Synthesis and Opioid Activity of Side-Chain-to-Side-Chain Cyclic Dynorphin A-(1-11) Amide Analogues Cyclized between Positions 2 and 5. 1. Substitutions in Position 3

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

Research output: Contribution to journalArticle

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Abstract

cyclo[D-Asp2,Dap5]Dyn A-(1-13)NH2 (Dap, 2,3-diaminopropionic acid; Dyn A, dynorphin A), synthesized previously in our laboratory, showed sub-nanomolar affinity for κ opioid receptors and potent agonist activity in the guinea pig ileum assay (Arttamangkul et al., J. Med. Chem. 1995, 38, 2410-2417). Various modifications were made in position 3 of cyclo[D-Asp2,Dap5]Dyn A-(1-11)NH2 that could influence the opioid receptor affinity, selectivity, and/or efficacy of this peptide. An optimized orthogonal synthetic strategy was developed for the synthesis of these cyclic peptides in which the final peptides could be cleaved from the solid support with trifluoroacetic acid. Substitutions of Gly 3 by Ala, D-Ala, Trp, and D-Trp in cyclo[D-Asp2,Dap 5]Dyn A-(1-11)NH2 and its linear counterpart [D-Asp 2,Dap5]Dyn A-(1-11)NH2 were generally well tolerated by both κ and μ opioid receptors. Despite differences in the size and stereochemistry of the substitutions, most of the peptides (except for cyclo[D-Asp2,Pro3,Dap5]Dyn A-(1-11)NH 2 and [D-Asp2,D-Ala3,Dap5]Dyn A-(1-11)NH2) exhibited low nanomolar affinity for both κ (Ki = 0.21 to 2.2 nM) and μ (Ki = 0.22 to 7.27 nM) opioid receptors. All of the 3-substituted cyclic and linear analogues synthesized showed reduced affinity for δ opioid receptors. Incorporation of D-Ala at position 3 of cyclo[D-Asp2,Dap5]Dyn A-(1-11)NH2 exhibited 2-fold higher κ opioid receptor affinity and 16-fold higher selectivity for κ over μ opioid receptors than the parent cyclic peptide. In contrast, substitution of Ala at position 3 resulted in an analogue with 2.4-fold lower affinity and very low preference for κ over μ opioid receptors. The Trp and D-Trp cyclic and linear analogues exhibited similar nanomolar affinities for κ opioid receptors. cyclo[D-Asp2,Pro3,Dap5]Dyn A-(1-11)NH 2 showed the largest decreases in affinity for all three opioid receptors compared to the parent cyclic peptide. Except for cyclo[D-Asp 2, Pro3,Dap5]Dyn A-(1-11)NH2, which was a partial agonist, all of the cyclic peptides exhibited full agonist activity in the adenylyl cyclase assay using cloned κ opioid receptors.

Original languageEnglish
Pages (from-to)446-455
Number of pages10
JournalJournal of Medicinal Chemistry
Volume47
Issue number2
DOIs
StatePublished - Jan 15 2004
Externally publishedYes

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Opioid Receptors
Opioid Analgesics
Substitution reactions
Cyclic Peptides
Peptides
Assays
dynorphin A (1-11)-amide
Dynorphins
Trifluoroacetic Acid
Stereochemistry
Ileum
Adenylyl Cyclases
Guinea Pigs

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

@article{1a1258cafc794dfd82a140a5532e0aed,
title = "Synthesis and Opioid Activity of Side-Chain-to-Side-Chain Cyclic Dynorphin A-(1-11) Amide Analogues Cyclized between Positions 2 and 5. 1. Substitutions in Position 3",
abstract = "cyclo[D-Asp2,Dap5]Dyn A-(1-13)NH2 (Dap, 2,3-diaminopropionic acid; Dyn A, dynorphin A), synthesized previously in our laboratory, showed sub-nanomolar affinity for κ opioid receptors and potent agonist activity in the guinea pig ileum assay (Arttamangkul et al., J. Med. Chem. 1995, 38, 2410-2417). Various modifications were made in position 3 of cyclo[D-Asp2,Dap5]Dyn A-(1-11)NH2 that could influence the opioid receptor affinity, selectivity, and/or efficacy of this peptide. An optimized orthogonal synthetic strategy was developed for the synthesis of these cyclic peptides in which the final peptides could be cleaved from the solid support with trifluoroacetic acid. Substitutions of Gly 3 by Ala, D-Ala, Trp, and D-Trp in cyclo[D-Asp2,Dap 5]Dyn A-(1-11)NH2 and its linear counterpart [D-Asp 2,Dap5]Dyn A-(1-11)NH2 were generally well tolerated by both κ and μ opioid receptors. Despite differences in the size and stereochemistry of the substitutions, most of the peptides (except for cyclo[D-Asp2,Pro3,Dap5]Dyn A-(1-11)NH 2 and [D-Asp2,D-Ala3,Dap5]Dyn A-(1-11)NH2) exhibited low nanomolar affinity for both κ (Ki = 0.21 to 2.2 nM) and μ (Ki = 0.22 to 7.27 nM) opioid receptors. All of the 3-substituted cyclic and linear analogues synthesized showed reduced affinity for δ opioid receptors. Incorporation of D-Ala at position 3 of cyclo[D-Asp2,Dap5]Dyn A-(1-11)NH2 exhibited 2-fold higher κ opioid receptor affinity and 16-fold higher selectivity for κ over μ opioid receptors than the parent cyclic peptide. In contrast, substitution of Ala at position 3 resulted in an analogue with 2.4-fold lower affinity and very low preference for κ over μ opioid receptors. The Trp and D-Trp cyclic and linear analogues exhibited similar nanomolar affinities for κ opioid receptors. cyclo[D-Asp2,Pro3,Dap5]Dyn A-(1-11)NH 2 showed the largest decreases in affinity for all three opioid receptors compared to the parent cyclic peptide. Except for cyclo[D-Asp 2, Pro3,Dap5]Dyn A-(1-11)NH2, which was a partial agonist, all of the cyclic peptides exhibited full agonist activity in the adenylyl cyclase assay using cloned κ opioid receptors.",
author = "Vig, {Balvinder S.} and Murray, {Thomas F.} and Aldrich, {Jane V.}",
year = "2004",
month = "1",
day = "15",
doi = "10.1021/jm030298e",
language = "English",
volume = "47",
pages = "446--455",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "2",

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T1 - Synthesis and Opioid Activity of Side-Chain-to-Side-Chain Cyclic Dynorphin A-(1-11) Amide Analogues Cyclized between Positions 2 and 5. 1. Substitutions in Position 3

AU - Vig, Balvinder S.

AU - Murray, Thomas F.

AU - Aldrich, Jane V.

PY - 2004/1/15

Y1 - 2004/1/15

N2 - cyclo[D-Asp2,Dap5]Dyn A-(1-13)NH2 (Dap, 2,3-diaminopropionic acid; Dyn A, dynorphin A), synthesized previously in our laboratory, showed sub-nanomolar affinity for κ opioid receptors and potent agonist activity in the guinea pig ileum assay (Arttamangkul et al., J. Med. Chem. 1995, 38, 2410-2417). Various modifications were made in position 3 of cyclo[D-Asp2,Dap5]Dyn A-(1-11)NH2 that could influence the opioid receptor affinity, selectivity, and/or efficacy of this peptide. An optimized orthogonal synthetic strategy was developed for the synthesis of these cyclic peptides in which the final peptides could be cleaved from the solid support with trifluoroacetic acid. Substitutions of Gly 3 by Ala, D-Ala, Trp, and D-Trp in cyclo[D-Asp2,Dap 5]Dyn A-(1-11)NH2 and its linear counterpart [D-Asp 2,Dap5]Dyn A-(1-11)NH2 were generally well tolerated by both κ and μ opioid receptors. Despite differences in the size and stereochemistry of the substitutions, most of the peptides (except for cyclo[D-Asp2,Pro3,Dap5]Dyn A-(1-11)NH 2 and [D-Asp2,D-Ala3,Dap5]Dyn A-(1-11)NH2) exhibited low nanomolar affinity for both κ (Ki = 0.21 to 2.2 nM) and μ (Ki = 0.22 to 7.27 nM) opioid receptors. All of the 3-substituted cyclic and linear analogues synthesized showed reduced affinity for δ opioid receptors. Incorporation of D-Ala at position 3 of cyclo[D-Asp2,Dap5]Dyn A-(1-11)NH2 exhibited 2-fold higher κ opioid receptor affinity and 16-fold higher selectivity for κ over μ opioid receptors than the parent cyclic peptide. In contrast, substitution of Ala at position 3 resulted in an analogue with 2.4-fold lower affinity and very low preference for κ over μ opioid receptors. The Trp and D-Trp cyclic and linear analogues exhibited similar nanomolar affinities for κ opioid receptors. cyclo[D-Asp2,Pro3,Dap5]Dyn A-(1-11)NH 2 showed the largest decreases in affinity for all three opioid receptors compared to the parent cyclic peptide. Except for cyclo[D-Asp 2, Pro3,Dap5]Dyn A-(1-11)NH2, which was a partial agonist, all of the cyclic peptides exhibited full agonist activity in the adenylyl cyclase assay using cloned κ opioid receptors.

AB - cyclo[D-Asp2,Dap5]Dyn A-(1-13)NH2 (Dap, 2,3-diaminopropionic acid; Dyn A, dynorphin A), synthesized previously in our laboratory, showed sub-nanomolar affinity for κ opioid receptors and potent agonist activity in the guinea pig ileum assay (Arttamangkul et al., J. Med. Chem. 1995, 38, 2410-2417). Various modifications were made in position 3 of cyclo[D-Asp2,Dap5]Dyn A-(1-11)NH2 that could influence the opioid receptor affinity, selectivity, and/or efficacy of this peptide. An optimized orthogonal synthetic strategy was developed for the synthesis of these cyclic peptides in which the final peptides could be cleaved from the solid support with trifluoroacetic acid. Substitutions of Gly 3 by Ala, D-Ala, Trp, and D-Trp in cyclo[D-Asp2,Dap 5]Dyn A-(1-11)NH2 and its linear counterpart [D-Asp 2,Dap5]Dyn A-(1-11)NH2 were generally well tolerated by both κ and μ opioid receptors. Despite differences in the size and stereochemistry of the substitutions, most of the peptides (except for cyclo[D-Asp2,Pro3,Dap5]Dyn A-(1-11)NH 2 and [D-Asp2,D-Ala3,Dap5]Dyn A-(1-11)NH2) exhibited low nanomolar affinity for both κ (Ki = 0.21 to 2.2 nM) and μ (Ki = 0.22 to 7.27 nM) opioid receptors. All of the 3-substituted cyclic and linear analogues synthesized showed reduced affinity for δ opioid receptors. Incorporation of D-Ala at position 3 of cyclo[D-Asp2,Dap5]Dyn A-(1-11)NH2 exhibited 2-fold higher κ opioid receptor affinity and 16-fold higher selectivity for κ over μ opioid receptors than the parent cyclic peptide. In contrast, substitution of Ala at position 3 resulted in an analogue with 2.4-fold lower affinity and very low preference for κ over μ opioid receptors. The Trp and D-Trp cyclic and linear analogues exhibited similar nanomolar affinities for κ opioid receptors. cyclo[D-Asp2,Pro3,Dap5]Dyn A-(1-11)NH 2 showed the largest decreases in affinity for all three opioid receptors compared to the parent cyclic peptide. Except for cyclo[D-Asp 2, Pro3,Dap5]Dyn A-(1-11)NH2, which was a partial agonist, all of the cyclic peptides exhibited full agonist activity in the adenylyl cyclase assay using cloned κ opioid receptors.

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