Aladan scanning: The structure-activity relationship of dynorphin A

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. Supported by the National Natural Science Foundation of China (Grant No. 30672560) and the Ascended Project for Natural Scientific Research of Universities in Guangdong Province (Grant No. 05Z012).