Design and comprehensive conformational studies of Tyr1-cyclo(D-Pen2-Gly3-Phe 4-L-3-Mpt5) and Tyr1-cyclo(D-Pen2-Gly3-Phe 4-D-3-Mpt5): Novel conformationally constrained opioid peptides

Gregory V. Nikiforovich, Katalin E. Kövér, Stephen A. Kolodziej, Bruce Nock, Clifford George, Jeffrey R. Deschamps, Judith L. Flippen-Anderson, Garland R. Marshall

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Abstract

Two compounds, Tyr1-cyclo(D-Pen2-Gly3-Phe 4-L-3-Mpt5) (DPMPT; 3-Mpt is trans-3-mercaptoproline) and Tyr1-cyclo(D-Pen2-Gly3-Phe 4-D-3-Mpt5) (DPDMPT), were designed employing energy calculations. Geometrical comparison showed that some low-energy 3D structures of DPMPT and DPDMPT are compatible with the model for the δ-receptor-bound conformation of the well-known δ-selective DPDPE peptide Tyr1-cyclo(D-Pen2-Gly3-Phe 4-D-Pen5, which was proposed by us earlier. DPMPT and DPDMPT were tested for their binding to δ-, μ- and κ-opioid receptors. The corresponding Ki values were 3.5, 68, and >5000 nM for DPMPT, and 103.7, >5000, and >5000 nM for DPDMPT, respectively. Independent studies by homo- and heteronuclear NMR spectroscopy and energy calculations showed that DPMPT exists in DMSO solution in conformational equilibrium among several backbone conformations with the same type of 3D structure for the cyclic moiety, but with somewhat different conformers of the acyclic part of the molecule and two types of rotamers for the D-Pen side chain, namely, t and g-. For DPDMPT, energy calculations combined with the NMR data suggest that any one out of four low-energy conformers belonging to the same type of the backbone of the cyclic moiety may be a possible candidate for the DPDMPT conformer in DMSO. The DPDMPT structure revealed by X-ray crystallography showed remarkable similarity to DPDMPT solution conformations. The determined solution conformations of both compounds were compared to their suggested δ-receptor-bound conformers. Results of comparison showed that all four of the possible solution conformations of DPDMPT are nonsimilar to the DPDMPT δ-receptor-bound conformation, whereas two of the possible solution conformations of DPMPT are compatible with the suggested δ-receptor-bound conformation of DPMPT. This finding can explain the difference in binding of DPMPT and DPDMPT to δ-opioid receptors by a suggestion that the δ-receptor-bound conformation of DPMPT already preexists in solution, whereas solution conformations of DPDMPT should be more significantly distorted to match the δ-receptor-bound conformation of DPDMPT.

Original languageEnglish
Pages (from-to)959-969
Number of pages11
JournalJournal of the American Chemical Society
Volume118
Issue number5
Publication statusPublished - Dec 1 1996

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ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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