New endomorphin analogs with μ-agonist and δ-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, A. Borsodi

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25 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)951-957
Number of pages7
JournalPure and Applied Chemistry
Issue number5
StatePublished - May 2004

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)


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