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Pure Appl. Chem. 76(5), 951-957, 2004

Pure and Applied Chemistry

Vol. 76, Issue 5

New endomorphin analogs with mu-agonist and delta-antagonist properties

G. T�th, A. Keresztes, Cs. T�mb�ly, A. P�ter, F. F�l�p, D. Tourw�, E. Navratilova, �. Varga, W. R. Roeske, H. I. Yamamura, M. Szucs, and A. Borsodi

Institute of Biochemistry, Biological Research Center of Hungarian Academy of Sciences, Szeged, Hungary; University of Szeged, Hungary; Department of
Organic Chemistry, Vrije University, Brussels, Belgium; University of Arizona
Health Science Center, Tucson, AZ 85724, USA

Abstract: Endomorphins (endomorphin-1,H-Tyr-Pro-Trp-Phe-NH 2 ,endomorphin-2, Tyr-Pro-Phe-Phe-NH2) are potent and selective µ-opioid receptor agonists. In order to improve the affinity and chemical stability of endomorphins, we have designed, synthesized,
and characterized novel analogs with unnatural (2 ',6 '-dimethyltyrosine, Dmt) and/or ß-alicyclic amino acids (ACPC and ACHC). Radioligand binding assay indicated that several of
the novel analogs exhibit high affinity for both µ-and d-opioid receptors in rat-or mouse-brain membrane preparations. The most promising derivatives—such as Dmt-Pro-Trp/Phe-Phe-NH2, Dmt-(1 S,2R)-ACPC-Phe-Phe-NH2, and Dmt-(1S,2R)-ACHC-Phe-Phe-NH2 )—were characterized in recombinant cell lines expressing human µ-or d-opioid receptors. Interestingly, while these novel peptides were potent opioid agonists in the functional
[35S]GTPgammaS binding assays in Chinese hamster ovary cells expressing the µ-opioid receptors, some behaved as antagonist or inverse agonist in the human d-opioid receptor-expressing
CHO cells. Since it has previously been demonstrated that the coadministration of d-antagonists with µ-analgesics attenuates the development of analgesic tolerance, introduction of high-affinity
d-antagonist properties into the µ-agonist endomorphins is expected to lead to potent analgesics that produce limited tolerance.

*Lecture presented at the Polish-Austrian-German-Hungarian-Italian Joint Meeting on Medicinal Chemistry, Krak�w, Poland, 15-18 October 2003. Other presentations are published in this issue, pp. 907 -1032.


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