Letter
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7375
(5), appear to have higher affinity (approximately 3- to 20-
fold) than the well-studied nonpeptide MOR affinity label
β-FNA (IC50 =2.2 nM).6,23
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In conclusion, we have successfully identified a series of
dermorphin-based affinity label analogues that show excep-
tionally high affinity (IC50 = 0.1-5 nM) for MOR. These
analogues were designed by modifying position 2 of dermor-
phin, which is a new strategy for designing peptide-based
affinity label derivatives of opioid peptides that has not
been previously reported. This resulted in a substantial im-
provement in binding affinity (between 10- to 100-fold)
compared to the previous dermorphin-based analogues
synthesized in our laboratory in which the para position of
Phe3 or a Phe in position 5 of dermorphin or [Lys7]der-
morphin were modified.18 All four potential affinity labels
in the present study show subnanomolar to nanomolar affi-
nityforMOR instandard binding assays, indicating favorable
interactions of the side chains in [D-Orn(X)2]dermorphin and
[D-Lys(X)2]dermorphin (X=-COCH2Br or dCdS) with the
binding pocket of MOR. [D-Orn(COCH2Br)2]dermorphin (2)
shows exceptional selectivity for MOR over DOR, and
[D-Lys(CdS)2]dermorphin (4) exhibits selectivity comparable
to the parent peptide dermorphin. All four potential affinity
labels also exhibit WRIB to MOR, suggesting that these
compounds are electrophilic affinity labels that bind cova-
lently toMOR. Three of the fouraffinitylabel peptides exhibit
WRIB to MOR at e1 nM. Thus we have identified peptide-
based electrophillic affinity labels with exceptionally high
affinity for MOR. These novel dermorphin analogues will
be valuable tools to study MOR and the interactions of
the peptides with this receptor. The next step will be to
use these peptide-based electrophilic affinity labels to char-
acterize MOR. These studies are currently underway in our
laboratory.
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dynorphin A analogs. J. Pept. Res. 2000, 56, 80–87.
(20) Balse-Srinivasan, P.; Grieco, P.; Cai, M.; Trivedi, D.; Hruby, V. J.
Structure-activity relationships of novel cyclic alpha-MSH/beta-
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3728–3733.
Acknowledgment. This research was supported by NIDA
grant R01 DA010035.
Supporting Information Available: Detailed experimental
procedures for the synthesis and pharmacological evaluation
of the peptide analogues and analytical (HPLC and mass
spectral) data for peptides 1-6. This material is available free
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