45 ꢁ 0.25 ꢁ 0.2 mm
Pharmacology
Radioligand binding assay. The opioid receptor binding
assays were performed using rat brain (for the ꢆ and ꢇ recep-
tors) or guinea pig brain (for the ꢁ receptor) membrane
preparations, as reported in detail elsewhere [17]. Binding

10 Medicinal Chemistry, 2013, Vol. 9, No. 1
Gyulai et al.
ogical importance of morphine analogues. Acta Physiol. Hung.,
2008, 95, 3-44.
induced contractions were recorded. Each concentration was
allowed to incubate for 10 minutes.
[9]
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ACKNOWLEDGEMENTS
The authors are indebted for the support of the Hungarian
Science Fund (NKTH-OTKA K68482, K81701 and 101372)
and the Research Group of Homogeneous Catalysis, MTA-
DE. A. Udvardy acknowledges the predoctoral employment
grant TÁMOP-4.2.2/B-10/1/KONV-2010-0024. The project
is co-financed by the European Union and the European So-
cial Fund. The work was also supported by Juventus Plus
Program of the Polish Ministry of Science and Higher Edu-
cation #IP 2010 008970 (to JF).
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Received: November 16, 2011
Revised: April 25, 2012
Accepted: April 26, 2012