Syntheses, opioid binding affinities, and potencies of dynorphin A analogues substituted in positions 1, 6, 7, 8 and 10

ANDREW M. KAWASAKI, RICHARD J. KNAPP, AMANDA WALTON, WILLIAM S. WIRE, TERESA ZALEWSKA, HENRY I. YAMAMURA, FRANK PORRECA, THOMAS F. BURKS, VICTOR J. HRUBY

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Structural, stereochemical, stereoelectronic and conformational requirements for biological activity of dynorphin A1–11‐NH2 analogues at opioid receptors were explored by substitution of Tyr1, Arg6, Arg7, Ile8 and Pro10 with other amino acid residues. Interestingly, substitution of Tyr1 with Nα‐Ac‐Tyrl, D‐Tyr1, Phe1 or p‐BrPhe1 led to analogues that were quite potent at κ opioid receptors, and additional substitution of Ile8with D‐Ala8 and/or Pro10 with D‐Pro10 retained high potency in brain binding assay: [Nα‐Ac‐Tyr1]‐ (1), [D‐Tyr1]‐ (2) [Phe1]‐ (3), [Phe1. D‐Ala8]‐ (5), [p‐BrPhe1, D‐Alas]‐ (6), [Phe1, D‐Pro10]‐ (7) and [Phe1, D‐Ala8, D‐Pro10]‐Dyn A1–11‐NH2 (8) had IC50(nM) binding affinities of 13.2, 18.6, 1.64, 1.26, 1.84, 2.44 and 1.62 nM, respectively. The D‐Phe1 analogue 4, however, was only weakly active (610 nM). All of the analogues except 4 were modestly selective for κ vs. μ guinea pig brain opioid receptor (11‐ to 88–fold) and quite selective for κ vs. δ receptors (65–576). However, all of the analogues appeared to have very low or essentially no activity in the guinea pig ileum and mouse vas deference functional bioassays, and one analogue, 5, appeared to have weak antagonist activities. On the other hand, if constrained amino acids such as β‐methylphenylalanine or 1,2,3,4‐tetrahydroisoquinoline carboxylic acid, and hydroxyproline were placed in the 1 position, inactive analogues or analogues with greatly reduced potency and biological activity were obtained (compounds 12–14). It had previously been suggested that the Arg6 and Arg7 residues were critical for biological activity. However, when we replace either one of these residues, [Nle6]Dyn A1–11 (9) and [Nle7]Dyn A1–11‐NH2 (10) were both highly potent binders in κ receptor binding studies (IC50= 0.95 and 0.43 nM, respectively), and interestingly also were potent in μ and δ binding studies. Furthermore, both of the analogues were modestly potent in the GPI and MVD assays (94, 65 nM; 31, 81 nM, respectively). These results demonstrate that basic residues at positions 6 and 7 in dynorphin are not very important for binding to κ opioid receptors. Finally, many of the compounds reported here showed high selectivity for central vs. peripheral κ opioid receptors, with compound 4 being the most selective (63 000‐fold).

Original languageEnglish (US)
Pages (from-to)411-419
Number of pages9
JournalInternational journal of peptide and protein research
Volume42
Issue number5
DOIs
StatePublished - Nov 1993

Keywords

  • constrained dynorphin A analogues
  • dynorphin A
  • dynorphin A analogues
  • dynorphin A antagonist
  • stereochemical and stereoelectronic effects
  • structure‐activity relationships

ASJC Scopus subject areas

  • Biochemistry

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