Synthesis of Novel Basic Head-to-Side-Chain Cyclic Dynorphin A Analogs

Strategies and Side Reactions

Balvinder S. Vig, Thomas F. Murray, Jane V. Aldrich

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Novel N-terminus-to-side-chain cyclic analogs of the opioid peptide dynorphin (Dyn) A-(1-11)NH2 were prepared that retain the basicity of the N-terminal amine and restrict the backbone conformation around the important Tyr1 residue. Cyclic peptides were synthesized in which the N-terminal amine and the Nε-amine of a Lys at position 3 or 5 were attached to the α-carbon and carbonyl of an acetyl group, respectively. Several synthetic strategies were explored with detailed analysis of the side reactions in order to obtain the desired cyclic peptides. One of the side reactions observed involved premature loss of the N-terminal 9-fluorenylmethoxycarbonyl (Fmoc) group during the neutralization step following deprotection of the Mtt (4-methyltrityl) protecting group from the side chain of Lys. The successful strategy involved the synthesis of the linear peptide up through Gly2 and functionalization through the N ε-amine of Lys. A linear N-terminal alkylated analog was prepared by alkylation of the peptide on the resin with an equimolar amount of bromoacetamide, followed by treatment of the peptide with Fmoc-OSu prior to cleavage from the resin to facilitate separation by reversed phase high performance liquid chromatography of unreacted peptide from the desired alkylated product. The novel N-terminal cyclic Dyn A analogs and the linear analog were evaluated for their opioid receptor affinities. These peptides exhibited large losses in affinity for opioid receptors; the low affinity of the linear N-terminal alkylated peptide suggested that the α-acetamide group on the N-terminal amine resulted in unfavorable interactions with opioid receptors.

Original languageEnglish
Pages (from-to)620-637
Number of pages18
JournalBiopolymers
Volume71
Issue number6
DOIs
StatePublished - 2003
Externally publishedYes

Fingerprint

Dynorphins
Peptides
Amines
Head
Opioid Receptors
Cyclic Peptides
Resins
Opioid Peptides
Alkylation
High performance liquid chromatography
Reverse-Phase Chromatography
Alkalinity
Conformations
Carbon
High Pressure Liquid Chromatography

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics

Cite this

Synthesis of Novel Basic Head-to-Side-Chain Cyclic Dynorphin A Analogs : Strategies and Side Reactions. / Vig, Balvinder S.; Murray, Thomas F.; Aldrich, Jane V.

In: Biopolymers, Vol. 71, No. 6, 2003, p. 620-637.

Research output: Contribution to journalArticle

@article{64a0f8436527465dadf685d4f50ae749,
title = "Synthesis of Novel Basic Head-to-Side-Chain Cyclic Dynorphin A Analogs: Strategies and Side Reactions",
abstract = "Novel N-terminus-to-side-chain cyclic analogs of the opioid peptide dynorphin (Dyn) A-(1-11)NH2 were prepared that retain the basicity of the N-terminal amine and restrict the backbone conformation around the important Tyr1 residue. Cyclic peptides were synthesized in which the N-terminal amine and the Nε-amine of a Lys at position 3 or 5 were attached to the α-carbon and carbonyl of an acetyl group, respectively. Several synthetic strategies were explored with detailed analysis of the side reactions in order to obtain the desired cyclic peptides. One of the side reactions observed involved premature loss of the N-terminal 9-fluorenylmethoxycarbonyl (Fmoc) group during the neutralization step following deprotection of the Mtt (4-methyltrityl) protecting group from the side chain of Lys. The successful strategy involved the synthesis of the linear peptide up through Gly2 and functionalization through the N ε-amine of Lys. A linear N-terminal alkylated analog was prepared by alkylation of the peptide on the resin with an equimolar amount of bromoacetamide, followed by treatment of the peptide with Fmoc-OSu prior to cleavage from the resin to facilitate separation by reversed phase high performance liquid chromatography of unreacted peptide from the desired alkylated product. The novel N-terminal cyclic Dyn A analogs and the linear analog were evaluated for their opioid receptor affinities. These peptides exhibited large losses in affinity for opioid receptors; the low affinity of the linear N-terminal alkylated peptide suggested that the α-acetamide group on the N-terminal amine resulted in unfavorable interactions with opioid receptors.",
author = "Vig, {Balvinder S.} and Murray, {Thomas F.} and Aldrich, {Jane V.}",
year = "2003",
doi = "10.1002/bip.10591",
language = "English",
volume = "71",
pages = "620--637",
journal = "Biopolymers",
issn = "0006-3525",
publisher = "John Wiley and Sons Inc.",
number = "6",

}

TY - JOUR

T1 - Synthesis of Novel Basic Head-to-Side-Chain Cyclic Dynorphin A Analogs

T2 - Strategies and Side Reactions

AU - Vig, Balvinder S.

AU - Murray, Thomas F.

AU - Aldrich, Jane V.

PY - 2003

Y1 - 2003

N2 - Novel N-terminus-to-side-chain cyclic analogs of the opioid peptide dynorphin (Dyn) A-(1-11)NH2 were prepared that retain the basicity of the N-terminal amine and restrict the backbone conformation around the important Tyr1 residue. Cyclic peptides were synthesized in which the N-terminal amine and the Nε-amine of a Lys at position 3 or 5 were attached to the α-carbon and carbonyl of an acetyl group, respectively. Several synthetic strategies were explored with detailed analysis of the side reactions in order to obtain the desired cyclic peptides. One of the side reactions observed involved premature loss of the N-terminal 9-fluorenylmethoxycarbonyl (Fmoc) group during the neutralization step following deprotection of the Mtt (4-methyltrityl) protecting group from the side chain of Lys. The successful strategy involved the synthesis of the linear peptide up through Gly2 and functionalization through the N ε-amine of Lys. A linear N-terminal alkylated analog was prepared by alkylation of the peptide on the resin with an equimolar amount of bromoacetamide, followed by treatment of the peptide with Fmoc-OSu prior to cleavage from the resin to facilitate separation by reversed phase high performance liquid chromatography of unreacted peptide from the desired alkylated product. The novel N-terminal cyclic Dyn A analogs and the linear analog were evaluated for their opioid receptor affinities. These peptides exhibited large losses in affinity for opioid receptors; the low affinity of the linear N-terminal alkylated peptide suggested that the α-acetamide group on the N-terminal amine resulted in unfavorable interactions with opioid receptors.

AB - Novel N-terminus-to-side-chain cyclic analogs of the opioid peptide dynorphin (Dyn) A-(1-11)NH2 were prepared that retain the basicity of the N-terminal amine and restrict the backbone conformation around the important Tyr1 residue. Cyclic peptides were synthesized in which the N-terminal amine and the Nε-amine of a Lys at position 3 or 5 were attached to the α-carbon and carbonyl of an acetyl group, respectively. Several synthetic strategies were explored with detailed analysis of the side reactions in order to obtain the desired cyclic peptides. One of the side reactions observed involved premature loss of the N-terminal 9-fluorenylmethoxycarbonyl (Fmoc) group during the neutralization step following deprotection of the Mtt (4-methyltrityl) protecting group from the side chain of Lys. The successful strategy involved the synthesis of the linear peptide up through Gly2 and functionalization through the N ε-amine of Lys. A linear N-terminal alkylated analog was prepared by alkylation of the peptide on the resin with an equimolar amount of bromoacetamide, followed by treatment of the peptide with Fmoc-OSu prior to cleavage from the resin to facilitate separation by reversed phase high performance liquid chromatography of unreacted peptide from the desired alkylated product. The novel N-terminal cyclic Dyn A analogs and the linear analog were evaluated for their opioid receptor affinities. These peptides exhibited large losses in affinity for opioid receptors; the low affinity of the linear N-terminal alkylated peptide suggested that the α-acetamide group on the N-terminal amine resulted in unfavorable interactions with opioid receptors.

UR - http://www.scopus.com/inward/record.url?scp=1542374136&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1542374136&partnerID=8YFLogxK

U2 - 10.1002/bip.10591

DO - 10.1002/bip.10591

M3 - Article

VL - 71

SP - 620

EP - 637

JO - Biopolymers

JF - Biopolymers

SN - 0006-3525

IS - 6

ER -