| Abstrakt: |
The N-terminal tetrapeptide segments of dermorphin (Tyr- D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) and deltorphin (Tyr- D-Ala-Phe-Asp/Glu-Val-Val-Gly-NH2) are agonists at the opioid receptors µ and δ, respectively. [ D-Arg2, Lys4]-dermorphin-(1-4) amide (Tyr- D-Arg-Phe-Lys-NH2, DALDA) and [Dmt1]DALDA (where Dmt is 2′,6′-dimethyltyrosine) are among the most potent and selective µ-agonists reported to date, both in vitro (having picomolar µ receptor affinity) and in vivo. In this communication, conformation-activity studies of the following four cyclic analogs of DALDA are presented and discussed: the lead peptide S2, S4-cyclo (Tyr- D-Cys-Phe-Cys-NH2), constrained by means of an S4.2 S4.4 disulfide between Cys2 and Cys4; its two cis and trans C4.2 C4.4-olefinic dicarba analogs, and the product of saturation of them both. They are potent nonselective or moderately µ-selective opioid agonists in vitro. They have been synthesized and tested earlier [Berezowska I, Chung NN, Lemieux C, Wilkes BC, and Schiller PW, Acta Biochim Polon 53, 2006, 73-76]. We have studied their conformations using NMR and molecular dynamics. With major conformational constraints imposed by the 11-membered ring spanning residues 2-4, they show well defined conformations of this ring, while the exocylic Tyr1 and Phe3 side chains still have significant conformational freedom. The more active and selective µ versus δ disulfide and saturated dicarba agonists seem to have in common: (i) their ring structures more flexilble than those of the other two and (ii) their ring structures similar to each other and more diverse than those in the other two. Given this and the small size of the peptides having confirmed bioactivity profiles, there is a chance that their conformations determined in solution approach receptor-bound conformations. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR] |
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