Synthesis and Opioid Activity of Side-Chain-to-Side-Chain Cyclic Dynorphin A-(1-11) Amide Analogues Cyclized between Positions 2 and 5. 1. Substitutions in Position 3

Balvinder S. Vig, Thomas F. Murray, Jane V. Aldrich

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cyclo[D-Asp2,Dap5]Dyn A-(1-13)NH2 (Dap, 2,3-diaminopropionic acid; Dyn A, dynorphin A), synthesized previously in our laboratory, showed sub-nanomolar affinity for κ opioid receptors and potent agonist activity in the guinea pig ileum assay (Arttamangkul et al., J. Med. Chem. 1995, 38, 2410-2417). Various modifications were made in position 3 of cyclo[D-Asp2,Dap5]Dyn A-(1-11)NH2 that could influence the opioid receptor affinity, selectivity, and/or efficacy of this peptide. An optimized orthogonal synthetic strategy was developed for the synthesis of these cyclic peptides in which the final peptides could be cleaved from the solid support with trifluoroacetic acid. Substitutions of Gly 3 by Ala, D-Ala, Trp, and D-Trp in cyclo[D-Asp2,Dap 5]Dyn A-(1-11)NH2 and its linear counterpart [D-Asp 2,Dap5]Dyn A-(1-11)NH2 were generally well tolerated by both κ and μ opioid receptors. Despite differences in the size and stereochemistry of the substitutions, most of the peptides (except for cyclo[D-Asp2,Pro3,Dap5]Dyn A-(1-11)NH 2 and [D-Asp2,D-Ala3,Dap5]Dyn A-(1-11)NH2) exhibited low nanomolar affinity for both κ (Ki = 0.21 to 2.2 nM) and μ (Ki = 0.22 to 7.27 nM) opioid receptors. All of the 3-substituted cyclic and linear analogues synthesized showed reduced affinity for δ opioid receptors. Incorporation of D-Ala at position 3 of cyclo[D-Asp2,Dap5]Dyn A-(1-11)NH2 exhibited 2-fold higher κ opioid receptor affinity and 16-fold higher selectivity for κ over μ opioid receptors than the parent cyclic peptide. In contrast, substitution of Ala at position 3 resulted in an analogue with 2.4-fold lower affinity and very low preference for κ over μ opioid receptors. The Trp and D-Trp cyclic and linear analogues exhibited similar nanomolar affinities for κ opioid receptors. cyclo[D-Asp2,Pro3,Dap5]Dyn A-(1-11)NH 2 showed the largest decreases in affinity for all three opioid receptors compared to the parent cyclic peptide. Except for cyclo[D-Asp 2, Pro3,Dap5]Dyn A-(1-11)NH2, which was a partial agonist, all of the cyclic peptides exhibited full agonist activity in the adenylyl cyclase assay using cloned κ opioid receptors.

Original languageEnglish
Pages (from-to)446-455
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number2
Publication statusPublished - Jan 15 2004
Externally publishedYes


All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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