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.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery