New series of potent δ-opioid antagonists containing the H-Dmt-Tic-NH-hexyl-NH-R motif

Article abstract of DOI:10.1016/j.bmcl.2005.08.073

Heterodimeric compounds H-Dmt-Tic-NH-hexyl-NH-R (R = Dmt, Tic, and Phe) exhibited high affinity to δ- (K_iδ = 0.13-0.89 nM) and μ-opioid receptors (K_iμ = 0.38-2.81 nM) with extraordinary potent δ antagonism (pA₂ = 10.2-10.4). These compounds represent the prototype for a new class of structural homologues lacking μ-opioid receptor-associated agonism (IC₅₀ = 1.6-5.8 μM) based on the framework of bis-[H-Dmt-NH]-alkyl (Okada, Y.; Tsuda, Y.; Fujita, Y.; Yokoi, T.; Sasaki, Y.; Ambo, A.; Konishi, R.; Nagata, M.; Salvadori, S.; Jinsmaa, Y.; Bryant, S. D.; Lazarus, L. H. J. Med. Chem. 2003, 46, 3201), which exhibited both high μ affinity and bioactivity.

Full text of DOI:10.1016/j.bmcl.2005.08.073

Bioorganic & Medicinal Chemistry Letters 15 (2005) 5517–5520
New series of potent d-opioid antagonists containing the
H-Dmt-Tic-NH-hexyl-NH-R motif
Tingyou Li,a Kimitaka Shiotani,a Anna Miyazaki,b Yoshio Fujita,a Yuko Tsuda,a,b
Akihiro Ambo,c Yusuke Sasaki,c Yunden Jinsmaa,d Ewa Marczak,d Sharon D. Bryant,d
Lawrence H. Lazarusd,* and Yoshio Okadaa,b,
*
aThe Graduate School of Food and Medicinal Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan
bFaculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan
cDepartment of Biochemistry, Tohoku Pharmaceutical University, Aoba-ku, Sendai 981-8558, Japan
dMedicinal Chemistry Group, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences,
Research Triangle Park, NC 27709, USA
Received 28 June 2005; revised 20 August 2005; accepted 26 August 2005
Available online 23 September 2005
Abstract—Heterodimeric compounds H-Dmt-Tic-NH-hexyl-NH-R (R = Dmt, Tic, and Phe) exhibited high affinity to d-
(Kid = 0.13–0.89 nM) and l-opioid receptors (Kil = 0.38–2.81 nM) with extraordinary potent d antagonism (pA2 = 10.2–10.4).
These compounds represent the prototype for a new class of structural homologues lacking l-opioid receptor-associated agonism
(IC50 = 1.6–5.8 lM) based on the framework of bis-[H-Dmt-NH]-alkyl (Okada, Y.; Tsuda, Y.; Fujita, Y.; Yokoi, T.; Sasaki, Y.;
Ambo, A.; Konishi, R.; Nagata, M.; Salvadori, S.; Jinsmaa, Y.; Bryant, S. D.; Lazarus, L. H. J. Med. Chem. 2003, 46, 3201), which
exhibited both high l affinity and bioactivity.
Ó 2005 Elsevier Ltd. All rights reserved.
The combination of two unnatural amino acids, 20,60-di-
methyl-L-tyrosine (Dmt) and 1,2,3,4-tetrahydroisoquin-
oline-3-carboxylic acid (Tic), produced a new family of
d-opioid antagonists.1 This dipeptide H-Dmt-Tic-OH
not only had d-opioid receptor antagonism (pA2 = 8.2)
with high affinity [Kid = 0.022 nM] and extraordinarily
selectivity for d-opioid receptors [Kil/Kid = 150,800],1
but also exhibited in vivo antagonism following systemic
administration against deltorphin II-induced analgesia.2
Due to the unique biological properties of the Dmt-Tic
motif, intensive structure–activity studies were conduct-
ed in order to develop bifunctional or heterofunctional
opioid ligands.3 The extensive modifications included
N-alkylation,4 change of the position of hydroxyl and
methyl groups on the tyramine ring,5 introduction of a
b-methyl to the Dmt residue,6 modification of the 5–7
positions of Tic aromatic ring with various groups, such
hydroxyl, halogen, nitro, and phenyl,7 as well as substi-
tution of Tic with its D-isomer, D- or L-Phe,8 heteroaro-
matic or heteroaliphatic nuclei,9 the conversion of the C-
terminal carboxyl group to amide,1,4b ester,4b and alco-
hol,1,10 and conjugation of a third aromatic center at the
C-terminal with or without interposing linkers.4c,11
Many of the analogues exhibited the desired properties,
including enhanced d-opioid antagonism,1–11 conversion
from a d antagonist to a d agonist,11a the appearance
of opioids with mixed
l
agonist/d antagonist
properties,4b,c,11a,b and the development of an irrevers-
ible fluorescent d antagonist.11c
Recently, a series of homodimeric Dmt-Tic compounds
were prepared by covalent linkage through a diam-
inoalkane and a symmetric or asymmetric 3,6-diam-
inoalkyl-2(1H)-pyrazinone.12 The extraordinarily high
d-opioid-mediated antagonism (pA2 = 10.3–11.2) was
independent of the chemical nature or length of the
linker between the Dmt-Tic pharmacophores.12 Previ-
ously, Balboni et al.11a proposed that Dmt-Tic-medi-
ated antagonism in C-terminally extended analogues
containing benzimidazole or phenyl as the third aro-
matic center primarily depended on the length of the
interposing linker between Tic and to a lesser degree
on the aromatic moiety. In order to investigate the
effect of another type of aromatic pharmacophore
Keywords: Opioid; d-Opioid receptor antagonist.
*
Corresponding authors. Tel.: +1 919 541 3238; fax: +1 919 541 0696
(L.H.L.); Tel.: +81 78 974 1551; fax: +81 78 974 5689 (Y.O.); e-mail
addresses: lazarus@niehs.nih.gov; okada@pharm.kobegakuin.ac.jp
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.073

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T. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5517–5520
i, ii
removal of solvent in vacuo, the residue was coupled
Fmoc-NH-(CH2)6-NH-Xaa-Boc
Fmoc-NH-(CH2)6-NH-Boc
with Boc-Dmt-Tic-OH using PyBop as coupling reagent
in DMF to give compounds 4–6. The Boc-protecting
group was removed with TFA/anisole, and the crude
compounds (7–9) were precipitated with ether and puri-
fied by semi-preparative RP-HPLC.16
1 Xaa = Dmt
2 Xaa = Tic
3 Xaa = Phe
iii, iv
i
Boc-Dmt-Tic-NH-(CH2)6-NH-Xaa-Boc
The d- and l-opioid receptor affinities of the heterodi-
mers were determined as previously published with rat
brain membranes17 (Table 1). The heterodimers 7–9
had quite high binding affinities to both d- and l-opioid
receptors, comparable to those of the Dmt-Tic homo-
dimers12 and other Dmt-Tic analogues.3b Relative to
the parent compound H-Dmt-Tic-NH2 (Table 1), the
heterodimers increased affinity to d-opioid receptors by
several fold, while l affinity rose by over two orders
magnitude. The third aromatic center interacted with
and enhanced the affinity toward l-opioid receptors as
seen consistently with other Dmt-Tic analogues
containing hydrophobic or aromatic groups at the
C-terminus.3b,4b Interestingly, the replacement of one
H-Dmt-Tic pharmacophoric unit from bis-[H-Dmt-
Tic-NH]-hexyl12 with H-Dmt (7) increased l-opioid
receptor affinity nearly 5-fold (Kil = 0.38 nM) (Table
1). This phenomenon supports the observations that
Dmt primarily improves the affinity to l-opioid recep-
tors more than to d-opioid receptors,18 although as a
single amino acid (H-Dmt-NH-CH3) it binds only to
l-opioid receptors.19 The combination of Dmt with
Tic, on the other hand, greatly enhanced the interaction
with d-opioid receptors.1 Furthermore, substitution of
Dmt (7) by Tic (8) or Phe (9) revealed a weaker l-opioid
receptor affinity than 7 demonstrating the efficacy of
Dmt in the interaction with opioid receptor binding
sites. Although Phe was observed to enhance the inter-
action with l-opioid receptors,4c,8 Tic and Phe had sim-
ilar Ki values to that of the homodimer,12 substantiating
earlier studies that Tic has a preference for d-opioid
receptors.1–11
4 Xaa = Dmt
5 Xaa = Tic
6 Xaa = Phe
Dmt-Tic-NH-(CH2)6-NH-Xaa
7 Xaa = Dmt
8 Xaa = Tic
9 Xaa = Phe
Scheme 1. Synthesis of Dmt-Tic-NH-(CH2)6-NH-Xaa. Reagents: (i)
TFA/anisole; (ii) Boc-Xaa-OH, DIPEA, PyBop, DMF; (iii) 20%
piperidine/DMF; (iv) Boc-Dmt-Tic-OH, DIPEA, PyBop, DMF.
and a longer alkyl spacer, heterodimers of H-Dmt-Tic-
NH-hexyl-NH-R (R = Dmt, Tic, and Phe) were pre-
pared (Scheme 1). These compounds had a biological
activity profile similar to that of the Dmt-Tic homodi-
mers, suggesting that the activity was affected predom-
inantly by the Dmt-Tic pharmacophore. Furthermore,
the third aromatic center (Dmt, Tic, or Phe) appeared
to enhance interaction with l-opioid receptors, but not
biological activity as observed in other Dmt-Tic ana-
logues containing C-terminal hydrophobic moieties3,4
and various enkephalin analogues.13
Dmt was prepared according to Dygos et al.14 and the
catalyst, (R,R)-(ꢀ)-1,2-bis[(O-methoxyphenyl)(phenyl)-
phosphino]ethane-(1,5-cyclooctadiene)rhodium(I) tetra-
fluorobroate,14 was a product of Strem Chemicals Inc.
Boc-Dmt-Tic-OH was prepared as described.4b Fmoc-
NH-(CH2)6-NH-Boc was prepared from Boc-NH-
15
(CH2)6-NH2
by the usual method. Asymmetric
bipharmacophoric compounds (7–9) were synthesized
as shown in Scheme 1. Removal of Boc-group of
Fmoc-NH-(CH2)6-NH-Boc with TFA/anisole and pre-
cipitation of the Fmoc-protected diaminohexane with
ether yielded an oily material; therefore, the solvent
was removed in vacuo and the oily material was used
The functional biological activities were evaluated
using classic pharmacological methods: isolated guin-
ea-pig ileum (GPI) for l-opioid receptors and mouse
vas deferens (MVD) for d-opioid receptors20
(Table 2). A third aromatic center in the heterodimers
(7–9) induced a greater than 50-fold increase in d-re-
ceptor antagonism comparable to that observed with
homodimers,12 and being 2–3 orders of magnitude
greater than the parent compounds and 10-fold greater
directly
for
condensation
with
Boc-Xaa-OH
(Xaa = Dmt, Tic, and Phe) using PyBop as coupling re-
agent to give compounds 1–3. The Fmoc-group of 1–3
was removed with 20% piperidine in DMF. After
Table 1. Rat brain membrane opioid receptor binding affinity of Dmt-Tic heterodimers
Compound
Peptide
Kid (nM)a,b
Kil (nM)a,c
Kid/Kil
7
8
9
H-Dmt-Tic-NH-(CH2)6-NH-Dmt-H
H-Dmt-Tic-NH-(CH2)6-NH-Tic-H
H-Dmt-Tic-NH-(CH2)6-NH-Phe-H
H-Dmt-Tic-NH-(CH2)6-NH-Tic-Dmt-Hd
H-Dmt-Tic-OHe
0.23 0.02 (3)
0.13 0.03 (4)
0.89 0.10 (4)
0.13 0.03
0.022
0.38 0.03 (3)
2.81 0.16 (3)
1.91 0.26 (5)
1.79 0.08
3320
2
22
2
14
150,780
227
e
H-Dmt-Tic-NH2
1.22
277
a Ki values reported as mean SE; the number of independent repetitions is noted in parentheses (n).
b Versus [3H]deltorphin II.
c Versus [3H]DAMGO.
d Data cited from Ref. 12.
e Data cited from Ref. 1.

T. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5517–5520
5519
Table 2. Functional bioactivities of Dmt-Tic heterodimers
Compound Peptide
MVDa
GPIa
Agonism IC50, nM Antagonsimb pA2 Agonism IC50, nM Antagonism pA2
7
8
9
H-Dmt-Tic-NH-(CH2)6-NH-Dmt-H
H-Dmt-Tic-NH-(CH2)6-NH-Tic-H
H-Dmt-Tic-NH-(CH2)6-NH-Phe-H
>10,000
>10,000
>10,000
10.2
10.4
10.3
10.6
8.5
5900 780
1600 250
5550 900
2720 1360
—
ND
ND
ND
ND
—
H-Dmt-Tic-NH-(CH2)6-NH-Tic-Dmt-Hc >10,000
H-Dmt-Tic-OH
H-Dmt-Tic-NH2
Naltrindoled
—
—
d
7.2
9.2
>10,000
—
—
7.3
A dash (—) = none recorded; ND = not determined.
a The data are means of at least five to six independent repetitions using different isolated tissue preparations.
b Versus deltorphin II as the d agonist.
c Data cited from Ref. 12.
d Data cited from Ref. 1.
than naltrindole (Table 2). Thus, while a single Dmt-
Tic pharmacophoric unit contributed to the d antago-
nism, the presence of a third aromatic center (Dmt,
Tic, or Phe) C-terminal to the hexyl linker in the het-
erodimers apparently played an auxiliary role in recog-
nition by the l-opioid receptor,3,4 or possibly acted in
the stabilization of the ligand within the receptor.18d In
contrast to the high l-opioid affinity, the heterodimers
7–9 exhibited very weak l agonism. In fact, while the
presence of a third aromatic center in H-Dmt-Tic-NH-
linker-R compounds generally enhances l-receptor
affinity with or without l-opioid receptor-associated
agonism,4c,11a,11b the lack of a biological response by
these analogues suggests a difference between receptor
binding and the triggering of l agonism as observed
previously.3,4,13 Although the argument has been advo-
cated that the difference in tissues used between assays
might account for the discrepancies observed, the liter-
ature is replete with complete correlations between
receptor affinity and functional bioactivity and consid-
ered sine qua non;6,7,10,19 however, in some notable
cases, a discrepancy occurs among these assays that
lacks a plausible answer.3,4,13c
(JSPS) Fellows (1503306) to T.L. in part by the
Intramural Research Program of the NIH and
NIEHS.
References and notes
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Balboni, G.; Bianchi, C.; Bryant, S. D.; Copper, P. S.;
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In conclusion, we developed a new series of Dmt-Tic
heterodimers (H-Dmt-Tic-NH-hexyl-NH-R) in which
the R group is an aromatic or hydrophobic center that
contributes to their significantly increased l affinity,
although the compounds remained potent d antagonists.
Moreover, they should exhibit greater stability than the
original dipeptides, H-Dmt-Tic-OH and H-Dmt-Tic-
NH2, which spontaneously cyclize to diketopipera-
zines.21 Although the presence of a third aromatic center
permitted interaction with l-opioid receptor, that bind-
ing was insufficient to engage the tissue-bound receptor
(GPI) to initiate l agonism, presumably due to the con-
siderably more potent effect dictated by the Dmt-Tic
pharmacophore that is known to predominantly elicit
d antagonism.3–5,7
´
7. (a) Page, D.; McClory, A.; Mischki, T.; Schmidt, R.;
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Bioorg. Med. Chem. Lett. 2000, 10, 2745.
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Lazarus, L. H.; Temussi, P. A.; Salvadori, S. FEBS Lett.
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Acknowledgments
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The work was supported in part by a Grant-in-Aid
for Japan Society for the Promotion of the Science

5520
T. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5517–5520
25
´
10. Page, D.; Naismith, A.; Schmidt, R.; Coupal, M.; Labarre,
M.; Gosselin, M.; Bellemare, D.; Payza, K.; Brown, W.
J. Med. Chem. 2001, 44, 2387.
0.75 (n-BnOH:H2O:AcOH:pyridine = 4:1:1:2); ½aꢁD ꢀ14.53
(c = 0.52, H2O); m/z 627 (MH+). Anal. Calcd for
C37H47N5O4Æ2HClÆ3H2O: C, 59.0; H, 7.31; N, 9.30. Found:
C, 58.8; H, 6.95; N, 9.29.
11. (a) Balboni, G.; Guerrini, R.; Salvadori, S.; Bianchi,
C.; Rizzi, D.; Bryant, S. D.; Lazarus, L. H. J. Med.
Chem. 2002, 45, 713; (b) Balboni, G.; Salvadori, S.;
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Bryant, S. D.; Lazarus, L. H. J. Med. Chem. 2002, 45,
5556; (c) Balboni, G.; Salvadori, S.; Piaz, A. D.;
Bortolotti, F.; Argazzi, R.; Negri, L.; Lattanzi, R.;
Bryant, S. D.; Jinsmaa, Y.; Lazarus, L. H. J. Med.
Chem. 2004, 47, 6541.
12. Li, T.; Fujita, Y.; Shiotani, K.; Miyazaki, A.; Tsuda, Y.;
Ambo, A.; Sasaki, Y.; Jinsmaa, Y.; Marczak, E.; Bryant S.
D.; Salvadori, S.; Lazarus, L. H.; Okada, Y. J. Med.
Chem., submitted for publication.
13. (a) Shimohigashi, Y.; Costa, T.; Pfeiffer, A.; Herz, A.;
Kimura, H.; Stammer, C. H. FEBS Lett. 1987, 222, 71; (b)
Shimohigashi, Y.; Takano, Y.; Kamiya, H.; Costa, T.;
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Vaughn, L. K.; Wire, W. S.; Davis, P.; Shimohigashi, Y.;
Toth, G.; Knapp, R. J.; Hruby, V. J.; Burks, T. F.;
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14. Dygos, J. H.; Yonan, E. E.; Scaros, M. G.; Goodmonson,
O. J.; Getman, D. P.; Periana, R. A.; Beck, G. R.
Synthesis 1992, 741.
15. Callahan, J. F.; Ashton-Shue, D.; Bryan, H. G.; Bryan, W.
M.; Hcekman, G. D.; Kinter, L. B.; McDonald, J. E.;
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Dmt-Tic-NH-(CH2)6-NH-PheÆ2HCl (9). Yield 104.6 mg
(95.1%); Rf1 = 0.17 (n-BnOH:H2O:AcOH = 4:1:5); Rf2
=
25
0.72 (n-BnOH:H2O:AcOH:pyridine = 4:1:1:2); ½aꢁD +34.2
(c = 0.58, H2O); m/z 615 (MH+). Anal. Calcd for C36H47
N5O4Æ2HClÆ3.5H2O: C, 57.7; H, 7.47; N, 9.34. Found: C,
57.8; H, 7.19; N, 9.39.
17. (a) Li, T.; Fujita, Y.; Tsuda, Y.; Miyazaki, A.; Ambo, A.;
Sasaki, Y.; Jinsmaa, Y.; Bryant, S. D.; Lazarus, L. H.;
Okada, Y. J. Med. Chem. 2005, 48, 586; (b) Lazarus, L.
H.; Guglietta, A.; Wilson, W. E.; Irons, B. J.; Castiglione,
R. J. Biol. Chem. 1989, 264, 354.
18. (a) Hansen, D. W., Jr.; Stapelfeld, A.; Savage, M. A.;
Reichman, M.; Hammond, D. L.; Haaseth, R. C.; Mosberg,
H. I. J. Med. Chem. 1992, 35, 684; (b) Sasaki, Y.; Suto, T.;
Ambo, A.; Ouchi, H.; Yamamoto, Y. Chem. Pharm. Bull.
1999, 47, 1506; (c) Okada, Y.; Fujita, Y.; Motoyama, T.;
Tsuda, Y.; Yokoi, T.; Li, T.; Sasaki, Y.; Ambo, A.; Jinsmaa,
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11, 1983; (d) Okada, Y.; Tsuda, Y.; Fujita, Y.; Yokoi, T.;
Sasaki, Y.; Ambo, A.; Konishi, R.; Nagata, M.; Salvadori,
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2003, 46, 3201; (e) Jinsmaa, Y.; Miyazaki, A.; Fujita, Y.; Li,
T.; Fujisawa, Y.; Shiotani, K.; Tsuda, Y.; Yokoi, T.; Ambo,
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19. Fujita, Y.; Tsuda, Y.; Motoyama, T.; Li, T.; Miyazaki, A.;
Yokoi, T.; Sasaki, Y.; Ambo, A.; Jinsmaa, Y.; Bryant, S. D.;
Lazarus, L. H.; Okada, Y. Bioorg. Med. Chem. Lett. 2005,
15, 599.
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16. Physicochemical data of compounds 7–9. Dmt-Tic-NH-
(CH2)6-NH-DmtÆ2HCl (7). Yield 104.3 mg (94%); Rf1
0.19 (n-BnOH:H2O:AcOH = 4:1:5); Rf2 = 0.73 (n-BnOH:
=
25
H2O:AcOH:pyridine = 4:1:1:2); ½aꢁD +58.13 (c = 0.42,
H2O); m/z 659 (MH+). Anal. Calcd for C38H51N5O5Æ
2HClÆ4H2O: C, 56.9; H, 7.60; N, 8.72. Found: C, 56.6; H,
7.21; N, 8.75.
21. (a) Carpenter, K. A.; Weltrowska, G.; Wilkes, B. C.;
Schmidt, R.; Schiller, P. W. J. Am. Chem. Soc. 1994, 116,
8450; (b) Capasso, S.; Sica, F.; Mazzarella, L.; Balboni, G.;
Guerrini, R.; Salvadori, S. Int. J. Pept. Protein Res. 1995,
45, 567.
Dmt-Tic-H-(CH2)6-NH-TicÆ2HCl (8). Yield 95.4 mg
(86.8%); Rf1 = 0.18 (n-BnOH:H2O:AcOH = 4:1:5); Rf2
=