Dynorphin A analogs containing a conformationally constrained phenylalanine derivative in position 4: Reversal of preferred stereochemistry for opioid receptor affinity and discrimination of κ vs. δ receptors

Analogs of the opioid peptide [D-Ala⁸]dynorphin A-(1-11)NH₂ containing optically pure (R)- and (S)-2-aminotetralin-2-carboxylic acid (Atc) in position 4 were synthesized and evaluated for opioid receptor affinity. These peptides are the first reported dynorphin A analogs containing a conformationally constrained amino acid in place of the important aromatic residue Phe⁴. By incorporating resolved Atc isomers, the opioid receptor affinity and the stereochemistry of the constrained residue could be unambiguously correlated. Both Dyn A analogs containing Atc in position 4 retained nanomolar affinity for κ and μ opioid receptors. Unexpectedly the peptide containing (R)-Atc, corresponding to a conformationally constrained D-Phe analog, displaying higher affinity for both κ and μ receptors than the peptide containing (S)-Atc. In contrast [D-Phe⁴,D-Ala⁸] Dyn A-(1-11)NH₂ exhibited significantly lower affinity for κ and μ receptors than the parent peptide, as expected. Conformational restriction of the Phe⁴ sidechain or incorporation of D-Phe in position 4 had the largest effect on δ receptor affinity, yielding compounds with negligible affinity for these receptors. Thus, there appear to be distinctly different structural requirements for this residue for κ vs. δ receptors, and it is possible to completely distinguish between these two receptors by changing a single residue in Dyn A.