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, William R Roeske, H. I. Yamamura, M. Szucs, A. Borsodi

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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
Volume76
Issue number5
StatePublished - May 2004

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Opioid Receptors
Assays
Cells
Chemical stability
Analgesics
Peptides
Amino acids
Rats
Brain
Derivatives
Membranes
Opioid Analgesics
Amino Acids
CHO Cells
endomorphin 2

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Tóth, G., Keresztes, A., Tömböly, C., Péter, A., Fülöp, F., Tourwé, D., ... Borsodi, A. (2004). New endomorphin analogs with μ-agonist and δ-antagonist properties. Pure and Applied Chemistry, 76(5), 951-957.

New endomorphin analogs with μ-agonist and δ-antagonist properties. / Tóth, G.; Keresztes, A.; Tömböly, Cs; Péter, A.; Fülöp, F.; Tourwé, D.; Navratilova, E.; Varga, É; Roeske, William R; Yamamura, H. I.; Szucs, M.; Borsodi, A.

In: Pure and Applied Chemistry, Vol. 76, No. 5, 05.2004, p. 951-957.

Research output: Contribution to journalArticle

Tóth, G, Keresztes, A, Tömböly, C, Péter, A, Fülöp, F, Tourwé, D, Navratilova, E, Varga, É, Roeske, WR, Yamamura, HI, Szucs, M & Borsodi, A 2004, 'New endomorphin analogs with μ-agonist and δ-antagonist properties', Pure and Applied Chemistry, vol. 76, no. 5, pp. 951-957.
Tóth G, Keresztes A, Tömböly C, Péter A, Fülöp F, Tourwé D et al. New endomorphin analogs with μ-agonist and δ-antagonist properties. Pure and Applied Chemistry. 2004 May;76(5):951-957.
Tóth, G. ; Keresztes, A. ; Tömböly, Cs ; Péter, A. ; Fülöp, F. ; Tourwé, D. ; Navratilova, E. ; Varga, É ; Roeske, William R ; Yamamura, H. I. ; Szucs, M. ; Borsodi, A. / New endomorphin analogs with μ-agonist and δ-antagonist properties. In: Pure and Applied Chemistry. 2004 ; Vol. 76, No. 5. pp. 951-957.
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AU - Keresztes, A.

AU - Tömböly, Cs

AU - Péter, A.

AU - Fülöp, F.

AU - Tourwé, D.

AU - Navratilova, E.

AU - Varga, É

AU - Roeske, William R

AU - Yamamura, H. I.

AU - Szucs, M.

AU - Borsodi, A.

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