Synthesis and opioid activity of conformationally constrained dynorphin A analogues. 2. Conformational constraint in the 'address' sequence

Seksiri Arttamangkul, Jane E. Ishmael, Thomas F. Murray, David K. Grandy, Gary E. DeLander, Brigitte L. Kieffer, Jane V. Aldrich

Research output: Contribution to journalArticle

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Abstract

Several cyclic lactam analogues of Dyn A-(1-13)NH2 were prepared in order to reduce the conformational flexibility in different regions of the native linear peptide. Cyclo[D-Asp(i),Dap(i+3)]Dyn A-(1-13)NH2 (Dap = α,β- diaminopropionic acid) analogues were designed on the basis of molecular modeling using AMBER, which suggested that this constraint may be compatible with an α-helix. The cyclic portion of these constrained analogues spanned from residues 3 to 9, a region proposed by Schwyzer (Biochemistry 1986, 25, 4281) to adopt a helical conformation at K receptor sites. Analogues containing Dab (α,γ-diaminobutyric acid) or Orn in position i + 3 were also synthesized to examine the effects of larger ring size. The cyclic peptides exhibited marked differences in binding affinities for κ, μ, and δ receptors and in opioid activity in the guinea pig ileum (GPI). Cyclo[D- Asp6,Dap9]Dyn A-(1-13)NH2 showed both high κ receptor affinity and potent agonist activity in the GPI, while cyclo[D-Asp3,Dap6]Dyn A-(1-13)NH2 exhibited very weak binding affinity at all opioid receptors as well as very weak opioid activity in the GPI. Cyclo[D-Asp5,Dap8]Dyn A-(1-13)NH2 showed moderate binding affinity for κ receptors and was the most κ selective ligand in this study, but this peptide exhibited very weak agonist activity in the GPI assay. Compared to the corresponding linear peptides, all of the cyclic peptides exhibited decreased μ receptor affinity, while κ receptor affinity was retained or improved. Therefore the corresponding linear peptides were generally μ selective while the cyclic constrained peptides demonstrated slight selectivity for κ vs μ receptors or were nonselective. Increasing the ring size by incorporating Dab or Orn in positions 6, 8, or 9 did not significantly affect the binding affinity for the three opioid receptor types nor the opioid activity observed in the GPI. Circular dichroism spectra of the cyclo[D-Asp(i),Dap(i+3)] derivatives in 80% trifluoroethanol at 25 and 5 °C suggested differences in the stability of a helical structure when the constraint was incorporated near the N-terminus vs in the middle of the peptide.

Original languageEnglish
Pages (from-to)1211-1218
Number of pages8
JournalJournal of Medicinal Chemistry
Volume40
Issue number8
DOIs
StatePublished - Apr 11 1997
Externally publishedYes

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Dynorphins
Ileum
Opioid Analgesics
Guinea Pigs
Cyclic Peptides
Opioid Receptors
Peptides
Acids
Trifluoroethanol
Lactams
Biochemistry
Molecular modeling
Circular Dichroism
Conformations
Assays
Ligands
Derivatives

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

Synthesis and opioid activity of conformationally constrained dynorphin A analogues. 2. Conformational constraint in the 'address' sequence. / Arttamangkul, Seksiri; Ishmael, Jane E.; Murray, Thomas F.; Grandy, David K.; DeLander, Gary E.; Kieffer, Brigitte L.; Aldrich, Jane V.

In: Journal of Medicinal Chemistry, Vol. 40, No. 8, 11.04.1997, p. 1211-1218.

Research output: Contribution to journalArticle

Arttamangkul, Seksiri ; Ishmael, Jane E. ; Murray, Thomas F. ; Grandy, David K. ; DeLander, Gary E. ; Kieffer, Brigitte L. ; Aldrich, Jane V. / Synthesis and opioid activity of conformationally constrained dynorphin A analogues. 2. Conformational constraint in the 'address' sequence. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 8. pp. 1211-1218.
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abstract = "Several cyclic lactam analogues of Dyn A-(1-13)NH2 were prepared in order to reduce the conformational flexibility in different regions of the native linear peptide. Cyclo[D-Asp(i),Dap(i+3)]Dyn A-(1-13)NH2 (Dap = α,β- diaminopropionic acid) analogues were designed on the basis of molecular modeling using AMBER, which suggested that this constraint may be compatible with an α-helix. The cyclic portion of these constrained analogues spanned from residues 3 to 9, a region proposed by Schwyzer (Biochemistry 1986, 25, 4281) to adopt a helical conformation at K receptor sites. Analogues containing Dab (α,γ-diaminobutyric acid) or Orn in position i + 3 were also synthesized to examine the effects of larger ring size. The cyclic peptides exhibited marked differences in binding affinities for κ, μ, and δ receptors and in opioid activity in the guinea pig ileum (GPI). Cyclo[D- Asp6,Dap9]Dyn A-(1-13)NH2 showed both high κ receptor affinity and potent agonist activity in the GPI, while cyclo[D-Asp3,Dap6]Dyn A-(1-13)NH2 exhibited very weak binding affinity at all opioid receptors as well as very weak opioid activity in the GPI. Cyclo[D-Asp5,Dap8]Dyn A-(1-13)NH2 showed moderate binding affinity for κ receptors and was the most κ selective ligand in this study, but this peptide exhibited very weak agonist activity in the GPI assay. Compared to the corresponding linear peptides, all of the cyclic peptides exhibited decreased μ receptor affinity, while κ receptor affinity was retained or improved. Therefore the corresponding linear peptides were generally μ selective while the cyclic constrained peptides demonstrated slight selectivity for κ vs μ receptors or were nonselective. Increasing the ring size by incorporating Dab or Orn in positions 6, 8, or 9 did not significantly affect the binding affinity for the three opioid receptor types nor the opioid activity observed in the GPI. Circular dichroism spectra of the cyclo[D-Asp(i),Dap(i+3)] derivatives in 80{\%} trifluoroethanol at 25 and 5 °C suggested differences in the stability of a helical structure when the constraint was incorporated near the N-terminus vs in the middle of the peptide.",
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AU - Grandy, David K.

AU - DeLander, Gary E.

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AU - Aldrich, Jane V.

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N2 - Several cyclic lactam analogues of Dyn A-(1-13)NH2 were prepared in order to reduce the conformational flexibility in different regions of the native linear peptide. Cyclo[D-Asp(i),Dap(i+3)]Dyn A-(1-13)NH2 (Dap = α,β- diaminopropionic acid) analogues were designed on the basis of molecular modeling using AMBER, which suggested that this constraint may be compatible with an α-helix. The cyclic portion of these constrained analogues spanned from residues 3 to 9, a region proposed by Schwyzer (Biochemistry 1986, 25, 4281) to adopt a helical conformation at K receptor sites. Analogues containing Dab (α,γ-diaminobutyric acid) or Orn in position i + 3 were also synthesized to examine the effects of larger ring size. The cyclic peptides exhibited marked differences in binding affinities for κ, μ, and δ receptors and in opioid activity in the guinea pig ileum (GPI). Cyclo[D- Asp6,Dap9]Dyn A-(1-13)NH2 showed both high κ receptor affinity and potent agonist activity in the GPI, while cyclo[D-Asp3,Dap6]Dyn A-(1-13)NH2 exhibited very weak binding affinity at all opioid receptors as well as very weak opioid activity in the GPI. Cyclo[D-Asp5,Dap8]Dyn A-(1-13)NH2 showed moderate binding affinity for κ receptors and was the most κ selective ligand in this study, but this peptide exhibited very weak agonist activity in the GPI assay. Compared to the corresponding linear peptides, all of the cyclic peptides exhibited decreased μ receptor affinity, while κ receptor affinity was retained or improved. Therefore the corresponding linear peptides were generally μ selective while the cyclic constrained peptides demonstrated slight selectivity for κ vs μ receptors or were nonselective. Increasing the ring size by incorporating Dab or Orn in positions 6, 8, or 9 did not significantly affect the binding affinity for the three opioid receptor types nor the opioid activity observed in the GPI. Circular dichroism spectra of the cyclo[D-Asp(i),Dap(i+3)] derivatives in 80% trifluoroethanol at 25 and 5 °C suggested differences in the stability of a helical structure when the constraint was incorporated near the N-terminus vs in the middle of the peptide.

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