Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds

Article abstract of DOI:10.1016/j.bmcl.2010.01.055

The dimerization and trimerization of the Dmt-Tic, Dmt-Aia and Dmt-Aba pharmacophores provided multiple ligands which were evaluated in vitro for opioid receptor binding and functional activity. Whereas the Tic- and Aba multimers proved to be dual and bal

Full text of DOI:10.1016/j.bmcl.2010.01.055

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1610–1613
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba),
azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds
c
a
d
e
b
Steven Ballet a,b, , Ewa D. Marczak , Debby Feytens , Severo Salvadori , Yusuke Sasaki , Andrew D. Abell ,
*
Lawrence H. Lazarus c, Gianfranco Balboni f, Dirk Tourwé a
a Department of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels, Belgium
b School of Chemistry and Physics, University of Adelaide, 5005 SA, Australia
c Medicinal Chemistry Group, LP, National Institute of Environmental Health Sciences, NC 27709, USA
d Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, I-44100 Ferrara, Italy
e Department of Pharmacology, Tohoku Pharmaceutical University, 4-1 Komatsushima 4-chome. Aobe-Ku, Sendai 981-8558, Japan
f Department of Toxicology, University of Cagliari, I-09124 Cagliari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The dimerization and trimerization of the Dmt-Tic, Dmt-Aia and Dmt-Aba pharmacophores provided
multiple ligands which were evaluated in vitro for opioid receptor binding and functional activity.
Received 17 November 2009
Revised 12 January 2010
Accepted 13 January 2010
Available online 20 January 2010
Whereas the Tic- and Aba multimers proved to be dual and balanced d/
l antagonists, as determined
by the functional [S35]GTP
c
S binding assay, the dimerization of potent Aia-based ‘parent’ ligands unex-
pectedly resulted in substantial less efficient receptor binding and non-active dimeric compounds.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Designed multiple ligands
Constrained amino acids
Dual l/d opioid antagonists
The beneficial analgesic effect of common opioid ligands such as
morphine or fentanyl is accompanied by side-effects on chronic
administration. Therefore, significant effort has gone into design-
ing synthetic opioid ligands that selectively interact with the three
Linker
P'
P
Bifunctional ligand 1
recognized l-, d- and j-subtype opioid receptors. Recently, various
H-Tyr-D-Ala-Gly-Phe-NH-NH-Phe-Gly-D-Ala-Tyr-H 2
peptidic and non-peptidic dimers have been prepared to improve
the pharmacological properties of known opioid ligands.1,2 A gen-
eral representation of such homo- (1, P = P0) or hetero-bifunctional
(1, P – P0) ligands, possessing linkers of variable length, is shown in
Figure 1.
Designed multiple ligands (DMLs) of opioid agonists include:
peptidic dimers [e.g., enkephalin-based Biphalin 2,3–7 endomor-
phin analogs8 and dermorphin-like structures,9 non-peptidic DMLs
(e.g., oxymorphone-derived pharmacophores10–13) and combined
peptidic-non-peptidic bifunctional ligands (e.g., enkephalin-ana-
logs linked to a fentanyl unit (e.g., structure 3)].14,15 In specific
cases, improved pharmacodynamic and pharmacokinetic proper-
Enkephalin analog
Enkephalin analog
H-Dmt-D-Ala-Gly-Phe
Enkephalin analog
N
N
3
O
Fentanyl subunit
ψ
H-Dmt-D-Arg-Phe-Lys-NH-CH2-CH2-Phe-Cha- [NHCH2]Tic-Tyr-H
4
Dmt1-DALDA
ψ
TICP[ ]
Figure 1. General representation of bifunctional ligands 1 and literature examples
2 to 4.
Abbreviations: Aba, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one; Aia, 3-
amino-indolo[2,3-c]azepin-2-one; CM, cross metathesis; DML, designed multiple
ligand; Dmt, 20,60-dimethyl-
ileum; S,
35S]GTP 35S]guanosine-50-O-(
deferens; MOR, -opioid receptor; norBNI, norbinaltorphimine; Tic, 1,2,3,4-tetra-
hydroisoquinoline-3-carboxylic acid.
* Corresponding author. Tel.: +32 26293298; fax: +32 26293304.
E-mail address: sballet@vub.ac.be (S. Ballet).
L
-tyrosine; DOR, d-opioid receptor; GPI, guinea-pig
-thio)-triphosphate; MVD, mouse vas
ties like enhanced affinity, increased activity, relative to ‘the golden
standard’ morphine, and high metabolic stability were observed.3,6
The design rationale behind ligands of type 3, was based on conju-
gation of the peptidic sequence to a fentanyl moiety in order to
overcome the poor general bioavailability of opioid peptides.
[
c
l
[
c
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.055

S. Ballet et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1610–1613
1611
Boc-Dmt-Tic-OH 5 or
Boc-Dmt-Aba-Gly-OH 6b or
Boc-Dmt-D-Aia-Gly-OH 7b or
HO
H
X = H-Dmt-Tic- 9
Me2N-Dmt-Aia-Gly-OH 8
X
NH2
N
N
O
H2N
N
H
X = H-Dmt-Aba-Gly- 10
X = H-Dmt-D-Aia-Gly- 11
X = Me2N-Dmt-Aia-Gly- 12
X
OH
PyBOP, DIPEA, DMF
H2N
O
TFA/DCM/H2O
49:49:2
H-Dmt-Tic-OH 5
Coupling
Acidolysis
NH2
HN
X
X = H-Dmt-D-Aia-Gly- 13
H2N
X
NH
O
N
O
N
H
N
H
TFA/DCM/H2O
49:49:2
O
10 mol% Grubbs
NH2
H
Boc-Tic
H
N
2nd Generation cat.
X
N
N
Boc-Tic-NH-hAll
N
H
HO
HO
H-Dmt-Aba-Gly-NH-Bn 6
Tic-Boc
X
Boc-Dmt-OH
DCM, 40°C, on, Ar
74%
H
18
17
PyBOP, DIPEA,
X = Dmt-Tic- 14
DMF, rt
NH
NH2
Boc-Dmt-Tic-OH 5 or
O
X
O
X = H-Dmt-Tic- 15
X = H-Dmt-Aba-Gly- 16
N
Boc-Dmt-Aba-Gly-OH 6b
NH
N
N
R
H
NH2
O
PyBOP, DIPEA,
X
N
R'
N
TFA/DCM/H2O
49:49:2
H2N
R'
N
H
DMF, rt
X
R = NHBn; R' = H: H-Dmt-D-Aia-Gly-NHBn 7
N
H
R = OH; R' = Me: Me2Dmt-L-Aia-Gly-OH 8
Figure 2. Structures of H-Dmt-Tic-OH 5, H-Dmt-Aba-Gly-NH-Bn 6, H-Dmt-
ligands 9 to 16.
D
-Aia-Gly-NH-Bn 7 and Me2Dmt-
L
-Aia-Gly-OH 8 pharmacophores and synthesis of bifunctional
-antagonism (pA2d = 10.51 and pA2 = 6.99).23
l
Relative to the reference peptide Dmt-
D
-Ala-Gly-Phe-NH2 the tar-
balanced, d- and
l
geted improved d-receptor affinity was obtained, a goal that finds
its roots in the therapeutic advantages of compounds combining
In general, peptidic bifunctional opioid ligands seem to be more
active at MOR when the pharmacophores are connected by short
linkers.3,5,9 Because of this general trend, and in order to obtain a
both
nists at the
Similarly to compounds with a dual
attenuation of dependency and tolerance to opiates is seen with
d antagonists16 or neutral antagonists.19 Because of these thera-
peutic advantages, Schiller and co-workers successfully prepared
chimeric compound 4 with mixed -opioid agonist/d-opioid antag-
l
- and d-opioid agonism over drugs which act solely as ago-
l
-opioid receptor.16–18
more balanced dual l/d antagonist, we first opted for the ethylene
l/d agonist profile, an
diamine linker, to give dimer 9 (Fig. 2). The monomers for the eth-
ylene diamine-linked dimers 9 to 12 were prepared according to
literature procedures,25,26,22 followed by standard peptide coupling
and deprotection steps (Fig. 2). Ethylene diamine or tris(2-amino-
ethyl)amine were coupled to the building blocks 5 to 8 by means of
PyBOP in the presence of DIPEA.23 The N-terminal Boc-group was
removed from the crude intermediates by acidolysis (TFA/DCM/
water 49:49:2), followed by RP-HPLC purification.
The affinities for the MOR and DOR were measured in equilib-
rium binding assays in rat brain membranes by displacement of
[3H]DAMGO and [3H]deltorphin-II, respectively (Table 1). Func-
tional bioactivity was determined in guinea-pig ileum (GPI) for
l
l
onist profile in order to obtain a bifunctional structure with analge-
sic effect and low propensity to induce analgesic tolerance and
physical dependence.1,20 Chimeric structure 4 combines the
l
-opi-
oid agonist effect of [Dmt1]DALDA (Fig. 1) with the potent and
selective d-antagonist (inverse agonist) TICP[ (H-Tyr-
Tic [CH2NH]Cha-Phe-OH).
In previous work, structures 5 to 8 (Fig. 2) were reported to be
potent opioid ligands.21,22 Beside the d-selective antagonist
Dmt-Tic 5, compounds of type 6 and 7 displayed full -agonist
d
W]
W
l
-opioid receptors and in mouse vas deferens (MVD) for d-opioid
receptors. Moreover, the effect on Loperamide or deltorphin C
stimulated GTP S binding in SK-N-SH and NG108-15 cells, respec-
l
activities, with potencies comparable to endogenous opioid pep-
tides like endomorphin-1 and -2. N,N-Dimethylation proved to be
crucial for the d-antagonist properties of structure 8. Structure 8
antagonizes the effect of Deltorphin C in vitro with a potency in
the same range as Dmt-Tic 5 (pA2d (5):8.48 versus pA2d (8):8.30).22
This work discusses the preparation and biological evaluation of
symmetric dimeric and trimeric peptidomimetic opioid ligands
based on opioid scaffolds 5 to 8. The designed ligands contain
compact linkers, that only allow binding in a monovalent mode.1
Earlier work of Li et al. involving the linkage of Dmt-Tic 5 by means
of diaminoalkyl chains of variable length, resulted in dimeric
ligands with increased d-antagonist potency.23 The d-antagonism
potency was improved by two to three orders of magnitude rela-
tive to the monomer Dmt-Tic-OH (pA2 values between 10.42 and
11.28 versus 8.48 for Dmt-Tic-OH).23 The reported dimers repre-
sented the most potent in vitro d-opioid antagonists reported in
the literature.23 The linker length in these ligands was shown to
be of no importance for d-antagonism, and the observed increase
in potency was suggested to be due to a high concentration of
the pharmacophore in the vicinity of the recognition site.24 In con-
trast with its more extended analogs, the compact diaminobutane
linked dimer butylene-bis[Dmt-Tic-NH] possesses dual, but not
c
tively, was determined.
Next to the expected low nanomolar affinity and typical Tic-re-
l
lated d-opioid receptor selectivity values of 9 (Kid 0.96 nM and Ki
10.20 nM, Table 1), the activity pattern of this dimeric ligand con-
firms the expected d-opioid receptor antagonism. In addition,
dimer 9 blocks efficiently the effect of the MOR selective agonist
Loperamide in an equipotent manner as compared to blockage of
l
the agonist effect of Deltorphin C at the d-opioid receptor (pA2
d
9.03 vs pA2 9.04, see Fig. 3). This confirms that more balanced
l
/d-antagonism is obtained by shorter linkers than for the longer
(e.g., diaminobutane) linkers used by Li.23
The dimerization of the
l-selective Dmt-Aba-Gly peptidomi-
l
metic 6 (Ki 0.46 nM, GPI (IC50) 51 nM)21 led to bifunctional struc-
ture 10. This ethylene diamine-linked Dmt-Aba-Gly dimer
-selective binding character (Kid/Ki = 9.5), although
l
preserves its
l
with decreased binding affinities. Unexpectedly however, the ago-
nist properties of reference compound 6 are converted into an
l
antagonist profile with a potency at MOR (pA2 8.54) and DOR
(pA2d 7.74) that is lower than those for dimer 9. This indicates that
activity or efficacy can change upon introduction of the parent
compound into bifunctional constructs.

1612
S. Ballet et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1610–1613
Table 1
Receptor affinities, selectivities and functional bioactivity of monomers 5 to 8 and bifunctional ligands 9 to 16
Compounds
Receptor affinitya (nM)
Selectivity
Functional bioactivityb
MVD IC50 (nM) GTP c
Sc (pA2)d GPI IC50 (nM) GTP Sc (pA2)
l
l
l
Kid
Ki
Kid
/
Ki
/
c
l
Ki
Kid
5
6
7
8
9
H-Dmt-Tic-OHd,e
0.022e
11 2.3
160 23
6.64 0.89
0.96 0.19 (4) 10.20 0.10(3)
153.5 8.6 (3)
211.0 13 (3)
101.2 6.4 (3)
360.6 33 (3)
3.317e
0.46 0.07
3.35 0.28
874 100
150e
8.48d
H-Dmt-Aba-Gly-NH-Bnf
24
48
830 70
1500 139
51
14.9 1.6
5
H-Dmt-
D
-Aia-Gly-NH-Bnf
Me2Dmt-Aia-Gly-OHf
132
11
8.30
Ethylene-bis(H-Dmt-Tic-NH)
>10,000
>10,000
NT
NT
NT
9.04 0.01
7.74 0.33
NA
NA
NA
>10,000
>10,000
NT
NT
NT
9.03 0.13
8.54 0.47
NA
NA
NA
10 Ethylene-bis(H-Dmt-Aba-Gly-NH)
11 Ethylene-bis(H-Dmt- -Aia-Gly-NH)
12 Ethylene-bis(Me2Dmt-Aia-Gly-NH)
16.10 1.2 (3)
138.7 41 (3)
343.5 32 (3)
176.9 22 (3)
9.5
1.5
D
3.4
13 (p-Xylylene)bis(H-Dmt-
D
-Aia-Gly-
2
NH)
14 1,6-(Hex-3-ene)bis(H-Dmt-Tic-NH)
15 Tris-[H-Dmt-Tic-NH-ethylene]-N
16 Tris-[H-Dmt-Aba-Gly-NH-ethylene]-
N
0.24 0.04 (4)
3.75 0.81 (4)
196.1 13 (3)
1.50 0.07 (3)
7.78 0.63 (3)
8.06 0.83 (4) 24
6.3
2.1
>10,000
>10,000
>10,000
8.94 0.08
8.64 0.63
7.64 0.54
>10,000
>10,000
>10,000
8.31 0.38
7.48 0.11
6.95 0.21
a
The Ki-values (nM) were determined according to Cheng and Prusoff,29 using published methods.30 Radioligands were [3H]DAMGO (Perkin–Elmer) for
l-opioid receptors
and [3H]deltorphin II (NEN) for d and affinity determined using the P2 preparation of rat brain membranes. The mean SEM values of three to six repetitions are based on
independent binding assays conducted in duplicate using five to eight grade doses of peptides with different synaptosomal preparations.
b
Agonism was expressed as IC50 obtained from dose response curves.31 These values represent the mean SEM of at least six fresh tissue samples. Deltorphin C and
dermorphin were the internal standards for MVD (d-opioid receptor bioactivity) and GPI (l-opioid receptor bioactivity) tissue preparations, respectively.
c
Effect of compounds 10 to 16 on Loperamide and deltorphin C stimulated GTP
c
S binding in SK-N-SH and NG108-15 cell membranes, respectively. NA: not active
(>20,000 nM); NT: not tested.
d
Values taken from Ref. 23.
Values taken from Ref. 32.
Values taken from Ref. 22.
e
f
100
80
100
80
60
40
20
60
40
20
0
0
-11 -10 -9 -8 -7 -6 -5 -4
-11 -10 -9 -8 -7 -6 -5 -4 -3
Log loperamide (M)
Log Delt C (M)
Deltorphin C
Loperamide
Delt C + 9 (30 nM)
Delt C + 9 (300 nM)
Lop + 9 (30 nM)
Lop + 9 (300 nM)
Figure 3. Effect of Dmt-Tic-dimer 9 on Loperamide and deltorphin C stimulated GTPcS binding in SK-N-SH and NG108-15 cell membranes, respectively.
Dimerization of the monomeric ligand 722 to the corresponding
dimer 11 (Fig. 2) surprisingly resulted in a substantially decreased
part of ligand 7 consisting of a benzyl moiety. Coupling of Boc-
Dmt-D-Aia-Gly-OH to (p-xylylene) bis amine and subsequent acid-
olysis gave DML 13. Unfortunately, the presence of this aromatic
l
l
binding affinity (Ki (7) 3.35 nM vs Ki (11) 138.7 nM). Moreover,
the receptor selectivity of 7 (Kid/Ki = 48) was almost completely
group within the spacer did not improve binding ((Ki (13)
l
l
l
lost in 11 (Kid/Ki = 1.5). This observation was unexpected and, to
176 nM and Kid (13) 360 nM), nor functional activity with respect
to dimer 11. These Aia-containing compounds bind to MOR and
DOR, albeit with high nanomolar values, but do not display either
agonist or antagonist activity. Clearly, the presence of a second Aia-
based pharmacophore is detrimental for opioid affinity and
activity.
the best of our knowledge, unprecedented. Literature shows only
examples in which dimeric opioid compounds retain or ameliorate
the monomer potency upon ‘tail-to-tail’ dimerization (i.e., C-ter-
mini coupled to each other).2 Dimer 11 was unable to diminish
the GTPcS binding induced by Loperamide and Deltorphin C (data
not shown), proving that in contrast to 10, 11 does not act as an
antagonist at MOR and DOR. A similar result was obtained for 12,
the dimer of the potent and selective monomer ligand 8. The affin-
ity at DOR was strongly decreased upon dimerization of 8 (Kid (8)
6.64 nM ? Kid (12) 101 nM). The loss of d-receptor selectivity in
The nature of the linker in various multiple ligands has often
been shown to be of importance via its role in hydrophilic/hydro-
phobic balance,34 membrane permeability35 and rigidity.13 Com-
pound 14 was prepared using a recently introduced methodology
which allows the synthesis of dimers of biologically active pharma-
cophores by means of cross metathesis (CM).36 The versatile intro-
duction of the olefin containing tether and subsequent CM reaction
gave readily access to 3,4-ene-hexylene-bis[Boc-Tic-NH] 18 (Fig. 2)
which was further transformed into 14 according to a standard
deprotection/coupling procedure. Ligand 14 displayed sub- to
low nanomolar DOR and MOR binding affinity respectively.
12 (Ki /Kid (8) = 132 ? (Ki /Kid (12) = 3.4) can be readily explained
by the absence of the C-terminal free carboxyl group, a structural
feature that is present in 8 and is known to induce d-receptor
selectivity.20,33
l
l
An attempt to recover the activity of the monomeric parent li-
gand 7 was investigated by adding the ‘address’ part or C-terminal

S. Ballet et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1610–1613
1613
Previously, the saturated equivalent of 14, 1,6-bis[H-Dmt-Tic-
Supplementary data
NH]hexane, was determined to be a weak
l-agonist (GPI(IC50)
d
2715 nM) and potent d-antagonist (pA2 10.62).23 In contrast to
Supplementary data (experimental procedures, HPLC and high
resolution mass spectrometry data) associated with this article
can be found, in the online version, at doi:10.1016/j.bmcl.2010.
01.055.
this saturated analog, olefin-linked 14 is a potent dual, and bal-
anced, d/
sponse curves of deltorphin
l
antagonist as proven by the rightward shift of dose–re-
and Loperamide, respectively
C
(Supplementary data). Relative to the ethylene-linked dimer 9,
14 shows improved Ki-values, which are however not translated
into higher antagonist potencies (Table 1). The discrepancy be-
tween binding and functional activity is commonly observed with
opioid ligands containing the Dmt-Tic scaffold.27,28
With the aim of increasing the concentration of the Dmt-Tic
pharmacophore 5 at the receptor recognition sites, we prepared
trifunctional ligand 15, derived from tris(2-aminoethyl)amine.
The low nanomolar affinity as well as the balanced antagonism
of trimer 15 showed that this compound indeed has the expected
profile, although the antagonist activity decreased by one to two
orders of magnitude, relative to dimers of type 9 and 14, respec-
tively. Finally, trifunctional structure 16 was prepared and evalu-
ated. The small loss in d-binding in respect to dimer 10,
References and notes
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5. Costa, T.; Wuster, M.; Herz, A.; Shimohigashi, Y.; Chen, H. C.; Rodbard, D.
Biochem. Pharmacol. 1985, 34, 25.
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W. Life Sci. 1987, 40, 2283.
7. Portoghese, P. S.; Lipkowski, A. W.; Takemori, A. E. J. Med. Chem. 1987, 30, 238.
8. Gao, Y. F.; Zhai, M. X.; Liu, W-X.; Liu, X.; Yuan, Y.; Qi, Y.-M.; Wang, R. Protein
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10. Portoghese, P. S.; Larson, D. L.; Yim, C. B.; Sayre, L. M.; Ronsisvalle, G.;
Lipkowski, A. W.; Takemori, A. E.; Rice, K. C.; Tam, S. W. J. Med. Chem. 1985, 28,
1140.
11. Takemori, A. E.; Yim, C. B.; Larson, D. L.; Portoghese, P. S. Eur. J. Pharmacol. 1990,
186, 285.
12. Portoghese, P. S.; Lipkowski, A. W.; Takemori, A. E. Life Sci. 1987, 40, 1287.
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Med. Chem. 1988, 31, 836.
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Vardanyan, R.; Hruby, V. J. J. Med. Chem. 2007, 50, 5528.
16. Jiang, Q.; Mosberg, H. I.; Porreca, F. Eur. J. Pharmacol. 1990, 186, 137.
17. Schiller, P. W.; Weltrowska, G.; Berezowska, I.; Nguyen, T. M. D.; Wilkes, B. C.;
Lemieux, C.; Chung, N. N. Biopolymers 1999, 51, 411.
18. Liu, Z.; Zhang, J.; Zhang, A. Curr. Pharm. Des. 2009, 15, 682.
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combined with a gain in l-affinity, resulted in enhanced l-recep-
tor selectivity (Kid/Ki = 24). The improved binding to MOR was
l
unfortunately not translated in effective functional activity. Only
l
moderate
l
-antagonism (pA2 = 6.95) was observed for 16, indicat-
ing that both dimerization and trimerization of the
l-selective
agonist scaffold 6 leads to limited -antagonism. The results for tri-
l
mers 15 and 16 indicated that no improvement in opioid receptor
binding and functional activity was obtained by augmenting the
pharmacophore density within vicinity of the opioid recognition
sites in these trifunctional compounds.
In conclusion, interesting results were obtained for the activity
profile of the discussed bi- or trifunctional ligands, obtained by
cross-linking different types of peptidomimetic opioid ligands.
The compact ethylene-linked Dmt-Tic dimer 9 shows a more bal-
anced dual antagonist character than those reported for dimers
using longer linkers,23 in agreement with the design principle. Its
potency is slightly lower than that reported for the butylene-
bis(Dmt-Tic), in a different assay however.
20. Weltrowska, G.; Lemieux, C.; Chung, N. N.; Schiller, P. W. J. Pept. Res. 2004, 63,
63.
21. Ballet, S.; Salvadori, S.; Trapella, C.; Bryant, S. D.; Jinsmaa, Y.; Lazarus, L. H.;
Negri, L.; Giannini, E.; Lattanzi, R.; Tourwé, D.; Balboni, G. J. Med. Chem. 2006,
49, 3990.
This study also indicated that dimerization of potent opioid li-
gands can lead to a loss of affinity, as observed for dimerization
of 7 to 11 and of 8 to 12, but also to changes is selectivity and in
the conversion of an agonist into an antagonist (6 ? 10). Cross
metathesis is shown to be an efficient tool to provide DML’s. The
cross metathesis compound 14 shows similar receptor affinities
22. Ballet, S.; Feytens, D.; De Wachter, R.; De Vlaeminck, M.; Marczak, E. D.;
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as its saturated analog,23 but the weak
changed into -antagonism, making 14 an interesting balanced
/d antagonist.
Because of efficacy problems of naltrexone, the approved drug
l-agonism of the latter is
l
l
of choice in alcohol cessation and rapid heroin detoxification pro-
grams,37,38 balanced and general opioid antagonists have non-neg-
ligible therapeutic potential. The compact multimers 9, 10 and 14
could serve as interesting pharmacological tools in the develop-
ment of novel opioid antagonist structures with suppressed side-
effects.
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S. Ballet and D. Feytens are Research Assistants of the Fund of
Scientific Research–Flanders (Belgium). This research was sup-
ported by the Australian Research Council (Grant 20103228) and
in part supported by the Intramural Research Program of the NIH
and NIEHS. We also thank Professor Peter Schiller (IRCM, Montreal)
for the valuable comments during the preparation of this
manuscript.
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