caa a22 4500 378911198 CHVBK 20180305123542.0 cr unu---uuuuu 161128e20040101xx s 000 0 eng 10.1351/pac200476050951 doi (NATIONALLICENCE)gruyter-10.1351/pac200476050951 New endomorphin analogs with mu-agonist and delta-antagonist properties [Elektronische Daten] [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] 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. © 2013 Walter de Gruyter GmbH, Berlin/Boston Tóth G. 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 aut Keresztes A. 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 aut Tömböly Cs 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 aut Péter A. 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 aut Fülöp F. 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 aut Tourwé D. 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 aut Navratilova E. 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 aut Varga É. 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 aut Roeske W. R. 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 aut Yamamura H. I. 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 aut Szucs M. 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 aut Borsodi A. 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 aut Pure and Applied Chemistry De Gruyter 76/5(2004-01-01), 951-957 0033-4545 76:5<951 2004 76 pac https://doi.org/10.1351/pac200476050951 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.1351/pac200476050951 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tóth G. 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 aut NATIONALLICENCE 700 1- Keresztes A. 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 aut NATIONALLICENCE 700 1- Tömböly Cs 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 aut NATIONALLICENCE 700 1- Péter A. 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 aut NATIONALLICENCE 700 1- Fülöp F. 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 aut NATIONALLICENCE 700 1- Tourwé D. 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 aut NATIONALLICENCE 700 1- Navratilova E. 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 aut NATIONALLICENCE 700 1- Varga É. 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 aut NATIONALLICENCE 700 1- Roeske W. R. 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 aut NATIONALLICENCE 700 1- Yamamura H. I. 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 aut NATIONALLICENCE 700 1- Szucs M. 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 aut NATIONALLICENCE 700 1- Borsodi A. 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 aut NATIONALLICENCE 773 0- Pure and Applied Chemistry De Gruyter 76/5(2004-01-01), 951-957 0033-4545 76:5<951 2004 76 pac CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter