Design, synthesis, and pharmacological activities of dynorphin aanalogues cyclized by ring-closing metathesis

Wei Jie Fang, Yanjun Cui, Thomas F. Murray, Jane V. Aldrich

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Dynorphin A (Dyn A) is an endogenous ligand for κ opioid receptors. To restrict the conformational mobility, we synthesized several cyclic Dyn A-(1-11)NH2 analogues on solid phase utilizing ring-closing metathesis (RCM) between the side chains of allylglycine (AllGly) residues incorporated in positions 2, 5, and/or 8. Cyclizations between the side chains of AllGly gave reasonable yields (56-74%) of all of the desired cyclic peptides. Both the cis and trans isomers were obtained for all of the cyclic peptides, with the ratio of cis to trans isomers depending on the position and stereochemistry of the AllGly. Most of the cyclic Dyn A-(1-11)NH2 analogues examined exhibit low nanomolar binding affinity for κ opioid receptors (Ki = 0.84-11 nM). In two of the three cases, the configuration of the double bond has a significant influence on the opioid receptor affinities and agonist potency. All of the peptides inhibited adenylyl cyclase activity in a concentration-dependent manner with full or close to full agonist activity. These potent Dyn A analogues are the first ones cyclized by RCM.

Original languageEnglish
Pages (from-to)5619-5625
Number of pages7
JournalJournal of Medicinal Chemistry
Volume52
Issue number18
DOIs
StatePublished - Sep 24 2009

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Allylglycine
Dynorphins
Opioid Receptors
Cyclic Peptides
Pharmacology
Cyclization
Adenylyl Cyclases
Ligands
Peptides
dynorphin A (1-11)-amide

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Design, synthesis, and pharmacological activities of dynorphin aanalogues cyclized by ring-closing metathesis. / Fang, Wei Jie; Cui, Yanjun; Murray, Thomas F.; Aldrich, Jane V.

In: Journal of Medicinal Chemistry, Vol. 52, No. 18, 24.09.2009, p. 5619-5625.

Research output: Contribution to journalArticle

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abstract = "Dynorphin A (Dyn A) is an endogenous ligand for κ opioid receptors. To restrict the conformational mobility, we synthesized several cyclic Dyn A-(1-11)NH2 analogues on solid phase utilizing ring-closing metathesis (RCM) between the side chains of allylglycine (AllGly) residues incorporated in positions 2, 5, and/or 8. Cyclizations between the side chains of AllGly gave reasonable yields (56-74{\%}) of all of the desired cyclic peptides. Both the cis and trans isomers were obtained for all of the cyclic peptides, with the ratio of cis to trans isomers depending on the position and stereochemistry of the AllGly. Most of the cyclic Dyn A-(1-11)NH2 analogues examined exhibit low nanomolar binding affinity for κ opioid receptors (Ki = 0.84-11 nM). In two of the three cases, the configuration of the double bond has a significant influence on the opioid receptor affinities and agonist potency. All of the peptides inhibited adenylyl cyclase activity in a concentration-dependent manner with full or close to full agonist activity. These potent Dyn A analogues are the first ones cyclized by RCM.",
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AU - Cui, Yanjun

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AU - Aldrich, Jane V.

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N2 - Dynorphin A (Dyn A) is an endogenous ligand for κ opioid receptors. To restrict the conformational mobility, we synthesized several cyclic Dyn A-(1-11)NH2 analogues on solid phase utilizing ring-closing metathesis (RCM) between the side chains of allylglycine (AllGly) residues incorporated in positions 2, 5, and/or 8. Cyclizations between the side chains of AllGly gave reasonable yields (56-74%) of all of the desired cyclic peptides. Both the cis and trans isomers were obtained for all of the cyclic peptides, with the ratio of cis to trans isomers depending on the position and stereochemistry of the AllGly. Most of the cyclic Dyn A-(1-11)NH2 analogues examined exhibit low nanomolar binding affinity for κ opioid receptors (Ki = 0.84-11 nM). In two of the three cases, the configuration of the double bond has a significant influence on the opioid receptor affinities and agonist potency. All of the peptides inhibited adenylyl cyclase activity in a concentration-dependent manner with full or close to full agonist activity. These potent Dyn A analogues are the first ones cyclized by RCM.

AB - Dynorphin A (Dyn A) is an endogenous ligand for κ opioid receptors. To restrict the conformational mobility, we synthesized several cyclic Dyn A-(1-11)NH2 analogues on solid phase utilizing ring-closing metathesis (RCM) between the side chains of allylglycine (AllGly) residues incorporated in positions 2, 5, and/or 8. Cyclizations between the side chains of AllGly gave reasonable yields (56-74%) of all of the desired cyclic peptides. Both the cis and trans isomers were obtained for all of the cyclic peptides, with the ratio of cis to trans isomers depending on the position and stereochemistry of the AllGly. Most of the cyclic Dyn A-(1-11)NH2 analogues examined exhibit low nanomolar binding affinity for κ opioid receptors (Ki = 0.84-11 nM). In two of the three cases, the configuration of the double bond has a significant influence on the opioid receptor affinities and agonist potency. All of the peptides inhibited adenylyl cyclase activity in a concentration-dependent manner with full or close to full agonist activity. These potent Dyn A analogues are the first ones cyclized by RCM.

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