Aladan scanning: The structure-activity relationship of dynorphin A

Abstract

An unnatural amino acid, β-[6′-(N, N-dimethyl)amino-2′-naphthoyl]alanine (Ald) showing polarity-sensitive fluorescence characteristics, was synthesized. A thorough Ald-scan of dynorphin A (Dyn A), the putative endogenous ligand for. opioid receptors, was then performed. Replacement of the amino acid residues in positions 5, 8, 10, 12 or 14 of Dyn A(1–13)-NH₂ with Ald resulted in compounds that had almost equal κ binding affinity compared with that of the parent compound; on the other hand, substitution of residues in position 1 or 4 with Ald decreased κ-receptor binding affinity. These results indicate that Tyr and Phe in Dyn A are very important for maintaining its κ-opioid activity. Evidence from receptor binding assay clearly displays that [Ald⁵]Dyn A(1–13)-NH₂ is a highly selective κ-opioid receptor agonist. An evaluation of the interaction of Ald-containing Dyn A(1–13)-NH₂ analogues with SDS and DPC micelles was also performed. Interestingly, [Ald1]Dyn A(1–13)-NH₂ and [Ald⁴]Dyn A(1–13)-NH₂ showed quite different fluorescence emission maxima in SDS and DPC micelles. This indicates that both peptides are sensitive to electronic properties of the polar surface of the micelles.