Synthesis and opioid activity of 2-substituted dynorphin A-(1-13) amide analogues

S. C. Story, Thomas F. Murray, G. E. Delander, J. V. Aldrich

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

A series of 2-substituted dynorphin A-(1-13) (Dyn A-(1-13)NH2) analogues was prepared by solid phase peptide synthesis and evaluated for opioid receptor affinities in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI) assay. Amino acid substitution at the 2 position produced marked differences in both opioid receptor affinities and potency in the GPI assay; K(i) values for the analogues in the radioligand binding assays and IC50 values in the GPI assay varied over three to four orders of magnitude. The parent peptide, Dyn A-(1-13)NH2, exhibited the greatest affinity and selectivity for kappa receptors and was the most potent peptide examined in the GPI assay. The most important determinant of opioid receptor selectivity and opioid potency for the synthetic analogues was the stereochemistry of the amino acid at the 2 position. Except for [D-Lys2]Dyn A-(1-13)NH2 in the kappa receptor binding assay, the analogues containing a D-amino acid at position 2 were much more potent in all of the assays than their corresponding isomers containing an L-amino acid at this position. The L-amino acid-substituted analogues generally retained some selectivity for kappa opioid receptors. The more potent derivatives with a D-amino acid in position 2, however, preferentially interacted with mu opioid receptors. Introduction of a positively charged amino acid into the 2 position generally decreased opioid receptor affinities and potency in the GPI assay.

Original languageEnglish
Pages (from-to)89-96
Number of pages8
JournalInternational Journal of Peptide and Protein Research
Volume40
Issue number2
StatePublished - 1992
Externally publishedYes

Fingerprint

Amides
Opioid Analgesics
Assays
Ileum
Opioid Receptors
Guinea Pigs
Amino Acids
kappa Opioid Receptor
Radioligand Assay
Peptides
Solid-Phase Synthesis Techniques
mu Opioid Receptor
Amino Acid Substitution
Inhibitory Concentration 50
dynorphin (1-13)
Stereochemistry
Isomers
Substitution reactions
Derivatives

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Synthesis and opioid activity of 2-substituted dynorphin A-(1-13) amide analogues. / Story, S. C.; Murray, Thomas F.; Delander, G. E.; Aldrich, J. V.

In: International Journal of Peptide and Protein Research, Vol. 40, No. 2, 1992, p. 89-96.

Research output: Contribution to journalArticle

@article{9026dc923c0842ebbf6c5d0d569650bd,
title = "Synthesis and opioid activity of 2-substituted dynorphin A-(1-13) amide analogues",
abstract = "A series of 2-substituted dynorphin A-(1-13) (Dyn A-(1-13)NH2) analogues was prepared by solid phase peptide synthesis and evaluated for opioid receptor affinities in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI) assay. Amino acid substitution at the 2 position produced marked differences in both opioid receptor affinities and potency in the GPI assay; K(i) values for the analogues in the radioligand binding assays and IC50 values in the GPI assay varied over three to four orders of magnitude. The parent peptide, Dyn A-(1-13)NH2, exhibited the greatest affinity and selectivity for kappa receptors and was the most potent peptide examined in the GPI assay. The most important determinant of opioid receptor selectivity and opioid potency for the synthetic analogues was the stereochemistry of the amino acid at the 2 position. Except for [D-Lys2]Dyn A-(1-13)NH2 in the kappa receptor binding assay, the analogues containing a D-amino acid at position 2 were much more potent in all of the assays than their corresponding isomers containing an L-amino acid at this position. The L-amino acid-substituted analogues generally retained some selectivity for kappa opioid receptors. The more potent derivatives with a D-amino acid in position 2, however, preferentially interacted with mu opioid receptors. Introduction of a positively charged amino acid into the 2 position generally decreased opioid receptor affinities and potency in the GPI assay.",
author = "Story, {S. C.} and Murray, {Thomas F.} and Delander, {G. E.} and Aldrich, {J. V.}",
year = "1992",
language = "English",
volume = "40",
pages = "89--96",
journal = "International Journal of Peptide and Protein Research",
issn = "0367-8377",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Synthesis and opioid activity of 2-substituted dynorphin A-(1-13) amide analogues

AU - Story, S. C.

AU - Murray, Thomas F.

AU - Delander, G. E.

AU - Aldrich, J. V.

PY - 1992

Y1 - 1992

N2 - A series of 2-substituted dynorphin A-(1-13) (Dyn A-(1-13)NH2) analogues was prepared by solid phase peptide synthesis and evaluated for opioid receptor affinities in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI) assay. Amino acid substitution at the 2 position produced marked differences in both opioid receptor affinities and potency in the GPI assay; K(i) values for the analogues in the radioligand binding assays and IC50 values in the GPI assay varied over three to four orders of magnitude. The parent peptide, Dyn A-(1-13)NH2, exhibited the greatest affinity and selectivity for kappa receptors and was the most potent peptide examined in the GPI assay. The most important determinant of opioid receptor selectivity and opioid potency for the synthetic analogues was the stereochemistry of the amino acid at the 2 position. Except for [D-Lys2]Dyn A-(1-13)NH2 in the kappa receptor binding assay, the analogues containing a D-amino acid at position 2 were much more potent in all of the assays than their corresponding isomers containing an L-amino acid at this position. The L-amino acid-substituted analogues generally retained some selectivity for kappa opioid receptors. The more potent derivatives with a D-amino acid in position 2, however, preferentially interacted with mu opioid receptors. Introduction of a positively charged amino acid into the 2 position generally decreased opioid receptor affinities and potency in the GPI assay.

AB - A series of 2-substituted dynorphin A-(1-13) (Dyn A-(1-13)NH2) analogues was prepared by solid phase peptide synthesis and evaluated for opioid receptor affinities in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI) assay. Amino acid substitution at the 2 position produced marked differences in both opioid receptor affinities and potency in the GPI assay; K(i) values for the analogues in the radioligand binding assays and IC50 values in the GPI assay varied over three to four orders of magnitude. The parent peptide, Dyn A-(1-13)NH2, exhibited the greatest affinity and selectivity for kappa receptors and was the most potent peptide examined in the GPI assay. The most important determinant of opioid receptor selectivity and opioid potency for the synthetic analogues was the stereochemistry of the amino acid at the 2 position. Except for [D-Lys2]Dyn A-(1-13)NH2 in the kappa receptor binding assay, the analogues containing a D-amino acid at position 2 were much more potent in all of the assays than their corresponding isomers containing an L-amino acid at this position. The L-amino acid-substituted analogues generally retained some selectivity for kappa opioid receptors. The more potent derivatives with a D-amino acid in position 2, however, preferentially interacted with mu opioid receptors. Introduction of a positively charged amino acid into the 2 position generally decreased opioid receptor affinities and potency in the GPI assay.

UR - http://www.scopus.com/inward/record.url?scp=0026656023&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026656023&partnerID=8YFLogxK

M3 - Article

VL - 40

SP - 89

EP - 96

JO - International Journal of Peptide and Protein Research

JF - International Journal of Peptide and Protein Research

SN - 0367-8377

IS - 2

ER -