Synthesis and opioid activity of conformationally constrained dynorphin A analogues

Seksiri Arttamangkul, TF Murray, GE DeLander, JV Aldrich

Research output: Contribution to journalArticle

Abstract

Cyclic analogues of dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) were synthesized and their opioid receptor affinity and opioid activity determined. Cyclic peptides constrained in both the "message" and "address" regions of Dyn A-(1-13)NH2 (1) were prepared in order to investigate possible biological conformations of different regions of the peptides. The design of the constraint was based upon Schwyzer's proposal that Dyn A-(1-13) adopts an α-helix when it binds to κ opioid receptors in the lipid membrane (2). Molecular modeling with AMBER suggested that a four atom bridge between the α carbons of residues i (D-configuration) and i + 3 (L-configuration) may be compatible with a helical structure. Therefore we synthesized a series of cyclo[D-Aspi,Dapi+3]Dyn A-(1-13)NH2 analogues (Dap = α,β-diaminopropionic acid) with the lactam bridge between noncritical residues 2 and 5, 3 and 6, 5 and 8, or 6 and 9. Of these cyclic peptides, the [2,5] cyclic analogue exhibited the highest opioid receptor affinity and opioid activity.

Original languageEnglish (US)
Pages (from-to)13-14
Number of pages2
JournalRegulatory Peptides
Volume54
Issue number1
DOIs
StatePublished - Nov 10 1994

Fingerprint

Dynorphins
Opioid Receptors
Opioid Analgesics
Cyclic Peptides
Lactams
Molecular modeling
Membrane Lipids
Amides
Conformations
Carbon
Atoms
Peptides
Acids

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Physiology
  • Neuroscience(all)

Cite this

Synthesis and opioid activity of conformationally constrained dynorphin A analogues. / Arttamangkul, Seksiri; Murray, TF; DeLander, GE; Aldrich, JV.

In: Regulatory Peptides, Vol. 54, No. 1, 10.11.1994, p. 13-14.

Research output: Contribution to journalArticle

Arttamangkul, Seksiri ; Murray, TF ; DeLander, GE ; Aldrich, JV. / Synthesis and opioid activity of conformationally constrained dynorphin A analogues. In: Regulatory Peptides. 1994 ; Vol. 54, No. 1. pp. 13-14.
@article{1eca3ed719234952865961086175092c,
title = "Synthesis and opioid activity of conformationally constrained dynorphin A analogues",
abstract = "Cyclic analogues of dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) were synthesized and their opioid receptor affinity and opioid activity determined. Cyclic peptides constrained in both the {"}message{"} and {"}address{"} regions of Dyn A-(1-13)NH2 (1) were prepared in order to investigate possible biological conformations of different regions of the peptides. The design of the constraint was based upon Schwyzer's proposal that Dyn A-(1-13) adopts an α-helix when it binds to κ opioid receptors in the lipid membrane (2). Molecular modeling with AMBER suggested that a four atom bridge between the α carbons of residues i (D-configuration) and i + 3 (L-configuration) may be compatible with a helical structure. Therefore we synthesized a series of cyclo[D-Aspi,Dapi+3]Dyn A-(1-13)NH2 analogues (Dap = α,β-diaminopropionic acid) with the lactam bridge between noncritical residues 2 and 5, 3 and 6, 5 and 8, or 6 and 9. Of these cyclic peptides, the [2,5] cyclic analogue exhibited the highest opioid receptor affinity and opioid activity.",
author = "Seksiri Arttamangkul and TF Murray and GE DeLander and JV Aldrich",
year = "1994",
month = "11",
day = "10",
doi = "10.1016/0167-0115(94)90365-4",
language = "English (US)",
volume = "54",
pages = "13--14",
journal = "Regulatory Peptides",
issn = "0167-0115",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Synthesis and opioid activity of conformationally constrained dynorphin A analogues

AU - Arttamangkul, Seksiri

AU - Murray, TF

AU - DeLander, GE

AU - Aldrich, JV

PY - 1994/11/10

Y1 - 1994/11/10

N2 - Cyclic analogues of dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) were synthesized and their opioid receptor affinity and opioid activity determined. Cyclic peptides constrained in both the "message" and "address" regions of Dyn A-(1-13)NH2 (1) were prepared in order to investigate possible biological conformations of different regions of the peptides. The design of the constraint was based upon Schwyzer's proposal that Dyn A-(1-13) adopts an α-helix when it binds to κ opioid receptors in the lipid membrane (2). Molecular modeling with AMBER suggested that a four atom bridge between the α carbons of residues i (D-configuration) and i + 3 (L-configuration) may be compatible with a helical structure. Therefore we synthesized a series of cyclo[D-Aspi,Dapi+3]Dyn A-(1-13)NH2 analogues (Dap = α,β-diaminopropionic acid) with the lactam bridge between noncritical residues 2 and 5, 3 and 6, 5 and 8, or 6 and 9. Of these cyclic peptides, the [2,5] cyclic analogue exhibited the highest opioid receptor affinity and opioid activity.

AB - Cyclic analogues of dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) were synthesized and their opioid receptor affinity and opioid activity determined. Cyclic peptides constrained in both the "message" and "address" regions of Dyn A-(1-13)NH2 (1) were prepared in order to investigate possible biological conformations of different regions of the peptides. The design of the constraint was based upon Schwyzer's proposal that Dyn A-(1-13) adopts an α-helix when it binds to κ opioid receptors in the lipid membrane (2). Molecular modeling with AMBER suggested that a four atom bridge between the α carbons of residues i (D-configuration) and i + 3 (L-configuration) may be compatible with a helical structure. Therefore we synthesized a series of cyclo[D-Aspi,Dapi+3]Dyn A-(1-13)NH2 analogues (Dap = α,β-diaminopropionic acid) with the lactam bridge between noncritical residues 2 and 5, 3 and 6, 5 and 8, or 6 and 9. Of these cyclic peptides, the [2,5] cyclic analogue exhibited the highest opioid receptor affinity and opioid activity.

UR - http://www.scopus.com/inward/record.url?scp=0028143789&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028143789&partnerID=8YFLogxK

U2 - 10.1016/0167-0115(94)90365-4

DO - 10.1016/0167-0115(94)90365-4

M3 - Article

AN - SCOPUS:0028143789

VL - 54

SP - 13

EP - 14

JO - Regulatory Peptides

JF - Regulatory Peptides

SN - 0167-0115

IS - 1

ER -