4'-Arylpyrrolomorphinans: effect of a pyrrolo-N-benzyl substituent in enhancing delta-opioid antagonist activity.

Article abstract of DOI:10.1021/jm010841w

A new method for the preparation of N-benzylpyrrolomorphinans has been developed. Thus Michael reaction of the benzylimines of oxycodones and oxymorphones with nitrostyrenes gave a series of 4'-aryl-N-benzylpyrrolomorphinans. These were selective delta an

Full text of DOI:10.1021/jm010841w

J . Med. Chem. 2002, 45, 537-540
537
4′-Ar ylp yr r olom or p h in a n s: Effect of a P yr r olo-N-ben zyl Su bstitu en t in
En h a n cin g δ-Op ioid An ta gon ist Activity
Sanjay K. Srivastava,† Stephen M. Husbands,‡ Mario D. Aceto,| Carl N. Miller,§ J ohn R. Traynor,§ and
J ohn W. Lewis*,†
School of Chemistry, University of Bristol, Bristol BS8 1TS, U.K., Department of Pharmacy and Pharmacology,
University of Bath, Bath BA2 7AY, U.K., Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109,
and Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond, Virginia 23298
Received February 7, 2001
A new method for the preparation of N-benzylpyrrolomorphinans has been developed. Thus
Michael reaction of the benzylimines of oxycodones and oxymorphones with nitrostyrenes gave
a series of 4′-aryl-N-benzylpyrrolomorphinans. These were selective δ antagonists of much
higher in vitro potency (with 5a having Ke δ ) <1 nM) than their binding affinities predicted.
In mice in vivo assays 5a showed good δ antagonist activity in the antiwrithing analgesic assay
and also inhibited δ agonist-induced convulsant activity.
In tr od u ction
The development of selective antagonists for µ, κ, and
δ opioid receptors has allowed both the role of these
receptors to be defined and the selectivity of agonists
to be determined.1 The functions in which δ receptors
are implicated are quite varied.1 δ Agonists were first
of interest as offering analgesia without the problems
associated with the traditional µ agonist analgesics, e.g.,
morphine.2,3 But δ agonists also have antidiarrheal
effects without affecting gastric mobility4,5 and are
immunostimulants6-8 and stimulants of respiration.9 δ
Antagonists are immunosuppressants10 and prevent the
and modest (2d ) or substantial δ selectivity (2b, 2c). In
development of tolerance and dependence with µ ago-
the mouse vas deferens assay, only the 4′-benzyl deriva-
nists11 so that opioids with mixed µ agonist, δ antagonist
tive (2c) showed potent δ antagonist activity and
profiles have beeen recognized as having potential as
significant δ selectivity. The unsubstituted pyrrolomor-
analgesics for the relief of severe pain.12
phinan (2a ) was a potent opioid antagonist without
The first non-peptide selective δ opioid antagonist was
naltrindole13 (1a , NTI) which was prepared from nal-
trexone (3a ) by Fischer indolization. The effect of
introducing the indolic group was to increase δ affinity
but also to reduce µ and κ affinity. N-Benzylnaltrindole
(1b, BNTI) showed improved δ antagonist selectivity
over NTI in smooth muscle preparations primarily as a
result of having reduced µ antagonist potency.14 BNTI
had prolonged duration of δ antagonist activity in vivo
by icv administration and displayed selectivity for a
subtype of δ receptor (δ2) for which the peptide δ agonist
DSLET showed preferential binding.
In a study of the effect of steric hindrance on δ
selectivity, Farouz-Grant and Portoghese15 synthesized
pyrrolomorphinans (e.g., 2b,c,d ) substituted in the 4′-
and 5′-positions in low yields by condensation of nal-
trexone with R-aminoketones under acidic conditions
(Knorr reaction). These pyrrolomorphinans displayed
high affinity for δ receptors in receptor binding assays
selectivity.16
We have recently investigated reactions of the ben-
zylimines of morphinan-6-ones with Michael acceptors
including nitro-alkenes.17 We here report the synthesis
and evaluation of a series of N-benzyl pyrrolomorphi-
nans (5) prepared by these procedures. It was expected
that the introduction of the pyrrole N-benzyl group, as
in BNTI (1b), would enhance δ opioid interaction with
a lipophilic binding site.
Syn th esis
Although the benzylimines of oxycodones and oxy-
morphones (3) could not be easily isolated, when gener-
ated in situ, they reacted smoothly with nitrostyrenes
to give the required N-benzylpyrrolomorphinans in 50-
70% yields (Scheme 1).
Resu lts
The new ligands were evaluated in binding assays in
human recombinant opioid receptors transfected into
Chinese hamster ovary (CHO) cells in which the dis-
placed radioligands were [3H]DAMGO (µ), [3H]Cl-DP-
DPE (δ), and [3H]U69593 (κ) (Table 1).18 The 4′-
phenylpyrrolomorphinans (5a -f) displayed modest
affinity for δ receptors. The values for the 17-N-
* Corresponding author: J ohn W. Lewis, Department of Pharmacy
and Pharmacology, University of Bath, Bath, BA2 7AY, U.K. Tel. U.K.
1225 826 826 ext 3103. Fax: 1225 826 114. E-mail: prxjwl@bath.ac.uk.
† University of Bristol.
‡ University of Bath.
§ University of Michigan.
| Medical College of Virginia.
10.1021/jm010841w CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/19/2001

538 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 2
Brief Articles
Ta ble 3. Effect of Preincubation Time on the Affinity (Ke) of
5a Evaluated against the δ Agonist DPDPE in the Mouse vas
Deferens Preparationa
Sch em e 1
5a
(nM)
preincubation
time
DPDPE
IC50
Ke
(nM)
fold-shift
0
3
30
0
2.87 (2.3-3.5)
2.85 (1.9-4.2)
9.03 (7.5-10.9)
3.83 (2.7-5.3)
22.85 (19.7-26.5)
30 min
30 min
-
3.14
14.0
0.6
3
2 h
5.97
a
IC50 values were determined by nonlinear curve fitting
(GraphPad Prizm; San Diego, CA) using pooled data from four
tissues. IC50 values are given with 95% confidence intervals (CI).
Significance differences occur if the 95% CIs do not overlap.
(5b) and particularly a 5′-methyl group (5c) resulted in
some loss of κ and δ antagonist potency and, in the case
of 5b, in the appearance of µ partial agonist activity.
The 17-propyl analogue (5d ) was similar to 5a but with
15-fold lower δ antagonist potency. All of these δ
antagonists showed substantial selectivity in vitro for
δ over κ. More limited differentiation between δ and µ
antagonist potency was observed. The 17-N-methyl
analogue (5f) showed δ partial agonist activity of modest
potency and efficacy. Though it was a very low potency
κ antagonist, as a µ antagonist 5f showed good potency
in line with its binding profile in which it had greater
affinity for µ than for δ receptors.
The δ antagonist activity of 5a was also determined
in MVD versus DPDPE.23 When 5a was preincubated
for 30 min with the tissue, a Ke of 14.5 nM was obtained,
showing very much lower potency than expected from
the δ antagonist potency in the [35S]GTPγS assay.
However, with increased incubation time (2 h), 5a
caused a much bigger shift in the concentration effect
curve for DPDPE such that the IC50 obtained was
significantly different when 3 nM 5a was incubated for
2 h compared to 30 nM 5a for 30 min. This resulted in
a bigger rightward shift and a Ke in line with results
from the [35S]GTPγS assay (Table 3).
Ta ble 1. Receptor Binding of Pyrrolomorphinans (5) to
Recombinant Human Opioid Receptors Transfected into CHO
Cells
Ki (nM)
ligand
µ
δ
κ
µ/δ
κ/δ
5a
5b
5c
5d
16.8 ( 6.2
77.9 ( 25
52.7 ( 19
40.1 ( 5.9
>10000
13.7 ( 0.3
23.5 ( 1.4
17.3 ( 0.2
21.2 ( 9.8
322 ( 43
116 ( 52
2.7 ( 1.1c
0.2 ( 0.05
120 ( 9.6
108 ( 11
183 ( 16
191 ( 3.9
>10000
1.2
3.3
3.0
1.9
>31
0.43
7.8
31
8.8
4.6
10.6
9.0
>31
1.6
5e
5f
49.5 ( 16
21 ( 7
187 ( 46
45 ( 5
2d a,b
NTI
16.7
50
6.3 ( 2.3
10.1 ( 0.65
a
b
Data from ref 15. Using ICR mouse brain membrane. c By
displacement of [3H]NTI.
Ta ble 2. Antagonist Activities of 4′-Phenylpyrrolomorphinans
in [35S]GTPγS Assays in Human Recombinant Receptors in
CHO Cells
Ke (nM)
ligand
µ
δ
κ
µ/δ
κ/δ
5a
5b
5c
5d
5f
NTI
8.09 ( 1.9
a, b
17.7 ( 2.5
45.3 ( 4.1
14.1 ( 1.8
4.26 ( 0.3
0.43 ( 0.09
2.37 ( 0.46
3.68 ( 0.75
6.4 ( 0.52
a, c
21.6 ( 1.7
61.1 ( 11
306 ( 9
19
50
26
83
33
An investigation of the in vivo δ antagonist activity
of 5a was undertaken in the mouse abdominal stretch
assay with p-phenylquinone as the nociceptive agent.22
The test drug was administered subcutaneously 10 min
before SNC8020 (18 mg/kg) as the selective δ agonist.
The AD50 dose for 5a was 4.34 (1.55-12.21) mg/kg
which compares with the AD50 for naltrindole of 1.69
(0.43-7.40) mg/kg. At a dose of 32 mg/kg, SNC8O causes
δ mediated convulsions in 6/6 mice.21 In the presence
5
7
210 ( 13
1155 ( 184
4.95 ( 0.32
0.11 ( 0.005
39
45
a
b
Partial agonist. EC50 ) 1360 nM; max effect ) 34% of
standard (DAMGO). c EC50 ) 55.2 nM; max effect ) 41% of
standard (Cl-DPDPE).
cyclopropylmethyl (5a -c) and 17-N-propyl (5d ) deriva-
tives were consistently in the Ki ) 10-30 nM range
whereas those for 17-N-methyl analogues (5e, 5f) were
>100nM. Though δ affinity was generally significantly
higher than κ affinity and marginally higher than µ,
there was no real selectivity of δ opioid receptor binding
in this series except for oxycodone derivative 5e, but it
had very low affinity.
The antagonist affinity (Ke) of ligands 5a -f was
determined in [35S]GTPγS assays in cloned human
opioid receptors transfected into CHO cells.18,19 Ke
values were obtained for the activity of the test com-
pounds in antagonizing the effect of standard agonists
for µ (DAMGO), δ (Cl-DPDPE), and κ (U69593) receptors
(Table 2). The 17-cyclopropylmethyl derivatives (5a -
c) and the 17-N-propyl derivative (5d ) were all potent
δ antagonists; 5a was the most potent and selective,
having Ke δ ) 0.43 nM. Introduction of a p-methyl group
2
of 10 and 32 mg/kg 5a , only 3/6 and /6 mice, respectively,
showed the convulsive response to SNC80, confirming
the in vivo δ antagonist action of 5a .
Discu ssion
Comparison of the data for the 4′-phenylpyrrolomor-
phinan (5a ) with the equivalent ligand lacking the 1′-
N-benzyl group (2d )15 shows that in binding to opioid
receptors, the effect of the N-benzyl group is to reduce
δ affinity with no effect on µ affinity and a smaller effect
on κ, resulting in lower δ selectivity. However, compari-
son in opioid receptor functional assays presents a
different picture. In the [35S]GTPγS assay, 5a was a δ
selective antagonist about a quarter as potent as NTI,
and in MVD, in which 2d had no δ antagonist activity,15
5a also was a potent δ antagonist. The much greater
potency of 5a over the nonbenzylated parent 2d in MVD

Brief Articles
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 2 539
mL, 1.50 mmol), EtOH (2.0 mL), and trans-4-methyl-â-
nitrostyrene (0.24 g, 1.47 mmol) were treated as described for
5a to provide 5b (0.57 g, 71%): Rf 0.82 (0.5% MeOH/DCM);
mp 243 °C; 1H NMR 7.31 (m, 5H, Ph), 7.10 (m, 4H, ArH), 6.80
(s, 1H, H-2′), 6.61 (d, 1H, J ) 8.1, H-2), 6.54 (d, 1H, J ) 8.1,
H-1), 5.41 (s, 1H, H-5), 5.34 (d, 1H, J ) 15.6, benzylic proton),
5.23 (d, 1H, J ) 15.6, benzylic proton), 3.28 (d, 1H, H-9), 3.14
(d, 1H, J ) 18.5, H-10), 2.80 (dd, 1H, J ) 6.6, 18.5, H-10),
2.65 (m, 2H), 2.42 (m, 2H), 2.25 (m, 6H), 1.65 (m, 1H), 0.88
(m, 1H, H-19), 0.52 (m, 2H, H-20, H-21), 0.15 (m, 2H, H-20,
H-21); 13C NMR 141.77, 139.83, 135.74, 134.46, 129.94, 129.68,
128.53, 128.48, 128.07, 126.37, 126.14, 123.91, 121.72, 119.65,
118.25, 117.46, 85.61, 74.47, 63.57, 60.39, 54.77, 51.44, 44.88,
32.75, 31.87, 23.98, 21.06, 10.17, 4.58, 4.05; EI MS m/z (relative
intensity) 544 (M+, 100%), 91 (70%). Anal. (C36H36N2O3‚2HCl‚
0.25H2O) C, H, N.
1′-Ben zyl-17-cyclop r op ylm eth yl-6,7-d ed ih yd r o-3,14-d i-
h yd r oxy-4,5r-ep oxy-5′-m eth yl-4′-p h en ylp yr r olo[2′,3′:6,7]-
m or p h in a n (5c). Naltrexone (0.80 mg, 2.35 mmol), benzyl-
amine (0.24 mL, 2.40 mmol), EtOH (2.0 mL), and trans-â-
methyl-â-nitrostyrene (0.39 g, 2.35 mmol) were treated as
described for 5a to give 5c (0.63 g, 49%): Rf 0.89 (0.5% MeOH/
DCM); mp 235 °C; 1H NMR 7.28 (m, 5H, Ph), 7.13 (m, 5H,
Ph), 6.60 (d, 1H, J ) 8.0, H-2), 6.52 (d, 1H, J ) 8.0, H-1), 5.47
(s, 1H, H-5), 5.44 (d, 1H, J ) 17.0, benzylic proton), 5.26 (d,
1H, J ) 17.0, benzylic proton), 3.24 (d, 1H, J ) 6.4, H-9), 3.10
(d, 1H, J ) 18.5, H-10), 2.72 (m, 2H), 2.50 (d, 2H, J ) 11.0),
2.40 (m, 2H), 2.24 (m, 2H), 2.04 (s, 3H, CH3), 1.64 (m, 1H),
0.87 (m, 1H, H-19), 0.54 (m, 2H, H-20, H-21), 0.14 (m, 2H,
H-20, H-21); 13C NMR 140.18, 130.76, 129.67, 129.04, 128.85,
128.06, 127.49, 126.36, 124.52, 119.53, 118.18, 86.06, 74.62,
63.55, 60.35, 48.37, 44.91, 32.75, 31.17, 23.96, 10.72, 10.19,
4.56, 4.05; EI MS m/z (relative intensity) 544 (M+, 100%), 91
(70%). Anal. (C36H36N2O3‚2HCl‚0.25H2O) C, H, N.
1′-Ben zyl-6,7-d ed ih yd r o-3,14-d ih yd r oxy-4,5r-ep oxy-17-
p r op yl-4′-p h en ylp yr r olo[2′,3′:6,7]m or p h in a n (5d ). 19,20-
Dihydronaloxone (0.92 g, 2.79 mmol), benzylamine (0.34 mL,
2.85 mmol), EtOH (2.0 mL), and trans-â-nitrostyrene (0.42 g,
2.79 mmol) were treated as described for 5a to give 5d (0.83
g, 58%): Rf 0.94 (0.5% MeOH/DCM); mp 241 °C; 1H NMR 7.26
(m, 9H, Ph), 7.06 (m, 1H, Ph), 6.81 (s, 1H, H-2′), 6.62 (d, 1H,
J ) 8.2, H-2), 6.55 (d, 1H, J ) 8.2, H-1), 5.40 (s, 1H, H-5),
5.34 (d, 1H, J ) 15.6, benzylic proton), 5.21 (d, 1H, J ) 15.6,
benzylic proton), 3.14 (d, 1H, J ) 18.6, H-10), 3.05 (d, 1H, J )
6.3, H-9), 2.82 (dd, 1H, J ) 6.3, 18.6, H-10), 2.55 (m, 5H), 2.23
(m, 2H), 1.54 (m, 3H), 0.91 (t, 3H, J ) 7.3, CH3); 13C NMR
142.87, 138.82, 128.58, 128.28, 127.37, 127.32, 126.72, 125.37,
124.50, 122.93, 121.35, 118.76, 85.08, 73.02, 62.95, 56.38,
50.50, 30.61, 23.41, 11.73; EI MS m/z (relative intensity) 518
(M+,80%), 489 (100%), 91 (90%). Anal. (C34H34N2O3‚2HCl‚
0.25H2O) C, H, N.
1′-Ben zyl-6,7-dedih ydr o-4,5r-epoxy-14-h ydr oxy-3-m eth -
oxy-17-m eth yl-4′-p h en ylp yr r olo[2′,3′:6,7]m or p h in a n (5e).
Oxycodone (1.0 g, 3.18 mmol), benzylamine (0.38 mL, 3.20
mmol), EtOH (3. 0 mL), and trans-â-nitrostyrene (0.48 g, 3.18
mmol) were treated as described for 5a to afford 5e (0.97 g,
61%): Rf 0.64 (0.15% MeOH/DCM); mp 218 °C; 1H NMR 7.28
(m, 9H, Ph), 7.08 (m, 1H, Ph), 6.84 (s, 1H, H-2′), 6.73 (d, 1H,
J ) 8.3, H-2), 6.65 (d, 1H, J ) 8.3, H-1), 5.44 (s, 1H, H-5),
5.26 (bs, 2H, benzylic proton), 3.88 (s, 3H, O-CH3), 3.25 (d,
1H, J ) 18.7, H-10), 2.96 (d, 1H, J ) 6.4, H-9), 2.79 (dd, 1H,
J ) 6.4, 18.7, H-10), 2.65 (m, 2H), 2.47 (d, 1H, J ) 7.0), 2.39
(s, 3H, N-CH3), 2.26 (m, 2H), 1.61 (m, 1H); 13C NMR 145.86,
144.68, 139.86, 137.38, 132.69, 129.69, 129.36, 128.51, 128.46,
128.21, 127.82, 126.39, 126.27, 124.16, 122.14, 119.82, 117.54,
116.03, 85.74, 74.69, 66.14, 57.32, 51.42, 46.38, 43.18, 32.52,
32.00, 23.40; EI MS m/z (relative intensity) 504 (M+, 100%),
91 (40%). Anal. (C33H32N2O3‚2HCl) C, H, N.
was unexpected since the potency of BNTI (1b) was only
half that of NTI (1a ).14 It was also surprising that 5a
displayed slow kinetics in MVD, requiring 2 h incuba-
tion to achieve high δ antagonist potency. BNTI attained
high potency in MVD after only 15 min pretreatment
of the tissue. The lead compound of this series (5a ) was
also a good δ antagonist of the selective δ agonist SNC80
in the mouse writhing assay with nearly half the
potency of NTI. This in vivo activity was not slow in
onset in contrast to the antagonist activity in MVD and
to the slow onset of the δ2-antagonism of BNTI after
icv administration.14
In summary, a series of pyrrolomorphinans has been
synthesized by a procedure that gave much higher yields
than those previously reported for this class. The pyrrole
N-benzyl group had marked effects on the opioid recep-
tor profiles of the new ligands. In particular, the
1′-benzyl-4′-phenyl derivative (5a ) was a much more
potent and selective δ antagonist than its 1′-H parent
(2d ) and had in vivo antagonist activity comparable to
NTI.
Exp er im en ta l Section
Ch em istr y. Solvents and reagents were purchased from
either Aldrich or Lancaster and used as supplied. All TLC data
(Rf values) were determined with aluminum sheets coated with
silica gel 60 F254 (Merck) and eluted with 20% MeOH/DCM.
All the compounds were purified by gravity-elution column
chromatography using flash silica gel (Fluka; silica gel 60,
mesh 220-240). Yields are of purified compounds and were
not optimized. The 1H (300 MHz) and 13C (75 MHz) NMR
spectra were recorded on a J EOL J NM -GX FT 300 spectrom-
eter at ambient temperature in CD3OD, and chemical shifts
are reported as δ in ppm relative to tetramethylsilane (TMS).
J values are reported in hertz. Mass spectra were obtained
on a Fission Autospectrometer with electron impact ionization
(70 eV). Compounds for pharmacological analysis were con-
verted into their hydrochloride salts by dissolving in methanol
and adding methanolic HCl. Melting points (of hydrochloride
salts) were determined in capillary tubes with a Reichert hot-
stage cap melting point apparatus and are uncorrected.
Elemental analyses were obtained from a Carlo Erba EA 1108
analyzer, and the results were within (0.4 of theoretical
values.
1′-Ben zyl-17-cyclop r op ylm eth yl-6,7-d ed ih yd r o-3,14-d i-
h yd r oxy-4,5r-ep oxy-4′-p h en ylp yr r olo[2′,3′:6,7]m or p h i-
n a n (5a ). Benzylamine (0.18 mL, 1.51 mmol) and p-toluene-
sulfonic acid monohydrate (1 mg) were added to a solution of
naltrexone (0.50 g, 1.47 mmol) in dry EtOH (1.5 mL) and
refluxed in the presence of molecular sieves (4 Å) under
nitrogen for 3 h. trans-â-Nitrostyrene (0.22 g, 1.47 mmol) was
added, and the resulting solution was further allowed to reflux
for 8 h. It was then cooled and filtered. The EtOH was removed
under reduced pressure, and the solid obtained was washed
with hexane. Purification of the crude product by column
chromatography using 1% MeOH/DCM gave 5a (0.47 g,
60%): Rf 0.70; mp 255 °C; 1H NMR 7.26 (m, 9H, Ph), 7.07 (m,
1H, Ph), 6.81 (s, 1H, H-2′), 6.62 (d, 1H, J ) 8.0, H-2), 6.55 (d,
1H, J ) 8.0, H-1), 5.41 (s, 1H, H-5), 5.33 (d, 1H, J ) 15.7,
benzylic proton), 5.21 (d, 1H, J ) 15.7, benzylic proton), 3.31
(d, 1H, H-9), 3.11 (d, 1H, J ) 18.7, H-10), 2.80 (dd, 1H, J )
6.6, 18.7, H-10), 2.66 (m, 3H), 2.42 (d, 2H, J ) 6.6), 2.49 (m,
2H), 1.62 (m, 1H), 0.85 (m, 1H, H-19), 0.50 (m, 2H, H-20, H-21),
0.13 (m, 2H, H-20, H-21); 13C NMR 142.91, 138.77, 128.58,
128.30, 127.38, 127.33, 126.77, 125.38, 122.95, 121.36, 118.79,
85.01, 72.99, 62.19, 59.32, 50.50, 30.90, 30.68, 4.31, 3.75; EI
MS m/z (relative intensity) 530 (M+, 100%), 91 (90%). Anal.
(C35H34N2O3‚2HCl‚1.25H2O) C, H, N.
1′-Ben zyl-6,7-d ed ih yd r o-4,5r-ep oxy-3,14-h yd r oxy-17-
m eth yl-4′-p h en ylp yr r olo[2′,3′:6,7]m or p h in a n (5f). Oxy-
morphone (0.71 g, 2.36 mmol), benzylamine (0.29 mL, 2.4
mmol), EtOH (3.0 mL), and trans-â-nitrostyrene (0.35 g, 2.36
mmol) were treated as described for 5a to give 5f (0.67 g,
1′-Ben zyl-17-cyclop r op ylm eth yl-6,7-d ed ih yd r o-3,14-d i-
h yd r oxy-4,5r-ep oxy-4′-p -t olylp yr r olo[2′,3′:6,7]m or p h i-
n a n (5b). Naltrexone (0.50 g, 1.47 mmol), benzylamine (0.15
1
58%): Rf 0.72 (0.5% MeOH/DCM); mp 239 °C; H NMR 7.24

540 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 2
Brief Articles
(11) Fundytus, M. E.; Schiller, P. W.; Shapiro, M.; Weltrowska, G.;
Coderre, T. J . The novel and highly selective delta-opioid
antagonist Tipp(Psi) attenuates morphine-tolerance and depen-
dence - comparison with the effects of naltrindole and Tipp.
Regul. Pept. 1994, 54, 97-98.
(12) Schiller, P. W.; Fundytus, M. E.; Merovitz, L.; Weltrowska, G.;
Nguyen, T. M. D.; Lemieux, C.; Chung, N. N.; Coderre, T. J . The
opioid mu agonist/delta antagonist Dipp-NH2[Psi] produces a
potent analgesic effect, no physical dependence, and less toler-
ance than morphine in rats. J . Med. Chem. 1999, 42, 3520-
3526.
(13) Portoghese, P. S.; Sultana, M.; Takemori, A. E. Design of
peptidomimetic delta-opioid receptor antagonists using the
message address concept. J . Med. Chem. 1990, 33, 1714-1720.
(14) Korlipara, V. L.; Takemori, A. E.; Portoghese, P. S. N-Benzyl-
naltrindoles as long-acting delta-opioid receptor antagonists. J .
Med. Chem. 1994, 37, 1882-1885.
(15) Farouz-Grant, F.; Portoghese, P. S. Pyrrolomorphinans as delta
opioid receptor antagonists. The role of steric hindrance in
conferring selectivity. J . Med. Chem. 1997, 40, 1977-1981.
(16) Portoghese, P. S.; Nagase, H.; Lipkowski, A. W.; Larson, D. L.;
Takemori, A. E. Binaltorphimine-related bivalent ligands and
their kappa-opioid receptor antagonist selectivity. J . Med. Chem.
1988, 31, 836-841.
(17) Srivastava, S. K.; Hall, L. D.; Husbands, S. M.; Lewis, J . W.
Michael reactions of benzylimines of morphinan-6-ones: Syn-
thesis of pyrrolo- and pyridinomorphinans. In preparation.
(18) Toll, L.; Berzetei-Gurske, I. P.; Polgar, W. E.; Brandt, S. R.;
Adapa, I. D.; Rodriguez, L.; Schwartz, R. W.; Haggart, D.;
O’Brien, A.; White, A.; Kennedy, J . M.; Craymer, K.; Farrington,
L.; Auh, J . S. Standard binding and functional assays related
to (NIDA) Medications Development Division testing for poten-
tial cocaine and narcotic treatment programs. NIDA Res.
Monogr. Series 1998, 178, 440-466.
(19) Traynor, J . R.; Nahorski, S. R. Modulation by mu-opioid agonists
of guanosine-5′-O-(3-[S-35]thio)triphosphate binding to mem-
branes from human neuroblastoma SH-SY5Y cells. Mol. Phar-
macol. 1995, 47, 848-854.
(20) Calderon, S. N.; Rothman, R. B.; Porreca, F.; Flippen-Anderson,
J . L.; McNutt, R. W.; Xu, H.; Smith, L. E.; Bilsky, E. J .; Davis,
P.; Rice, K. C. Probes for narcotic receptor mediated phenomena.
19. Synthesis of (+)-4-[(RR)-R-(2S,5R)-4-allyl-2,5-dimethyl-1-pi-
perazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80): a
highly selective nonpeptide δ-opioid receptor agonist. J . Med.
Chem. 1994, 37, 2125-2128.
(21) Hong, E. J .; Rice, K. C.; Woods, J . H.; and Traynor, J . R.
Convulsive behavior of non-peptide δ-opioid ligands: comparison
of SNC80 and BW373U86 in mice. Analgesia 1998, 3, 269-276.
(22) Aceto, M. D.; Bowman, E. R.; Harris, L. S.; May, E. L.
Dependence studies of new compounds in the rhesus monkey,
rat and mouse 1997. NIDA Res. Monogr. 1997, 178, 363-407.
(23) Elliott, J .; Traynor, J . R. Evidence for lack of modulation of mu-
opioid agonist action by delta-opioid agonists in the mouse vas
deferens and guinea-pig ileum. Br. J . Pharmacol. 1995, 114,
1064-1068.
(m, 9H, Ph), 7.05 (m, 1H, Ph), 6.78 (s, 1H, H-2′), 6.61 (d, 1H,
J ) 8.3, H-2), 6.53 (d, 1H, J ) 8.3, H-1), 5.38 (s, 1H, H-5),
5.30 (d, 1H, J ) 15.6, benzylic proton), 5.25 (d, 1H, J ) 15.6,
benzylic proton), 3.16 (d, 1H, J ) 18.7, H-10), 2.90 (d, 1H, J )
7.0, H-9), 2.74 (m, 1H), 2.64 (m, 2H), 2.42 (m, 1H), 2.32 (s,
3H, N-CH3), 2.21 (m, 2H), 1.56 (m, 1H); 13C NMR 144.69,
141.20, 139.71, 137.35, 132.28, 129.67, 129.32, 128.55, 128.50,
128.14, 127.42, 126.19, 126.05, 123.96, 122.02, 119.71, 118.28,
117.40, 85.48, 74.64, 66.18, 51.43, 46.41, 43.07, 32.36, 31.91,
23.37; EI MS m/z (relative intensity) 490 (M+, 60%), 91 (100%).
Anal. (C32H30N2O3‚2HCl‚0.25H2O) C, H, N.
Ack n ow led gm en t. This work was supported by
NIDA Grants DA 00254 and DA 07315 and ligand
binding and [35S]GTPγS assays carried out by NIDA-
OTDP.
Refer en ces
(1) Dondio, G.; Ronzoni, S.; Petrillo, P. Non-peptide delta opioid
agonists and antagonists. Expert Opin. Ther. Pat. 1997, 7, 1075-
1098.
(2) Rapaka, R. S.; Porreca, F. Development of delta opioid-peptides
as nonaddicting analgesics. Pharm. Res. 1991, 8, 1-8.
(3) Bilsky, E. J .; Calderon, S. N.; Wang, T.; Bernstein, R. N.; Davis,
P.; Hruby, V. J .; Mcnutt, R. W.; Rothman, R. B.; Rice, K. C.;
Porreca, F. SNC-80, a selective, nonpeptidic and systemically
active opioid-delta agonist. J . Pharmacol. Exp. Ther. 1995, 273,
359-366.
(4) Broccardo, M.; Improta, G. Antidiarrheal and colonic antipro-
pulsive effects of spinal and supraspinal administration of the
natural δ opioid receptor agonist [D-Ala2]deltorphin II in the
rat. Eur. J . Pharmacol. 1992, 218, 69-73.
(5) Broccardo, M.; Improta, G.; Tabacco, A. Central effect of SNC
80, a selective and systemically active delta-opioid receptor
agonist, on gastrointestinal propulsion in the mouse. Eur. J .
Pharmacol. 1998, 342, 247-251.
(6) Mazumder, S.; Nath, I.; Dhar, M. M. Immunomodulation of
human t-cell responses with receptor selective enkephalins.
Immunol. Lett. 1993, 35, 33-38.
(7) House, R. V.; Thomas, P. T.; Bhargava, H. N. A comparative
study of immunomodulation produced by in vitro exposure to
delta opioid receptor agonist peptides. Peptides 1996, 17, 75-
81.
(8) Sharp, B. M.; Gekker, G.; Li, M. D.; Chao, C. C.; Peterson, P. K.
Delta-opioid suppression of human immunodeficiency virus-1
expression in T cells (J urkat). Biochem. Pharmacol. 1998, 56,
289-292.
(9) Cheng, P. Y.; Wu, D. L.; Decena, J .; Soong, Y.; Mccabe, S.; Szeto,
H. H. Opioid-induced stimulation of fetal respiratory activity by
[D- Ala2]Deltorphin-I. Eur. J . Pharmacol. 1993, 230, 85-88.
(10) Arakawa, K.; Akami, T.; Okamoto, M.; Akioka, K.; Nakai, I.; Oka,
T.; Nagase, H. Immunosuppression by delta opioid receptor
antagonist. Transplant. Proc. 1993, 25, 738-740.
J M010841W