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

Analogs of the opioid peptide [D-Ala(8)]dynorphin A-(1-11)NH2 containing op tically pure (R)- and (S)-2-aminotetralin-2-carboxylic acid (Atc) in positi on 4 were synthesized and evaluated for opioid receptor affinity. These pep tides are the first reported dynorphin A analogs containing a conformationa lly constrained amino acid in place of the important aromatic residue Phe(4 ). By incorporating resolved Atc isomers, the opioid receptor affinity and the stereochemistry of the constrained residue could be unambiguously corre lated. Both Dyn A analogs containing Ate in position 4 retained nanomolar a ffinity for kappa and mu opioid receptors. Unexpectedly the peptide contain ing (R)-Atc, corresponding to a conformationally constrained D-Phe analog, displaying higher affinity for both kappa and mu receptors than the peptide containing (S)-Atc. In contrast [D-Phe(4),D-Ala(8)] Dyn A-(1-11)NH2 exhibi ted significantly lower affinity for kappa and mu 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 delta recept or affinity, yielding compounds with negligible affinity for these receptor s. Thus, there appear to be distinctly different structural requirements fo r this residue for kappa vs. delta receptors, and it is possible to complet ely distinguish between these two receptors by changing a single residue in Dyn A. Chirality 13:125-129, 2001. (C) 2001 Wiley-Liss, Inc.