Effect of modification of the basic residues of dynorphin A-(1-13) amide on κ opioid receptor selectivity and opioid activity

K. R. Snyder, S. C. Story, M. E. Heidt, Thomas F. Murray, G. E. DeLander, J. V. Aldrich

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

A series of dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) analogues containing lysine or N(ε)-acetyllysine (Lys(Ac)) was prepared by solid-phase peptide synthesis and evaluated for opioid receptor affinity in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI). Substitutions were made at positions 6, 7, 9, 11, and 13, the basic amino acids in the C-terminus of the peptide, in order to assess the individual contributions of these residues to the κ opioid receptor affinity and selectivity of Dyn A-(1-13)NH2. While substitutions of Lys(Ac) for Arg in position 6 did not affect κ receptor affinity, it enhanced affinity for μ and δ receptors and therefore caused a loss of κ receptor selectivity. When Lys(Ac) was substituted for Arg9, κ opioid receptor affinity was enhanced and κ receptor selectivity was retained. Replacement of Arg7, Lys11, or Lys13 by Lys(Ac) resulted in both decreased affinity and selectivity for κ receptors. These results demonstrate the importance of Arg6 to the receptor selectivity profile of Dyn A-(1-13)NH2 and indicate that, of the five basic residues in the C-terminus, only Arg9 can be replaced by a nonbasic residue without substantial loss of κ opioid receptor selectivity.

Original languageEnglish
Pages (from-to)4330-4333
Number of pages4
JournalJournal of Medicinal Chemistry
Volume35
Issue number23
DOIs
StatePublished - 1992
Externally publishedYes

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Opioid Receptors
Amides
Opioid Analgesics
Substitution reactions
Basic Amino Acids
Radioligand Assay
Peptides
Solid-Phase Synthesis Techniques
Ileum
Lysine
Assays
Guinea Pigs
dynorphin (1-13)

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

Effect of modification of the basic residues of dynorphin A-(1-13) amide on κ opioid receptor selectivity and opioid activity. / Snyder, K. R.; Story, S. C.; Heidt, M. E.; Murray, Thomas F.; DeLander, G. E.; Aldrich, J. V.

In: Journal of Medicinal Chemistry, Vol. 35, No. 23, 1992, p. 4330-4333.

Research output: Contribution to journalArticle

Snyder, K. R. ; Story, S. C. ; Heidt, M. E. ; Murray, Thomas F. ; DeLander, G. E. ; Aldrich, J. V. / Effect of modification of the basic residues of dynorphin A-(1-13) amide on κ opioid receptor selectivity and opioid activity. In: Journal of Medicinal Chemistry. 1992 ; Vol. 35, No. 23. pp. 4330-4333.
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