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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. Tóth, A. Keresztes, Cs. Tömböly, A. Péter, F. Fülöp, D. Tourwé, E. Navratilova, É. 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, Kraków, Poland, 15-18 October 2003. Other presentations are published in this issue, pp. 907 -1032.

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