Design, Synthesis, and Biological Properties of Highly Potent Cyclic Dynorphin A Analogues. Analogues Cyclized between Positions 5 and 11

Jean Philippe Meyer, Nathan Collins, Feng Di Lung, Peg Davis, Teresa Zalewska, Frank Porreca, Henry I. Yamamura, Victor J. Hruby

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

We have recently reported the synthesis of several cyclic disulfide bridge-containing peptide analogues of dynorphin A (Dyn A), which were conformationally constrained in the putative address segment of the opioid ligand. Several of these analogues, bridged between positions 5 and 11 of Dyn A1-11-NH2, exhibited unexpected selectivities for the κ and μ receptors of the central over the peripheral nervous systems. In order to further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, we have synthesized a systematic series of Dyn A1-11-NH2 analogues incorporating the sulfydryl containing amino acids l- and d-Cys and l- and d-Pen in positions 5 and 11, thus producing 16 cyclic peptides. In addition, Dyn A1-11-NH2, [d-Leu5]Dyn A1-11-NH2, and [d-Lysn11]Dyn A1-11-NH2 were synthesized as standards. Several of these cyclic analogues, especially c[Cys5, D-Cys11] Dyn A1-11NH2, c[Cys5, l- or d-Pen11]Dyn A1-11-NH2, c[Pen5, l-Pen11]Dyn A1-11-NH2 and c[Pen5, l- or d-Cys11]Dyn A1-11-NH2, retained the same affinity and selectivity (vs the μ and δ receptors) as the parent compound Dyn A1-11-NH2 in the guinea pig brain (GPB). These same analogues and most others exhibited a much lower activity in the guinea pig ileum (GPI), thus leading to centrally vs peripherally selective peptides, but showed a different structure-activity relationship than found previously. In a wider scope, this series of analogues also provided new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at κ opioid receptors. The results obtained in the GPB suggest that requirements for binding are not the same for the κ, μ, or δ central receptors.

Original languageEnglish (US)
Pages (from-to)3910-3917
Number of pages8
JournalJournal of Medicinal Chemistry
Volume37
Issue number23
DOIs
StatePublished - Nov 1 1994

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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