Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 125-129 |
| Number of pages | 5 |
| Journal | Chirality |
| Volume | 13 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2001 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Analytical Chemistry
- Drug Discovery
- Organic Chemistry
- Pharmacology
Cite this
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. / Aldrich, Jane V.; Zheng, Qi; Murray, Thomas F.
In: Chirality, Vol. 13, No. 3, 2001, p. 125-129.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dynorphin A analogs containing a conformationally constrained phenylalanine derivative in position 4
T2 - Reversal of preferred stereochemistry for opioid receptor affinity and discrimination of κ vs. δ receptors
AU - Aldrich, Jane V.
AU - Zheng, Qi
AU - Murray, Thomas F.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0035111402&partnerID=8YFLogxK
U2 - 10.1002/1520-636X(2001)13:3<125::AID-CHIR1008>3.0.CO;2-S
DO - 10.1002/1520-636X(2001)13:3<125::AID-CHIR1008>3.0.CO;2-S
M3 - Article
C2 - 11270320
AN - SCOPUS:0035111402
VL - 13
SP - 125
EP - 129
JO - Chirality
JF - Chirality
SN - 0899-0042
IS - 3
ER -