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-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 kappa and mu opioid receptors. Unexpectedly the peptide containing (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-Phe4,D-Ala8]Dyn A-(1-11)NH2 exhibited 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 receptor affinity, yielding compounds with negligible affinity for these receptors. Thus, there appear to be distinctly different structural requirements for this residue for kappa vs. delta receptors, and it is possible to completely distinguish between these two receptors by changing a single residue in Dyn A.
Aldrich
J V
JV
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 N. Pine Street, Baltimore, Maryland, USA. jaldrich@umaryland.edu
Zheng
Q I
QI
Murray
T F
TF
D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D004399:Dynorphins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry*; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
C110305:2-aminotetralin-2-carboxylic acid; D000596:Amino Acids; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D010649:Phenylalanine; D004399:Dynorphins; D015081:2-Naphthylamine