2390 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 15
Letters
(9) (a) Qian, X.; Kove´r, K.; Shenderovich, M. D.; Lou, B.-S.; Misicka,
A.; Zalewska, T.; Horva´th, R.; Davis, P.; Bilsky, E. J .; Porreca,
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H. I.; Hruby, V. J . The stereochemical requirements of the novel
δ-opioid selective dipeptide antagonist Tmt-Tic. Bioorg. Med.
Chem. Lett. 1997, 7, 3049-3052.
(10) Salvadori, S.; Guerrini, R.; Balboni, G.; Bianchi, C.; Bryant, S.
D.; Cooper, P. S.; Lazarus, L. H. Further studies on the Dmt-
Tic pharmacophore: hydrophobic substituents at the C-terminus
endow δ antagonists to manifest µ agonism or µ antagonism. J .
Med. Chem. 1999, 42, 5010-5019.
(11) Balboni, G.; Salvadori, S.; Guerrini, R.; Bianchi, C.; Santagada,
V.; Calliendo, G.; Bryant, S. D.; Lazarus, L. H. Opioid pseudopep-
tides containing heteroaromatic or heteroaliphatic nuclei. Pep-
tides 2000, 21, 1663-1671.
(12) (a) Page´, D.; McClory, A.; Mischki, T.; Schmidt, R.; Butter-
worth: J .; St-Onge, S.; Labarre, M.; Payza, K.; Brown, W. Novel
Dmt-Tic dipeptide analogues as selective delta-opioid receptor
antagonists. Bioorg. Med. Chem. Lett. 2000, 10, 167-170. (b)
Santagada, V.; Balboni, G.; Caliendo, G.; Guerrini, R.; Salvadori,
S.; Bianchi, C.; Bryant, S. D.; Lazarus, L. H. Assessment of
substitution in the second pharmacophore of Dmt-Tic analogues.
Bioorg. Med. Chem. Lett. 2000, 10, 2745-2748.
activities over the µ and κ receptors. Dipeptides bearing
urea/thiourea C-terminal functionalities proved to rep-
resent a new class of powerful δ agonists. The results
of this study place in evidence that the activation of the
opioid receptors is not only determined by the size of
the C-terminus group but also by its chemical nature.
It is nonetheless surprising to observe that small
modifications, as subtle as going from an amide to a
urea bond, can drastically change the pharmacological
profile of the compounds. In the specific case of the δ
receptor, the order of activation was shown to occur as
follows: urea/thiourea > amino . amido for bulky
subtituents (R ) phenyl or tert-butyl) at the C-terminus.
Other types of C-terminal substituents are currently
under investigation in our labs to further explore their
effects on the activation of the opioid receptors.
Ack n ow led gm en t. The authors are thankful to Dr.
K. Carpenter for NMR analysis of the dipeptides and
Dr. C. Walpole for helpful discussions. A sample of Dmt-
Tic was kindly provided by Dr. L. H. Lazarus (NIEHS).
(13) Schiller, P. W.; Weltrowska, G.; Schmidt, R.; Nguyen, T. M.-D.;
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L. S. Opioid infidelity: novel opioid peptides with dual high
affinity for δ- and µ-receptors. Trends Neurosci. 1996, 19, 31-
35.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, 1H NMR, MS, elemental analyses, HPLC K’s, and
biological methods. This material is available free of charge
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(16) Schiller, P. W.; Weltrowska, G.; Bolewska-Pedyczak, E.; Nguyen,
T. M-D.; Lemieux, C.; Chung, N. N. Subtleties of structure-δ
agonist vs δ antagonist relationships of opioid dipeptide deriva-
tives. In Peptides 1996, Proceedings of the Twenty-Fourth
European Peptide Symposium; Mayflower Scientific: Kingswin-
ford, U.K., 1998; pp 785-786.
(17) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J .
A facile synthesis of chiral N-protected â-amino alcohols. Tet-
rahedron Lett. 1991, 32, 923-926.
(18) Drake, B.; Patek, M.; Lebl, M. A convenient preparation of
monosubstituted N,N′-di(Boc)-protected guanidines. Synthesis
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(19) (a) Temussi, P. A.; Salvadori, S.; Amodeo, P.; Dianchi, C.;
Guerrini, R.; Tomalis, R.; Lazarus, L. H.; Picone, D.; Tancredi,
T. Selective opioid dipeptides. Biochem. Biophys. Res. Commun.
1994, 198, 933-939. (b) Wilkes, B. C.; Schiller, P. W. Theoretical
conformational analysis of the opioid δ antagonist H-Tyr-Tic-
Phe-OH and the µ agonist H-Tyr-D-Tic-Phe-NH2. Biopolymers
(Pept. Sci.) 1994, 34, 1213-1219. (c) Wilkes, B. C.; Schiller, P.
W. Comparative analysis of various proposed models of the
receptor-bound conformation of H-Tyr-Tic-Phe-OH related δ-o-
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(d) Wilkes, B. C.; Nguyen, T. M.-D.; Weltrowska, G.; Carpenter,
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51, 386-394.
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