ACS Medicinal Chemistry Letters
Letter
locus coeruleus (NLC), the main structures involved in
descending pain control.
possible effect; MVD, mouse vas deferens; Pra, propargylgly-
cine; TBTU, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluro-
nium tetrafluoroborate; Pbf, 2,2,4,6,7-pentamethyldihydroben-
zofuran-5-sulfonyl; Vbr, brain distribution volume
Opioid action via activation of the antinociceptive descend-
ing pathway is particularly important in chronic inflammatory
or neuropathic pain relief by modulating, for example, GABA-
ergic and adrenergic inputs.27,28 These observations emphasize
the importance of the supraspinal action of potential new drugs
for persistent pain relief. Hence, the discovery and design of
compounds counteracting chronic pain should focus on those
with both strong supraspinal action and long duration of action,
properties exhibited by compounds 4 and 5. Although these
glycosylated compounds did not show a net improvement in
antinociceptive potency, as compared to the parent structure 1,
they do represent alternative peptide lead molecules with a
potentially favorable dual MOR/DOR agonist profile.18 Given
that these peptides have permeabilities comparable to that of
mannitol, an oral bioavailability similar to that of morphine is
expected22 and may be sufficient for oral dosing, taking into
account the high potency of the peptides.
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ASSOCIATED CONTENT
* Supporting Information
■
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AUTHOR INFORMATION
Corresponding Author
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Author Contributions
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¶S.B. and C.B. contributed equally. The manuscript was written
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experimental in vivo data. C.T. performed the H-3 labeling.
C.U.N. and B.B. performed the Caco-2 cell monolayer
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Funding
The work of S.B., C.B., A.N., D.T., and P.W.S. was supported
by a collaboration convention between the Minister
Developpement Economique, de l′Innovation et de l′Exporta-
tion du Queb
̀
e du
́
́
ec and the Research Foundation−Flanders (FWO
Vlaanderen) (PSR-SIIRI-417), and by grants from the CIHR
(MOP-89716) and the NIH (DA-004443). Financial support
from the Hungarian Scientific Research Fund (K77783, CT)
́
and the Janos Bolyai Research Scholarship of the Hungarian
Academy of Sciences (CT) are also acknowledged.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
BBB, blood−brain barrier; CNS, central nervous system;
DAMGO, [D-Ala2,NMePhe4,Gly-ol5]enkephalin; DIC, N,N-
diisopropylcarbodiimide; DIPEA, N,N-diisopropylethylamine;
DMF, N,N-dimethylformamide; Dmt, 2′,6′-dimethyl-(S)-tyro-
sine; DOR, δ-opioid receptor; DSLET, [D-Ser2,Leu5]-
enkephalin-Thr6; GPI, guinea pig ileum; HOBt, 1-hydrox-
ybenzotriazole; Kin, unidirectional brain influx or uptake
transfer constant; KOR, κ-opioid receptor; kout, brain efflux
rate coefficient; MOR, μ-opioid receptor; MPE, maximal
(16) Schiller, P. W. Bi- or multifunctional opioid peptide drugs. Life
Sci. 2010, 86, 598−603.
(17) Hansen, D. W., Jr.; Stapelfeld, A.; Savage, M. A.; Reichman, M.;
Hammond, D. L.; Haaseth, R. C.; Mosberg, H. I. Systemic analgesic
E
dx.doi.org/10.1021/ml4004765 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX