Effects of the substitution of Phe4 in the opioid peptide [D-Ala8]dynorphin A-(1-11)NH2

Balvinder S. Vig, Mike Q. Zheng, Thomas F. Murray, Jane V. Aldrich

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Abstract

Phenylalanine at position 4 of the peptide dynorphin A (Dyn A) is an important residue for opioid receptor affinity and activity, but there is very little information available on the structure-activity relationships or conformational preference of this residue for interaction with κ-opioid receptors. Based on the hypothesis that the spatial orientation of the aromatic ring at position 4 of Dyn A is important for opioid receptor affinity and selectivity, a series of Dyn A analogues with various Phe derivatives substituted at position 4 were synthesized and evaluated for their opioid receptor affinity and activity. The L- and D-Homophe4 (homophenylalanine) analogues of [D-Ala8]Dyn A-(1-11)NH2 were compared to the (R)- and (S)-Atc4 (2-aminotetralin-2-carboxylic acid) derivatives (Aldrich et al. Chirality 2001, 13, 125-129). [L-Homophe 4,D-Ala8]Dyn A-(1-11)NH2 exhibited higher κ-opioid receptor affinity than the D-Homophe4 isomer, while [(R)-Atc4,D-Ala8]Dyn A-(1-11)NH2 exhibited higher κ-opioid receptor affinity than the (S)-Atc4 isomer. Comparing the structure of Atc to those of Phe and Homophe, these results suggest that the Atc isomers are functioning more as constrained Homophe rather than Phe analogues in these Dyn A derivatives. The higher κ-opioid receptor affinity of the (R)-Atc4 analogue suggests that Phe 4 of Dyn A most likely adopts a gauche (-) or trans conformation in the κ-opioid receptor binding site. Comparison of [D-Ala8]Dyn A-(1-11)NH2 derivatives containing Aic4 (2-aminoindan-2-carboxylic acid) and Tic4 (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) with the peptides containing their acyclic counterparts α-MePhe4 and N-MePhe4, respectively, suggest that the loss in opioid receptor affinity seen for the Aic4 and Tic4 analogues is probably due to an improper orientation of the aromatic ring in these residues. Most of the analogues in this series showed much lower affinity for δ-opioid receptors than the parent peptide, suggesting that κ- and δ-opioid receptors have distinct binding pockets for the residue at position 4 of Dyn A. All of the analogues with high affinity for κ-opioid receptors exhibited full agonist activity in the adenylyl cyclase assay using cloned κ-opioid receptors, indicating that changes in the position or orientation of the phenyl ring in this residue did not alter the ability of the peptides to activate the receptor.

Original languageEnglish
Pages (from-to)4002-4008
Number of pages7
JournalJournal of Medicinal Chemistry
Volume46
Issue number19
DOIs
StatePublished - Sep 11 2003
Externally publishedYes

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Opioid Peptides
Opioid Receptors
Substitution reactions
Dynorphins
Isomers
Derivatives
Peptides
dynorphin A (1-11)-amide
Chirality
Structure-Activity Relationship
Carboxylic Acids
Phenylalanine
Carboxylic acids
Adenylyl Cyclases
Conformations
Assays

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

Effects of the substitution of Phe4 in the opioid peptide [D-Ala8]dynorphin A-(1-11)NH2 . / Vig, Balvinder S.; Zheng, Mike Q.; Murray, Thomas F.; Aldrich, Jane V.

In: Journal of Medicinal Chemistry, Vol. 46, No. 19, 11.09.2003, p. 4002-4008.

Research output: Contribution to journalArticle

Vig, Balvinder S. ; Zheng, Mike Q. ; Murray, Thomas F. ; Aldrich, Jane V. / Effects of the substitution of Phe4 in the opioid peptide [D-Ala8]dynorphin A-(1-11)NH2 . In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 19. pp. 4002-4008.
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title = "Effects of the substitution of Phe4 in the opioid peptide [D-Ala8]dynorphin A-(1-11)NH2",
abstract = "Phenylalanine at position 4 of the peptide dynorphin A (Dyn A) is an important residue for opioid receptor affinity and activity, but there is very little information available on the structure-activity relationships or conformational preference of this residue for interaction with κ-opioid receptors. Based on the hypothesis that the spatial orientation of the aromatic ring at position 4 of Dyn A is important for opioid receptor affinity and selectivity, a series of Dyn A analogues with various Phe derivatives substituted at position 4 were synthesized and evaluated for their opioid receptor affinity and activity. The L- and D-Homophe4 (homophenylalanine) analogues of [D-Ala8]Dyn A-(1-11)NH2 were compared to the (R)- and (S)-Atc4 (2-aminotetralin-2-carboxylic acid) derivatives (Aldrich et al. Chirality 2001, 13, 125-129). [L-Homophe 4,D-Ala8]Dyn A-(1-11)NH2 exhibited higher κ-opioid receptor affinity than the D-Homophe4 isomer, while [(R)-Atc4,D-Ala8]Dyn A-(1-11)NH2 exhibited higher κ-opioid receptor affinity than the (S)-Atc4 isomer. Comparing the structure of Atc to those of Phe and Homophe, these results suggest that the Atc isomers are functioning more as constrained Homophe rather than Phe analogues in these Dyn A derivatives. The higher κ-opioid receptor affinity of the (R)-Atc4 analogue suggests that Phe 4 of Dyn A most likely adopts a gauche (-) or trans conformation in the κ-opioid receptor binding site. Comparison of [D-Ala8]Dyn A-(1-11)NH2 derivatives containing Aic4 (2-aminoindan-2-carboxylic acid) and Tic4 (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) with the peptides containing their acyclic counterparts α-MePhe4 and N-MePhe4, respectively, suggest that the loss in opioid receptor affinity seen for the Aic4 and Tic4 analogues is probably due to an improper orientation of the aromatic ring in these residues. Most of the analogues in this series showed much lower affinity for δ-opioid receptors than the parent peptide, suggesting that κ- and δ-opioid receptors have distinct binding pockets for the residue at position 4 of Dyn A. All of the analogues with high affinity for κ-opioid receptors exhibited full agonist activity in the adenylyl cyclase assay using cloned κ-opioid receptors, indicating that changes in the position or orientation of the phenyl ring in this residue did not alter the ability of the peptides to activate the receptor.",
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AU - Vig, Balvinder S.

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N2 - Phenylalanine at position 4 of the peptide dynorphin A (Dyn A) is an important residue for opioid receptor affinity and activity, but there is very little information available on the structure-activity relationships or conformational preference of this residue for interaction with κ-opioid receptors. Based on the hypothesis that the spatial orientation of the aromatic ring at position 4 of Dyn A is important for opioid receptor affinity and selectivity, a series of Dyn A analogues with various Phe derivatives substituted at position 4 were synthesized and evaluated for their opioid receptor affinity and activity. The L- and D-Homophe4 (homophenylalanine) analogues of [D-Ala8]Dyn A-(1-11)NH2 were compared to the (R)- and (S)-Atc4 (2-aminotetralin-2-carboxylic acid) derivatives (Aldrich et al. Chirality 2001, 13, 125-129). [L-Homophe 4,D-Ala8]Dyn A-(1-11)NH2 exhibited higher κ-opioid receptor affinity than the D-Homophe4 isomer, while [(R)-Atc4,D-Ala8]Dyn A-(1-11)NH2 exhibited higher κ-opioid receptor affinity than the (S)-Atc4 isomer. Comparing the structure of Atc to those of Phe and Homophe, these results suggest that the Atc isomers are functioning more as constrained Homophe rather than Phe analogues in these Dyn A derivatives. The higher κ-opioid receptor affinity of the (R)-Atc4 analogue suggests that Phe 4 of Dyn A most likely adopts a gauche (-) or trans conformation in the κ-opioid receptor binding site. Comparison of [D-Ala8]Dyn A-(1-11)NH2 derivatives containing Aic4 (2-aminoindan-2-carboxylic acid) and Tic4 (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) with the peptides containing their acyclic counterparts α-MePhe4 and N-MePhe4, respectively, suggest that the loss in opioid receptor affinity seen for the Aic4 and Tic4 analogues is probably due to an improper orientation of the aromatic ring in these residues. Most of the analogues in this series showed much lower affinity for δ-opioid receptors than the parent peptide, suggesting that κ- and δ-opioid receptors have distinct binding pockets for the residue at position 4 of Dyn A. All of the analogues with high affinity for κ-opioid receptors exhibited full agonist activity in the adenylyl cyclase assay using cloned κ-opioid receptors, indicating that changes in the position or orientation of the phenyl ring in this residue did not alter the ability of the peptides to activate the receptor.

AB - Phenylalanine at position 4 of the peptide dynorphin A (Dyn A) is an important residue for opioid receptor affinity and activity, but there is very little information available on the structure-activity relationships or conformational preference of this residue for interaction with κ-opioid receptors. Based on the hypothesis that the spatial orientation of the aromatic ring at position 4 of Dyn A is important for opioid receptor affinity and selectivity, a series of Dyn A analogues with various Phe derivatives substituted at position 4 were synthesized and evaluated for their opioid receptor affinity and activity. The L- and D-Homophe4 (homophenylalanine) analogues of [D-Ala8]Dyn A-(1-11)NH2 were compared to the (R)- and (S)-Atc4 (2-aminotetralin-2-carboxylic acid) derivatives (Aldrich et al. Chirality 2001, 13, 125-129). [L-Homophe 4,D-Ala8]Dyn A-(1-11)NH2 exhibited higher κ-opioid receptor affinity than the D-Homophe4 isomer, while [(R)-Atc4,D-Ala8]Dyn A-(1-11)NH2 exhibited higher κ-opioid receptor affinity than the (S)-Atc4 isomer. Comparing the structure of Atc to those of Phe and Homophe, these results suggest that the Atc isomers are functioning more as constrained Homophe rather than Phe analogues in these Dyn A derivatives. The higher κ-opioid receptor affinity of the (R)-Atc4 analogue suggests that Phe 4 of Dyn A most likely adopts a gauche (-) or trans conformation in the κ-opioid receptor binding site. Comparison of [D-Ala8]Dyn A-(1-11)NH2 derivatives containing Aic4 (2-aminoindan-2-carboxylic acid) and Tic4 (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) with the peptides containing their acyclic counterparts α-MePhe4 and N-MePhe4, respectively, suggest that the loss in opioid receptor affinity seen for the Aic4 and Tic4 analogues is probably due to an improper orientation of the aromatic ring in these residues. Most of the analogues in this series showed much lower affinity for δ-opioid receptors than the parent peptide, suggesting that κ- and δ-opioid receptors have distinct binding pockets for the residue at position 4 of Dyn A. All of the analogues with high affinity for κ-opioid receptors exhibited full agonist activity in the adenylyl cyclase assay using cloned κ-opioid receptors, indicating that changes in the position or orientation of the phenyl ring in this residue did not alter the ability of the peptides to activate the receptor.

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